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==Introduction== | |||
The use of pain-relieving substances dates back to the dawn of humanity. In particular, in animistic cultures, psychotropic substances were used for shamanic practices to seek a state of ecstasy that brought them closer to the primary source of life and knowledge. This laid the foundations for a proto-medicine whose primary goal was the relief of pain caused by wounds or illness. Pain, like illness, was often considered the result of a curse from demons or hostile deities, which could only be driven away through magic and the "food of the gods" or Vedic soma ("All the gods drink soma mixed with cow's milk and pressed by the priests..." from a passage of the Rig Veda) <ref>Arthur Cotterell. Grande Enciclopedia dei Miti e delle Leggende. Rizzoli</ref>. | The use of pain-relieving substances dates back to the dawn of humanity. In particular, in animistic cultures, psychotropic substances were used for shamanic practices to seek a state of ecstasy that brought them closer to the primary source of life and knowledge. This laid the foundations for a proto-medicine whose primary goal was the relief of pain caused by wounds or illness. Pain, like illness, was often considered the result of a curse from demons or hostile deities, which could only be driven away through magic and the "food of the gods" or Vedic soma ("All the gods drink soma mixed with cow's milk and pressed by the priests..." from a passage of the Rig Veda) <ref>Arthur Cotterell. Grande Enciclopedia dei Miti e delle Leggende. Rizzoli</ref>. | ||
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The temporal evolution and peculiar characteristics of pain allow for the identification of two types: acute and chronic. New classifications based on the type of stimulation received by pain receptors divide it into transient (without significant tissue or nerve damage), reversible (significant damage that heals within days or weeks), and irreversible (significant damage with persistent inflammation, tissue loss, or neuronal damage) <ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref>. | The temporal evolution and peculiar characteristics of pain allow for the identification of two types: acute and chronic. New classifications based on the type of stimulation received by pain receptors divide it into transient (without significant tissue or nerve damage), reversible (significant damage that heals within days or weeks), and irreversible (significant damage with persistent inflammation, tissue loss, or neuronal damage) <ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref>. | ||
Before delving into the discussion on pain, it is essential to define some commonly used terms: | Before delving into the discussion on pain, it is essential to define some commonly used terms:<blockquote>'''Inflammatory pain:''' refers to pain that originates from tissue damage, followed by an inflammatory reaction.</blockquote><blockquote>'''Neurogenic pain:''' a pain syndrome resulting from an alteration in the mechanisms of pain transmission and modulation in the central and peripheral nervous systems. When the pain is caused by damage to peripheral nerves, it is referred to as neuropathic pain.</blockquote><blockquote>'''Allodynia:''' refers to a decrease in pain threshold; a stimulus that is normally not painful is perceived as such. Allodynia can be classified based on the type of stimulus (thermal, mechanical, or chemical) and the mode of stimulation (pressure, prick, touch, heat, cold, type of chemical substance).</blockquote><blockquote>'''Hyperalgesia:''' refers to an erroneous perception of a painful stimulus that is nonetheless exaggerated in intensity. | ||
- </blockquote><blockquote>'''Hyperpathy:''' is a syndrome characterized by an increased threshold for pain, where the stimulus is not perceived as painful until it reaches a certain intensity or frequency. Subsequently, the stimuli are perceived in an exaggerated manner and for a prolonged period <ref>Hansson P. Neurogenic Pain: Diagnosis and Treatment. Pain: clinical updates. Vol II n.3 Dec 1994. IASP – International Association for the Study of Pain</ref>.</blockquote> | |||
- | |||
== Definition of Pain == | ==Definition of Pain== | ||
The International Association for the Study of Pain (IASP) defines PAIN as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or at least the subjective sensation of it" <ref>IASP – International Association for the Study of Pain. www.iasp-pain.org</ref>. For this reason, pain falls within the area of somatosensory perception. | The International Association for the Study of Pain (IASP) defines PAIN as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or at least the subjective sensation of it" <ref>IASP – International Association for the Study of Pain. www.iasp-pain.org</ref>. For this reason, pain falls within the area of somatosensory perception. | ||
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The theory is based on the following assumptions: | The theory is based on the following assumptions: | ||
*The interneurons of the Substantia Gelatinosa (SG) have an inhibitory effect on lamina V of the spinal cord, from which the lateral spinothalamic tract originates, transmitting the nociceptive stimulus centrally. | |||
* <math>A\delta</math> fibers project onto the SG with excitatory action, promoting the inhibitory effect on lamina V through the release of opioid peptides. | |||
* <math>C</math> fibers project onto the SG wi<math>A\delta</math>th inhibitory effects, blocking the release of endorphins and opening the gate, allowing the pain stimulus to pass. | |||
*<math>A\beta</math> fibers and the descending inhibitory system release opioid peptides and block the pain stimulus. | |||
*Lamina V gives rise to the axons of T cells, which form the lateral spinothalamic tract. This tract ascends to the ventral posterolateral (VPL) nucleus of the thalamus, where nociceptive sensitivity is processed. | |||
=== Acute Inflammatory Pain === | == Reversible Pain== | ||
===Acute Inflammatory Pain=== | |||
Among the various pain syndromes, acute inflammatory pain is the most representative of reversible pain. The inflammatory response is the common pathway of many events that cause tissue damage and is also one of the most frequent causes of peripheral pain. Historically, the signs of inflammation are “rubor, calor, tumor, dolor, and functio laesa.” Tissue damage induces the release of pain and inflammation mediators from damaged or necrotic cells. The pain initially perceived is due to an appropriate stimulus to low-threshold nociceptive fibers (polymodal C fibers), resulting in neuronal firing and the induction of a local vasoconstriction reflex; if this stimulus is not repeated, the firing tends to subside, as does the pain perception. | Among the various pain syndromes, acute inflammatory pain is the most representative of reversible pain. The inflammatory response is the common pathway of many events that cause tissue damage and is also one of the most frequent causes of peripheral pain. Historically, the signs of inflammation are “rubor, calor, tumor, dolor, and functio laesa.” Tissue damage induces the release of pain and inflammation mediators from damaged or necrotic cells. The pain initially perceived is due to an appropriate stimulus to low-threshold nociceptive fibers (polymodal C fibers), resulting in neuronal firing and the induction of a local vasoconstriction reflex; if this stimulus is not repeated, the firing tends to subside, as does the pain perception. | ||
The most important mediators of acute pain are the same ones that actively participate in inflammation: histamine, serotonin, bradykinin, substance P, and eicosanoids. The local release of intracellular enzymes triggers the complement and kinin cascades, which, together with high concentrations of K+ and ATP lost from cells, stimulate the activation of high-threshold nociceptive fibers. The identification of acid-sensitive ion channels in small-diameter nerve fibers opens up the possibility of their involvement in hyperalgesia mechanisms in inflamed and hypoperfused tissues (local acidosis) <ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref>. | The most important mediators of acute pain are the same ones that actively participate in inflammation: histamine, serotonin, bradykinin, substance P, and eicosanoids. The local release of intracellular enzymes triggers the complement and kinin cascades, which, together with high concentrations of <math>K^+</math> and ATP lost from cells, stimulate the activation of high-threshold nociceptive fibers. The identification of acid-sensitive ion channels in small-diameter nerve fibers opens up the possibility of their involvement in hyperalgesia mechanisms in inflamed and hypoperfused tissues (local acidosis) <ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref>. | ||
The products of inflammatory cascades and cellular degradation act as chemotactic factors for inflammatory cells, inducing increased blood flow, increased vascular permeability, and sensitization to painful stimuli. The activation of phospholipase A2, triggered by tissue damage or pro-inflammatory cytokines (IL-1, IL-6, TNF- | The products of inflammatory cascades and cellular degradation act as chemotactic factors for inflammatory cells, inducing increased blood flow, increased vascular permeability, and sensitization to painful stimuli. The activation of phospholipase A2, triggered by tissue damage or pro-inflammatory cytokines (<math>IL-1</math>,<math>IL-6</math>,<math>TNF-\alpha</math> and <math>INF</math>), induces the release of arachidonic acid from cell membranes. This comes into contact with 5-lipoxygenase (the most important enzyme in neutrophils) and cyclooxygenase (COX), both type 1 (constitutive in vascular endothelium) and type 2 (inducible by cytokines in inflammatory cells) <ref>Masferrer J.L. et al. Selective Inhibition of Inducible Cyclooxygenase 2 in vivo is Antiinflammatory and Nonulcerogenic. Proc Natl Acad Sci USA April 1994; 91: 3228–3232</ref>. This leads to the release of leukotrienes (LTB4), thromboxanes (TxA2), and prostaglandins (PGD2, PGI2, PGF2α, and PGE2), important mediators of edema, leukocyte recruitment, and pain <ref>Fletcher D. Does hyperalgesia take part in postoperative pain? IASP – International Association for the Study of Pain. Rif.14rc5</ref>. Prostaglandins induce hyperalgesia and sensitization by binding to metabotropic receptors present in polymodal C and Aδ fibers. The increase in intracellular <math>Ca^{2+}</math>and IP3/DAG activates kinases (Tyr kinase), leading to the phosphorylation of membrane channels and a reduction in the activation threshold for subliminal stimuli <ref>Masferrer J.L. et al. Selective Inhibition of Inducible Cyclooxygenase 2 in vivo is Antiinflammatory and Nonulcerogenic. Proc Natl Acad Sci USA April 1994; 91: 3228–3232</ref><ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref>. | ||
=== Acute Neurogenic Pain === | === Acute Neurogenic Pain=== | ||
Pain is defined as neurogenic when it originates in the nervous system. This type of pain can be divided into central or peripheral, depending on whether it originates in the central nervous system (cortex, thalamus, hypothalamus, or spinal cord) or in peripheral nerve trunks, respectively <ref>Hansson P. Neurogenic Pain: Diagnosis and Treatment. Pain: clinical updates. Vol II n.3 Dec 1994. IASP – International Association for the Study of Pain</ref>. | Pain is defined as neurogenic when it originates in the nervous system. This type of pain can be divided into central or peripheral, depending on whether it originates in the central nervous system (cortex, thalamus, hypothalamus, or spinal cord) or in peripheral nerve trunks, respectively <ref>Hansson P. Neurogenic Pain: Diagnosis and Treatment. Pain: clinical updates. Vol II n.3 Dec 1994. IASP – International Association for the Study of Pain</ref>. | ||
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Truncal pain has familiar characteristics for the patient as it resembles pain from tissue injury and is caused by an inflammatory process involving the perineurium with the activation of visceral nociceptors (projection via nervi nervorum). This type of pain is prevalent in leprous neuropathy, acute herpetic NP, and compressive NP caused by osteophytes or disc herniation. It is generally reversible, and if treated early, it may resolve with the healing of the inflammatory process. However, if left untreated, it often results in nerve degeneration, leading to the development of dysesthetic pain and chronicization. | Truncal pain has familiar characteristics for the patient as it resembles pain from tissue injury and is caused by an inflammatory process involving the perineurium with the activation of visceral nociceptors (projection via nervi nervorum). This type of pain is prevalent in leprous neuropathy, acute herpetic NP, and compressive NP caused by osteophytes or disc herniation. It is generally reversible, and if treated early, it may resolve with the healing of the inflammatory process. However, if left untreated, it often results in nerve degeneration, leading to the development of dysesthetic pain and chronicization. | ||
== Irreversible Pain == | == Irreversible Pain== | ||
=== Chronic Inflammatory Pain === | ===Chronic Inflammatory Pain === | ||
The mechanisms of chronic inflammatory pain are the most representative of irreversible pain. The chronicity of pain depends on both the persistence of the inflammatory process and spinal hyperalgesia mechanisms. When an inflammatory stimulus is prolonged (weeks or months), regardless of its cause, it tends to induce a response different from the acute phase: the cellular infiltrate changes towards a persistent reaction, with recruitment of mononuclear cells (activated macrophages and giant cells, T and B lymphocytes, and plasma cells), extensive tissue destruction, and attempts at repair through connective tissue replacement (fibrosis and neoangiogenesis). Macrophages play a fundamental role in maintaining the inflammatory process through the production of numerous substances (enzymes, active oxygen metabolites, cytokines, growth factors, and eicosanoids) that, on the one hand, cause further tissue damage and, on the other, stimulate the recruitment of lymphocytes and neovascularization, creating a vicious cycle. COX-2 is found in high concentrations in activated macrophages but not in other cells of the chronic infiltrate <ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref>. | The mechanisms of chronic inflammatory pain are the most representative of irreversible pain. The chronicity of pain depends on both the persistence of the inflammatory process and spinal hyperalgesia mechanisms. When an inflammatory stimulus is prolonged (weeks or months), regardless of its cause, it tends to induce a response different from the acute phase: the cellular infiltrate changes towards a persistent reaction, with recruitment of mononuclear cells (activated macrophages and giant cells, <math>T</math> and <math>B</math> lymphocytes, and plasma cells), extensive tissue destruction, and attempts at repair through connective tissue replacement (fibrosis and neoangiogenesis). Macrophages play a fundamental role in maintaining the inflammatory process through the production of numerous substances (enzymes, active oxygen metabolites, cytokines, growth factors, and eicosanoids) that, on the one hand, cause further tissue damage and, on the other, stimulate the recruitment of lymphocytes and neovascularization, creating a vicious cycle. COX-2 is found in high concentrations in activated macrophages but not in other cells of the chronic infiltrate <ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref>. | ||
The prolonged alteration of the tissue microenvironment establishes a vicious cycle involving nociception, with increased vascular permeability, infiltration of algogenic substances, and progressive disruption of the microenvironment itself. This results in increased excitability of peripheral nerve fibers. | The prolonged alteration of the tissue microenvironment establishes a vicious cycle involving nociception, with increased vascular permeability, infiltration of algogenic substances, and progressive disruption of the microenvironment itself. This results in increased excitability of peripheral nerve fibers. | ||
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The chronicity of spinal pain involves complex mechanisms, including spinal reflexes that trigger positive feedback between sensitized peripheral fibers, lamina I neurons, and anterior horn motor neurons; a local increase in the production of algogenic prostaglandins through COX-1 <ref>Masferrer J.L. et al. Selective Inhibition of Inducible Cyclooxygenase 2 in vivo is Antiinflammatory and Nonulcerogenic. Proc Natl Acad Sci USA April 1994; 91: 3228–3232</ref>; and alterations in the gene expression of various molecules, including neurotransmitters and receptors (especially among endorphins, nociceptin, nocistatin, and the ORL1 receptor¹, as well as increased expression of the capsaicin/VR1 receptor in the dorsal root ganglia and the posterior horns of the spinal cord) <ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref><ref>Fletcher D. Does hyperalgesia take part in postoperative pain? IASP – International Association for the Study of Pain. Rif.14rc5</ref>. Finally, at a higher level, hypothalamic or cortical mechanisms, such as neuronal damage, deafferentation, or altered control mechanisms over subspinal structures, can contribute to pain chronicity <ref>Hansson P. Neurogenic Pain: Diagnosis and Treatment. Pain: clinical updates. Vol II n.3 Dec 1994. IASP – International Association for the Study of Pain</ref>. | The chronicity of spinal pain involves complex mechanisms, including spinal reflexes that trigger positive feedback between sensitized peripheral fibers, lamina I neurons, and anterior horn motor neurons; a local increase in the production of algogenic prostaglandins through COX-1 <ref>Masferrer J.L. et al. Selective Inhibition of Inducible Cyclooxygenase 2 in vivo is Antiinflammatory and Nonulcerogenic. Proc Natl Acad Sci USA April 1994; 91: 3228–3232</ref>; and alterations in the gene expression of various molecules, including neurotransmitters and receptors (especially among endorphins, nociceptin, nocistatin, and the ORL1 receptor¹, as well as increased expression of the capsaicin/VR1 receptor in the dorsal root ganglia and the posterior horns of the spinal cord) <ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref><ref>Fletcher D. Does hyperalgesia take part in postoperative pain? IASP – International Association for the Study of Pain. Rif.14rc5</ref>. Finally, at a higher level, hypothalamic or cortical mechanisms, such as neuronal damage, deafferentation, or altered control mechanisms over subspinal structures, can contribute to pain chronicity <ref>Hansson P. Neurogenic Pain: Diagnosis and Treatment. Pain: clinical updates. Vol II n.3 Dec 1994. IASP – International Association for the Study of Pain</ref>. | ||
=== Chronic Neurogenic Pain === | ===Chronic Neurogenic Pain=== | ||
In spinal cord injuries, pain often coexists with sensory alterations. It can take on various forms: burning, stabbing, cramping, or constrictive. Generally, it is persistent and exacerbated by peripheral stimulation or movement. When caused by acute-onset conditions, it is often accompanied by autonomic reflexes such as piloerection, profuse sweating, and skin vasodilation; however, these associated symptoms tend to disappear when the pain becomes chronic. The most common cause of spinal pain is traumatic spinal cord injury, with a significant prevalence of thoracolumbar localization. | In spinal cord injuries, pain often coexists with sensory alterations. It can take on various forms: burning, stabbing, cramping, or constrictive. Generally, it is persistent and exacerbated by peripheral stimulation or movement. When caused by acute-onset conditions, it is often accompanied by autonomic reflexes such as piloerection, profuse sweating, and skin vasodilation; however, these associated symptoms tend to disappear when the pain becomes chronic. The most common cause of spinal pain is traumatic spinal cord injury, with a significant prevalence of thoracolumbar localization. | ||
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Dysesthetic, or neuropathic pain, is initiated or caused by a primary lesion or dysfunction of the nervous system <ref>Bonica. Trattamento del dolore</ref>. It has unusual perceptual characteristics for the patient, never experienced before. It occurs during neuronal regeneration and prevails in major peripheral neuropathies. It can manifest as pain associated with dysesthesia, burning, and stabbing sensations, sometimes accompanied by allodynia and hyperpathy. Even when treated, it rarely resolves completely <ref>Hansson P. Neurogenic Pain: Diagnosis and Treatment. Pain: clinical updates. Vol II n.3 Dec 1994. IASP – International Association for the Study of Pain</ref>. | Dysesthetic, or neuropathic pain, is initiated or caused by a primary lesion or dysfunction of the nervous system <ref>Bonica. Trattamento del dolore</ref>. It has unusual perceptual characteristics for the patient, never experienced before. It occurs during neuronal regeneration and prevails in major peripheral neuropathies. It can manifest as pain associated with dysesthesia, burning, and stabbing sensations, sometimes accompanied by allodynia and hyperpathy. Even when treated, it rarely resolves completely <ref>Hansson P. Neurogenic Pain: Diagnosis and Treatment. Pain: clinical updates. Vol II n.3 Dec 1994. IASP – International Association for the Study of Pain</ref>. | ||
== Neuropathic Pain == | ==Neuropathic Pain== | ||
Neuropathic pain refers to pain initiated or caused by a primary lesion or dysfunction of the nervous system <ref>Bonica. Trattamento del dolore</ref>. It is caused by heterogeneous alterations of the Peripheral and/or Central Nervous System (traumatic, metabolic, neoplastic, inflammatory, etc.), resulting in functional abnormalities characterized by hyperactivity of the nociceptive system, central induction of neuronal plasticity phenomena, and subsequent memory formation <ref>Hansson P. Neurogenic Pain: Diagnosis and Treatment. Pain: clinical updates. Vol II n.3 Dec 1994. IASP – International Association for the Study of Pain</ref>. It can also be evoked in the absence of peripheral stimuli <ref>IASP – International Association for the Study of Pain. www.iasp-pain.org</ref>. | Neuropathic pain refers to pain initiated or caused by a primary lesion or dysfunction of the nervous system <ref>Bonica. Trattamento del dolore</ref>. It is caused by heterogeneous alterations of the Peripheral and/or Central Nervous System (traumatic, metabolic, neoplastic, inflammatory, etc.), resulting in functional abnormalities characterized by hyperactivity of the nociceptive system, central induction of neuronal plasticity phenomena, and subsequent memory formation <ref>Hansson P. Neurogenic Pain: Diagnosis and Treatment. Pain: clinical updates. Vol II n.3 Dec 1994. IASP – International Association for the Study of Pain</ref>. It can also be evoked in the absence of peripheral stimuli <ref>IASP – International Association for the Study of Pain. www.iasp-pain.org</ref>. | ||
=== Pathophysiology of Neuropathic Pain === | ===Pathophysiology of Neuropathic Pain === | ||
Here are some of the mechanisms that may underlie neuropathic pain:<blockquote>Ectopic generators along the fiber**: | |||
*Regeneration neuritis and neuroma formation; | |||
*Site of chronic damage | |||
* Mechanical stimuli along the fiber or in the ganglion. | |||
</blockquote><blockquote>Synaptic modifications | |||
*Previously ineffective synapses become active | |||
* Increased efficacy in residual synapses | |||
*Formation of aberrant connections | |||
* Hypersensitivity to transmitters and neuromodulators. | |||
</blockquote><blockquote>Loss of inhibition | |||
*Deficit in peripheral tactile input from <math>A\beta</math> fibers | |||
*Deficit in descending inhibitory systems. | |||
</blockquote><blockquote>Mixed pain: Central Sensitization | |||
Currently, the most accepted hypothesis is neuronal damage. According to this hypothesis, the lesion affecting the peripheral or central somatosensory and visceral pathways would cause the onset of abnormal impulses originating from neuromas, axonal alterations, and sensitized nociceptors <ref>Hansson P. Neurogenic Pain: Diagnosis and Treatment. Pain: clinical updates. Vol II n.3 Dec 1994. IASP – International Association for the Study of Pain</ref>. This damage increases the sensitivity of the primary afferent nociceptor (peripheral sensitization) and the second-order sensory neuron (central sensitization), and it alters spinal and supraspinal modulatory systems <ref>Masferrer J.L. et al. Selective Inhibition of Inducible Cyclooxygenase 2 in vivo is Antiinflammatory and Nonulcerogenic. Proc Natl Acad Sci USA April 1994; 91: 3228–3232</ref>. | *Alteration of spinal receptive fields | ||
*Alteration of cortical perception <ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref><ref>Fletcher D. Does hyperalgesia take part in postoperative pain? IASP – International Association for the Study of Pain. Rif.14rc5</ref>. | |||
</blockquote>Currently, the most accepted hypothesis is neuronal damage. According to this hypothesis, the lesion affecting the peripheral or central somatosensory and visceral pathways would cause the onset of abnormal impulses originating from neuromas, axonal alterations, and sensitized nociceptors <ref>Hansson P. Neurogenic Pain: Diagnosis and Treatment. Pain: clinical updates. Vol II n.3 Dec 1994. IASP – International Association for the Study of Pain</ref>. This damage increases the sensitivity of the primary afferent nociceptor (peripheral sensitization) and the second-order sensory neuron (central sensitization), and it alters spinal and supraspinal modulatory systems <ref>Masferrer J.L. et al. Selective Inhibition of Inducible Cyclooxygenase 2 in vivo is Antiinflammatory and Nonulcerogenic. Proc Natl Acad Sci USA April 1994; 91: 3228–3232</ref>. | |||
Patients with painful neuropathy develop two closely related phenomena: hyperalgesia and allodynia. These are considered characteristic of this type of pain, as they are symptoms of anatomically or functionally detectable lesions. | Patients with painful neuropathy develop two closely related phenomena: hyperalgesia and allodynia. These are considered characteristic of this type of pain, as they are symptoms of anatomically or functionally detectable lesions. | ||
== Peripheral Mechanisms of Hyperalgesia == | ==Peripheral Mechanisms of Hyperalgesia== | ||
=== Nociceptors === | ===Nociceptors=== | ||
Generally, the nociceptors involved are unmyelinated free nerve fibers located in the skin, muscles, and viscera. The cutaneous nociceptors are numerous (200/cm²); most of them are polymodal C fibers and | Generally, the nociceptors involved are unmyelinated free nerve fibers located in the skin, muscles, and viscera. The cutaneous nociceptors are numerous (200/cm²); most of them are polymodal <math>C</math> fibers and <math>A\delta</math> fibers, which respond to various types of stimulation, while less frequently, there are specific C fibers (thermal or mechanical stimuli). <math>A\delta</math> fibers seem to mediate immediate sensitivity, while <math>C</math> fibers mediate delayed perception. The receptive fields of these fibers tend to overlap, so that a punctate stimulus can activate multiple fibers. Among the afferent fibers, <math>C</math> fibers predominate (80%) <ref>Bonica. Trattamento del dolore</ref>. | ||
=== Sensitization of Nociceptors === | ===Sensitization of Nociceptors=== | ||
The mechanisms of pain transduction are still only partially understood. Ion mobilization across membranes is responsible for the action potential, but this alone does not explain some complex processes. | The mechanisms of pain transduction are still only partially understood. Ion mobilization across membranes is responsible for the action potential, but this alone does not explain some complex processes. | ||
The reactivity of this system can be modified by the local microenvironment in the tissues. It has been shown that some substances can be algogenic, provoking nociceptive stimuli (e.g., 5HT, bradykinin, H+ and K+ ions), while other substances can be sensitizing (e.g., prostaglandins, leukotrienes, and histamine). Substance P, produced by both central and peripheral nerve terminals, can cause vasodilation and plasma exudation. The cellular infiltrate, caused by trauma and inflammation, releases various peptides locally, including Nerve Growth Factor (NGF), SP, and CGRP. All of this underlies the different responses elicited by various stimuli and lesions. Reduced threshold and latency of discharge, increased response to painful stimuli, and persistent discharges after prolonged stimuli, or even spontaneous activity, are phenomena suggesting increased system sensitivity. | The reactivity of this system can be modified by the local microenvironment in the tissues. It has been shown that some substances can be algogenic, provoking nociceptive stimuli (e.g., 5HT, bradykinin, H+ and K+ ions), while other substances can be sensitizing (e.g., prostaglandins, leukotrienes, and histamine). Substance P,(<math>SP</math>) produced by both central and peripheral nerve terminals, can cause vasodilation and plasma exudation. The cellular infiltrate, caused by trauma and inflammation, releases various peptides locally, including Nerve Growth Factor (<math>NGF</math>), <math>SP</math>, and <math>CGRP</math>. All of this underlies the different responses elicited by various stimuli and lesions. Reduced threshold and latency of discharge, increased response to painful stimuli, and persistent discharges after prolonged stimuli, or even spontaneous activity, are phenomena suggesting increased system sensitivity. | ||
Some authors have demonstrated that sensitization can propagate from mechanical allodynia and hyperalgesia mechanisms to thermal ones when receptive fields are restored through axon reflexes. After an initial tissue injury, the skin becomes much more sensitive to thermal stimuli. | Some authors have demonstrated that sensitization can propagate from mechanical allodynia and hyperalgesia mechanisms to thermal ones when receptive fields are restored through axon reflexes. After an initial tissue injury, the skin becomes much more sensitive to thermal stimuli. | ||
A pro-inflammatory effect and nociceptor sensitization have been obtained after antidromic activation of C fibers, without the involvement of the CNS, and this effect persisted even after nerve sectioning. Finally, it has been demonstrated that there are normally silent visceral and articular receptors that activate only after sensitization due to inflammatory processes. The recruitment of these receptors may be one of the causes of hyperalgesia and allodynia <ref>IASP – International Association for the Study of Pain. www.iasp-pain.org</ref>. | A pro-inflammatory effect and nociceptor sensitization have been obtained after antidromic activation of <math>C</math> fibers, without the involvement of the CNS, and this effect persisted even after nerve sectioning. Finally, it has been demonstrated that there are normally silent visceral and articular receptors that activate only after sensitization due to inflammatory processes. The recruitment of these receptors may be one of the causes of hyperalgesia and allodynia <ref>IASP – International Association for the Study of Pain. www.iasp-pain.org</ref>. | ||
Studies on induced neuropathic pain in guinea pigs and patients with neuropathic pain have demonstrated abnormal ectopic activity near or at the sites of nerve injury. The mechanisms identified include abnormal distribution of Na+ and | Studies on induced neuropathic pain in guinea pigs and patients with neuropathic pain have demonstrated abnormal ectopic activity near or at the sites of nerve injury. The mechanisms identified include abnormal distribution of <math>Na^+</math> and <math>Ca^{2+}</math> channels on regenerating nerve sprouts and/or neuromas; sensitization to various mediators or modulators (e.g., bradykinin, histamine, 5HT, capsaicin, etc.); increased sympathetic response, which may result in greater sensitivity to pain mediators; and production of cytokines (<math>IL-1</math> and<math>TNF-\alpha</math>) involved in central and peripheral pain sensitization, mediated by the protein kinase cascade <ref>Hansson P. Neurogenic Pain: Diagnosis and Treatment. Pain: clinical updates. Vol II n.3 Dec 1994. IASP – International Association for the Study of Pain</ref>. | ||
== Central Mechanisms of Hyperalgesia == | ==Central Mechanisms of Hyperalgesia== | ||
=== Primary and Secondary Hyperalgesia === | ===Primary and Secondary Hyperalgesia=== | ||
The area considered primary hyperalgesia, where peripheral mechanisms predominate, is where the skin is inflamed. The surrounding area is that of secondary hyperalgesia, where central processes are more significant, characterized by a reduced threshold to mechanical and thermal stimuli. Among the mechanisms of mechanical hyperalgesia, pressure stimuli are more extensive and last longer than tactile stimuli. | The area considered primary hyperalgesia, where peripheral mechanisms predominate, is where the skin is inflamed. The surrounding area is that of secondary hyperalgesia, where central processes are more significant, characterized by a reduced threshold to mechanical and thermal stimuli. Among the mechanisms of mechanical hyperalgesia, pressure stimuli are more extensive and last longer than tactile stimuli. | ||
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It is also highly likely that these hyperalgesic phenomena result from a combination of peripheral and central mechanisms: the extension of hyperalgesia progresses alongside receptor sensitization. Recent studies have shown that secondary hyperalgesia can extend beyond the area of edema and that these processes can be dissociated <ref>Bonica. Trattamento del dolore</ref>. | It is also highly likely that these hyperalgesic phenomena result from a combination of peripheral and central mechanisms: the extension of hyperalgesia progresses alongside receptor sensitization. Recent studies have shown that secondary hyperalgesia can extend beyond the area of edema and that these processes can be dissociated <ref>Bonica. Trattamento del dolore</ref>. | ||
=== Central Sensitization === | ===Central Sensitization=== | ||
Central sensitization manifests as a lasting reduction in the activation threshold and increased responsiveness to cutaneous stimulation by dorsal horn neurons. NMDA receptors, sensitized by inputs from high-threshold primary afferents, play an important role in its induction and maintenance <ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref>. | Central sensitization manifests as a lasting reduction in the activation threshold and increased responsiveness to cutaneous stimulation by dorsal horn neurons. NMDA receptors, sensitized by inputs from high-threshold primary afferents, play an important role in its induction and maintenance <ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref>. | ||
=== Neuronal Sensitization === | ===Neuronal Sensitization=== | ||
The stimulation of hyperalgesia after local injection of capsaicin can be prevented by the prior administration of local anesthetic, either partially through infiltration or totally through nerve block. When the anesthetic is administered after hyperalgesia has been induced, no effect is observed. It appears that this phenomenon is initiated by nociceptive impulses that do not originate peripherally. Using microneurography, it has been demonstrated in humans that the capsaicin receptor (VR1) is responsible for the sensitization of spinothalamic neurons. This increased sensitivity is not altered by local anesthesia <ref>IASP – International Association for the Study of Pain. www.iasp-pain.org</ref>. | The stimulation of hyperalgesia after local injection of capsaicin can be prevented by the prior administration of local anesthetic, either partially through infiltration or totally through nerve block. When the anesthetic is administered after hyperalgesia has been induced, no effect is observed. It appears that this phenomenon is initiated by nociceptive impulses that do not originate peripherally. Using microneurography, it has been demonstrated in humans that the capsaicin receptor (VR1) is responsible for the sensitization of spinothalamic neurons. This increased sensitivity is not altered by local anesthesia <ref>IASP – International Association for the Study of Pain. www.iasp-pain.org</ref>. | ||
=== Receptive Field Modifications === | === Receptive Field Modifications=== | ||
The plasticity of neuronal receptive fields is another important factor in hyperalgesia. Inflammation and thermal or electrical stimulation are responsible for a significant increase in receptive field size. The stimulation of multiple receptive fields could partially explain allodynia and hyperalgesia through the activation of multiple afferent fibers and quiescent synapses. D-CPP, a competitive antagonist, and MK-801, a non-competitive NMDA receptor antagonist, block the development and maintenance of central sensitization and hyperalgesia. Additionally, MK-801 reduces the area of the receptive fields of nociceptive neurons in the dorsal horn, confirming their actual expansion in hyperalgesia processes <ref>Hansson P. Neurogenic Pain: Diagnosis and Treatment. Pain: clinical updates. Vol II n.3 Dec 1994. IASP – International Association for the Study of Pain</ref> <ref>Fletcher D. Does hyperalgesia take part in postoperative pain? IASP – International Association for the Study of Pain. Rif.14rc5</ref>. | The plasticity of neuronal receptive fields is another important factor in hyperalgesia. Inflammation and thermal or electrical stimulation are responsible for a significant increase in receptive field size. The stimulation of multiple receptive fields could partially explain allodynia and hyperalgesia through the activation of multiple afferent fibers and quiescent synapses. D-CPP, a competitive antagonist, and MK-801, a non-competitive NMDA receptor antagonist, block the development and maintenance of central sensitization and hyperalgesia. Additionally, MK-801 reduces the area of the receptive fields of nociceptive neurons in the dorsal horn, confirming their actual expansion in hyperalgesia processes <ref>Hansson P. Neurogenic Pain: Diagnosis and Treatment. Pain: clinical updates. Vol II n.3 Dec 1994. IASP – International Association for the Study of Pain</ref> <ref>Fletcher D. Does hyperalgesia take part in postoperative pain? IASP – International Association for the Study of Pain. Rif.14rc5</ref>. | ||
Some studies have revealed forms of neuronal plasticity with pronounced spinal localization, the existence of which could clarify the nature of hyperalgesic states and ensure better clinical treatment. Three of these plasticity mechanisms have assumed primary importance in this context. | Some studies have revealed forms of neuronal plasticity with pronounced spinal localization, the existence of which could clarify the nature of hyperalgesic states and ensure better clinical treatment. Three of these plasticity mechanisms have assumed primary importance in this context.<blockquote>'''The Wind-up Phenomenon''' | ||
The wind-up phenomenon consists of a frequency-dependent progressive facilitation of a neuron's response to the repetitive application of a constant-intensity stimulus <ref>Kristensen JD, Svensson B, Gordh TJr. The NMDA receptor antagonist CPP abolishes neurogenic “wind-up pain” after intrathecal administration in humans. Pain 1992; 51: 249-253</ref> <ref>Ren K. WIND-UP and the NMDA receptor: from animal studies to humans. Pain 1994; 59: 157-158</ref>. This mechanism was explained by Thompson <ref>Thompson SWN, Woolf CJ, Sivilotti LG. Small caliber afferent inputs produce a heterosynaptic facilitation of the synaptic responses evoked by primary afferent A-fibers in the neonatal rat spinal cord in vitro. J Neurophysiol 1993; 69: 2116-2128</ref> through intracellular recordings of potentials in spinal dorsal horn neurons and motor neurons in the anterior horn: for each 0.5 Hz stimulus at the posterior root level, a burst of action potentials is induced in the anterior horn, which can last up to 60 seconds after the stimulation ends. This phenomenon is abolished by NMDA receptor antagonists. These results suggest that the wind-up phenomenon can be seen as the temporal summation of excitatory postsynaptic potentials (EPSPs) mediated by NMDA receptors.</blockquote><blockquote>'''Long-Term Potentiation (LTP)''' | |||
Long-term potentiation refers to the tetanic electrical stimulation of C fibers, which lasts for a few seconds and causes a significant increase in postsynaptic potentials (around 200%) during subsequent stimulations. LTP persists after the stimulation ends for a period of 8 hours. NMDA glutamate receptors and tachykinin receptors (NK1) seem to be involved, inducing the activation of PKC, PKA, and other kinases, leading to extensive phosphorylation of membrane and channel receptors. Such mechanisms have been widely reported for peripheral nerve injuries <ref>Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol 2001 Oct; 429: 23-37</ref>.</blockquote><blockquote>'''Long-Term Depression (LTD)''' | |||
Long-term depression (LTD) involves a prolonged reduction in synaptic transmission efficacy, triggered by a moderate increase in intracellular calcium and subsequent hyperpolarization. In this phenomenon, the same receptors involved in LTP are inhibited by phosphatases <ref>Fletcher D. Does hyperalgesia take part in postoperative pain? IASP – International Association for the Study of Pain. Rif.14rc5</ref> <ref>Hansson P. Neurogenic Pain: Diagnosis and Treatment. Pain: clinical updates. Vol II n.3 Dec 1994. IASP – International Association for the Study of Pain</ref>.</blockquote>'''Nociceptive Reflex''' | |||
Many studies have used the nociceptive reflex to analyze nervous system sensitization, which occurs due to the activation of <math>C</math> fibers from deep tissues like muscles but not from superficial tissues like the skin. The difference lies in the various substances released by these fibers. However, some studies may have been influenced by specific lesions present in the animal models used (spinalization or decerebration), which can increase sensitivity due to the interruption of descending cortical control pathways <ref>IASP – International Association for the Study of Pain. www.iasp-pain.org</ref>. | |||
'''Peripheral and Central Sensitization Mechanisms''' | |||
Lewis and Hardy, using peripheral nerve block techniques, demonstrated that secondary hyperalgesia depends on both central and peripheral activation. In inflammatory damage, as in capsaicin injection, the effectiveness of the peripheral block lies in preventing the development of secondary hyperalgesia, suggesting that central sensitization plays a prominent role. The development of allodynia and hyperalgesia requires the sensitization of both the central and peripheral nervous systems. Peripheral stimuli are essential for system activation and the maintenance of sensitization <ref>Fletcher D. Does hyperalgesia take part in postoperative pain? IASP – International Association for the Study of Pain. Rif.14rc5</ref>. | Lewis and Hardy, using peripheral nerve block techniques, demonstrated that secondary hyperalgesia depends on both central and peripheral activation. In inflammatory damage, as in capsaicin injection, the effectiveness of the peripheral block lies in preventing the development of secondary hyperalgesia, suggesting that central sensitization plays a prominent role. The development of allodynia and hyperalgesia requires the sensitization of both the central and peripheral nervous systems. Peripheral stimuli are essential for system activation and the maintenance of sensitization <ref>Fletcher D. Does hyperalgesia take part in postoperative pain? IASP – International Association for the Study of Pain. Rif.14rc5</ref>. | ||
The hypotheses outlined above appear valid in most cases, except for deafferentation neuropathies. The poor results from neurolesive therapies highlight alternative mechanisms that require more effective treatments <ref>IASP – International Association for the Study of Pain. www.iasp-pain.org</ref> <ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref>. | The hypotheses outlined above appear valid in most cases, except for deafferentation neuropathies. The poor results from neurolesive therapies highlight alternative mechanisms that require more effective treatments <ref>IASP – International Association for the Study of Pain. www.iasp-pain.org</ref> <ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref>. | ||
=== Molecular Sensitization Mechanisms === | ===Molecular Sensitization Mechanisms=== | ||
The phenomena of wind-up and hyperexcitability underlie the hyperalgesia and allodynia that develop in neuropathic pain. These phenomena are more complex than initially described, both biophysically and neurochemically. | The phenomena of wind-up and hyperexcitability underlie the hyperalgesia and allodynia that develop in neuropathic pain. These phenomena are more complex than initially described, both biophysically and neurochemically. | ||
'''Electrical Parameters''' | |||
Wind-up is a frequency-dependent phenomenon of C-fiber discharge. Below a critical frequency of 0.2-0.3 Hz, the phenomenon cannot be observed, whereas at frequencies above 20 Hz, a habituation effect called wind-down is observed. The largest response occurs at frequencies between 1 and 2 Hz. Wind-up also depends on other parameters that determine adequate stimulation of C fibers; in fact, the duration of stimulation is crucial (increasing the stimulation time can generate wind-up even at lower discharge frequencies). Therefore, wind-up is generated by the temporal and spatial summation of impulses from a larger population of C fibers, recruitable by broader impulses. Another important parameter for wind-up generation is the initial excitability level of spinal neurons: in cases of spinal hyperexcitability, lower frequencies and discharge amplitudes are required <ref>Kristensen JD, Svensson B, Gordh TJr. The NMDA receptor antagonist CPP abolishes neurogenic “wind-up pain” after intrathecal administration in humans. Pain 1992; 51: 249-253</ref>. | |||
Wind-up is a frequency-dependent phenomenon of <math>C</math>-fiber discharge. Below a critical frequency of 0.2-0.3 Hz, the phenomenon cannot be observed, whereas at frequencies above 20 Hz, a habituation effect called wind-down is observed. The largest response occurs at frequencies between 1 and 2 Hz. Wind-up also depends on other parameters that determine adequate stimulation of C fibers; in fact, the duration of stimulation is crucial (increasing the stimulation time can generate wind-up even at lower discharge frequencies). Therefore, wind-up is generated by the temporal and spatial summation of impulses from a larger population of <math>C</math> fibers, recruitable by broader impulses. Another important parameter for wind-up generation is the initial excitability level of spinal neurons: in cases of spinal hyperexcitability, lower frequencies and discharge amplitudes are required <ref>Kristensen JD, Svensson B, Gordh TJr. The NMDA receptor antagonist CPP abolishes neurogenic “wind-up pain” after intrathecal administration in humans. Pain 1992; 51: 249-253</ref>. | |||
==Mechanisms of Genesis == | |||
Several types of neurons in the dorsal horn of the spinal cord participate in the genesis of wind-up. The neurons most prone to developing this phenomenon are undoubtedly class 2 neurons in the deep areas of the dorsal horns, with a response to cutaneous stimulation of 200%; those located in more superficial areas show a lower response, equal to 44% of the normal; finally, class 3 neurons, which are even more superficial, do not show wind-up at all. Conversely, the afferent <math>C</math>-fibers exhibit a functional anatomy that is specular to this, likely due to the fact that the deeper fibers present polysynaptic potentials, with lower synchrony, and a role in neuronal inhibition. The potential fields of superficial <math>C</math>-fibers in the dorsal horns are widely represented in lamina II, corresponding to the central neurons of the Substantia Gelatinosa; these are neurons with excitatory activity, inhibited by afferent stimuli (inverse neurons). This is due to the connections that <math>C</math>-fibers make in lamina II with the dendrites of neurons whose somas are located outside this lamina. | |||
Characteristically, the responses of wind-up and nociceptive reflexes in the neurons of the dorsal horns of the spinal cord block signal progression after 16 and 8 stimuli, respectively; by contrast, the potential fields of C fibers show an increased response, up to 70-100 stimulations with a discharge frequency of 1 Hz. The reason for this difference is unclear, and some authors have hypothesized the existence of some inhibitory mechanism capable of counteracting the increase in response in the first two cases, which nevertheless does not alter the process of wind-up genesis in C fibers. This inhibitory mechanism has been described by Le Bars and colleagues as supraspinal and can be summarized in a few points: | |||
*Neurons on the surface of the dorsal horns receive less control from descending supraspinal structures compared to those located deeper; | |||
*There is a post-tetanic supraspinal depression of neuronal discharge; | |||
*Wind-up can be modulated by supraspinal structures due to other converging nociceptive messages. | |||
Alarcon and Cervero have demonstrated that viscerosomatic neurons in the spinal cord also show wind-up of their somatic afferents, functionally dissociated from the reflex circuit involving somatosensory neurons and trunk motor neurons <ref>Le Bars D, Cervero F. Pain modulation and the role of supraspinal structures in the inhibition of spinal nociceptive reflexes. Prog Neurobiol 1988; 31: 65-88.</ref>. | |||
'''Presynaptic Mechanisms''' | |||
Schouenborg proposed a model involving a presynaptic mechanism for wind-up generation: increased synaptic efficacy through a phenomenon similar to post-tetanic potentiation. Many similarities exist: post-tetanic potentiation describes an increase in the magnitude of a postsynaptic response; systems that exhibit it are subject to response facilitation during a train of conditioning stimuli. It decreases exponentially over time, and the time constant is inversely proportional to the number of conditioning stimuli. It appears to result from a progressive increase in intracellular free <math>Ca^{2+}</math>in nerve terminals caused by multiple depolarizations, leading to an increased number of vesicles (quanta) released. The similarities between wind-up and post-tetanic potentiation suggest that wind-up may be presynaptic and act by increasing neurotransmitter release from primary afferents. In normal circumstances, wind-up is induced only by primary afferent <math>C</math> fibers, which release GLUT and various peptides, including SP, in independent ways. The fact that different discharge frequencies can modulate the release of different molecules or peptides might seem inconsistent with the theory that wind-up facilitates their release, particularly when considering the low discharge frequencies that characterize the phenomenon. However, high frequencies are not necessary for adequate and consistent neuropeptide release, and it has been demonstrated that SP release at low frequencies is maximal <ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref>. | |||
'''Postsynaptic Mechanisms''' | |||
The most important substances normally released in the dorsal horns of the spinal cord fall into two classes: opioid peptides and excitatory amino acids. The receptors also belong to two groups: ionotropic and metabotropic. | The most important substances normally released in the dorsal horns of the spinal cord fall into two classes: opioid peptides and excitatory amino acids. The receptors also belong to two groups: ionotropic and metabotropic. <blockquote>'''Ionotropic receptors''' include NMDA, AMPA, kainate, and AP4 (activating protein): opening these channels allows <math>Ca^{2+}</math> ions to enter, which activates intracellular second messengers. </blockquote><blockquote>'''Metabotropic receptors''' are associated with G proteins that activate phospholipase C or adenylate cyclase; the second messenger activates an intracellular cascade that includes the production of nitric oxide (NO) and cyclic GMP. </blockquote>Evidence that glutamate (GLU) receptors are involved in the transmission of nociceptive information in the dorsal horns of the spinal cord comes from numerous immunocytochemical and autoradiographic studies. It has been shown that intense noxious stimulation causes the release and significant increase of GLU concentration in the dorsal roots, leading to an increase in the excitability of spinal sensory neurons (central sensitization); this is thought to be involved in the genesis of wind-up and LTP <ref>Bonica. Trattamento del dolore</ref> <ref>Fletcher D. Does hyperalgesia take part in postoperative pain? IASP – International Association for the Study of Pain. Rif.14rc5</ref>. | ||
Ionotropic receptors include NMDA, AMPA, kainate, and AP4 (activating protein): opening these channels allows | |||
Metabotropic receptors are associated with G proteins that activate phospholipase C or adenylate cyclase; the second messenger activates an intracellular cascade that includes the production of nitric oxide (NO) and cyclic GMP. | |||
Evidence that glutamate (GLU) receptors are involved in the transmission of nociceptive information in the dorsal horns of the spinal cord comes from numerous immunocytochemical and autoradiographic studies. It has been shown that intense noxious stimulation causes the release and significant increase of GLU concentration in the dorsal roots, leading to an increase in the excitability of spinal sensory neurons (central sensitization); this is thought to be involved in the genesis of wind-up and LTP <ref>Bonica. Trattamento del dolore</ref> <ref>Fletcher D. Does hyperalgesia take part in postoperative pain? IASP – International Association for the Study of Pain. Rif.14rc5</ref>. | |||
Substance P (SP) and NKA, belonging to the neurokinin family, appear to be involved in the genesis of the wind-up phenomenon. | Substance P (<math>SP</math>) and <math>NKA</math>, belonging to the neurokinin family, appear to be involved in the genesis of the wind-up phenomenon. There are also transcription regulators, such as the c-fos and c-jun proteins, which promote the transcription of important genes, including those for proenkephalin and prodynorphin. Some studies have shown the concomitant localization of c-fos with dynorphin and enkephalin mRNA in the superficial layers of the dorsal horns. The temporal expression of these mediators suggests that they may play a role in the long-term activation and sensitization of neurons: intrathecal administration of dynorphin has been shown to increase the size of receptive fields by 50% <ref>Bonica. Trattamento del dolore</ref> <ref>Fletcher D. Does hyperalgesia take part in postoperative pain? IASP – International Association for the Study of Pain. Rif.14rc5</ref>. | ||
There are also transcription regulators, such as the c-fos and c-jun proteins, which promote the transcription of important genes, including those for proenkephalin and prodynorphin. Some studies have shown the concomitant localization of c-fos with dynorphin and enkephalin mRNA in the superficial layers of the dorsal horns. The temporal expression of these mediators suggests that they may play a role in the long-term activation and sensitization of neurons: intrathecal administration of dynorphin has been shown to increase the size of receptive fields by 50% <ref>Bonica. Trattamento del dolore</ref> <ref>Fletcher D. Does hyperalgesia take part in postoperative pain? IASP – International Association for the Study of Pain. Rif.14rc5</ref>. | |||
==Ion Channels == | |||
These are a subtype of channel receptors, whose opening is determined not by a neurotransmitter but by membrane depolarization (activation threshold). Each subtype has its own kinetic characteristics for opening and closing, as well as different activation thresholds. They can be selective and specific for certain ions based on their charge or molecular weight, or they may not exhibit particular selectivity and allow multiple elements to pass through. | These are a subtype of channel receptors, whose opening is determined not by a neurotransmitter but by membrane depolarization (activation threshold). Each subtype has its own kinetic characteristics for opening and closing, as well as different activation thresholds. They can be selective and specific for certain ions based on their charge or molecular weight, or they may not exhibit particular selectivity and allow multiple elements to pass through. | ||
'''Voltage-gated <math>Na^{+}</math> Channels''' | |||
Various subtypes of voltage-gated Na+ channels (VGSCs), including | |||
Characterized by an activation potential of -40 mV, NaV1.8 is the isoform most expressed in the C fibers of dorsal root ganglia (DRG) and is crucial for action potentials. Immunological, electrophysiological, and functional studies have demonstrated the involvement of | Various subtypes of voltage-gated '''<math>Na^{+}</math>''' channels (VGSCs), including '''<math>Na_V1.6</math>''','''<math>Na_V1.7</math>''' ,'''<math>Na_V1.8</math>''', and'''<math>Na_V1.9</math>''', are normally expressed in the peripheral nervous system. Their expression and organization vary between '''<math>A</math>''' and '''<math>C</math>''' fibers under normal conditions and undergo significant changes during neuronal damage. Characterized by an activation potential of -40 mV, NaV1.8 is the isoform most expressed in the C fibers of dorsal root ganglia (DRG) and is crucial for action potentials. Immunological, electrophysiological, and functional studies have demonstrated the involvement of '''<math>Na_V1.8</math>''' in the genesis of experimental neuropathic pain (sciatic nerve ligation) in guinea pigs: it undergoes significant redistribution and reorganization in DRG cells, with initial upregulation in damaged fibers within the first 48 hours. Subsequently, at 7-10 days post-injury, after extensive degeneration of damaged fibers, '''<math>Na_V1.8</math>''' shows high expression in residual afferent fibers. Hyperalgesia and allodynia resulting from nerve injury are eliminated by intrathecal administration of antisense oligonucleotides specific to '''<math>Na_V1.8</math>'''. | ||
The | '''<math>Na_V1.9</math>''' with an activation potential of -70 mV, is selectively expressed in nociceptive neurons, where it modulates resting membrane potential and the response to sub-threshold stimuli. It becomes inactivated by persistent stimulation. Antisense oligonucleotide studies have not shown interference with hyperalgesia or hypersensitivity mechanisms. Immunohistological studies have shown that NaV1.9 is downregulated in severed fibers but not in those with chronic lesions. | ||
The '''<math>Na_V1.3</math>''' subtype is normally expressed at very low levels in primary nociceptors but undergoes rapid upregulation in DRGs following axonotomy, ligation, or chronic peripheral nerve constriction. Its kinetic characteristics (fast opening and closing) make it the best candidate for generating spontaneous ectopic discharges, although a direct correlation between these discharges and '''<math>Na_V1.3</math>''' expression has yet to be demonstrated. The distribution of '''<math>Na_V1.3</math>''' in large- and small-diameter fibers in DRG neurons suggests that transcript and protein upregulation occurs after axonotomy in both A and C fibers, although ectopic discharges are predominantly found in the former. | |||
This highlights the importance of VGSCs in the genesis of neuropathic pain <ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref> <ref>Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol 2001 Oct; 429: 23-37</ref>. | This highlights the importance of VGSCs in the genesis of neuropathic pain <ref>Seibet K. et al. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proc Natl Acad Sci USA. (1994 December 6); 91: 12013–12017</ref> <ref>Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol 2001 Oct; 429: 23-37</ref>. | ||
==== L-type | ====<math>L</math>-type <math>Ca^{2+}</math> Channels==== | ||
In the spinal cord, L-type | In the spinal cord, L-type <math>Ca^{2+}</math> channels are expressed by motor neurons and sensory interneurons, where they mediate a slow inward current in response to depolarization and show no significant inactivation. The slow activation and inactivation kinetics lead to plateau potentials. As a result, two different functional states of stability arise in both sensory and motor compartments, one of which is wind-up. Both types of phenomena, similar to wind-up, are voltage-dependent and dihydropyridine-sensitive, involving L-type <math>Ca^{2+}</math> channels. The gradual increase in depolarization in response to repeated current pulses is not due to cumulative depolarization of the membrane potential during the interstimulus interval but to depolarization-induced facilitation of L-type <math>Ca^{2+}</math> channels: this mechanism is known as warm-up. The simplest scheme to explain the warm-up phenomenon is a voltage-dependent transition between two closed states of L-type <math>Ca^{2+}</math> channels: one infrequent state with a high activation threshold and a more frequent state with a lower activation threshold. | ||
L-type | L-type <math>Ca^{2+}</math> channels are regulated by metabotropic receptors: in the sensory compartment, they are positively regulated by GLUT and SP and negatively by GABAB. These modulators contribute to the dynamic regulation of excitability and the intrinsic characteristics of plateau currents <ref>Zimmermann M. Pathobiology of neuropathic pain. Eur J Pharmacol 2001 Oct; 429: 23-37</ref>. | ||
== Transmitters and Receptors == | ==Transmitters and Receptors== | ||
=== Adenosine (P1) and ATP (P2) Receptors === | ===Adenosine (P1) and ATP (P2) Receptors{{Rosso inizio}}qui{{Rosso Fine}} === | ||
Adenosine and ATP are ubiquitous mediators released by a variety of cells. Adenosine acts by binding to metabotropic receptors ( | Adenosine and ATP are ubiquitous mediators released by a variety of cells. Adenosine acts by binding to metabotropic receptors (<math>A_1,A_{2A},A_{2B},A_3</math>) associated with excitatory or inhibitory G proteins, while ATP acts through both ion channel receptors (P2X) and metabotropic receptors (P2Y). Interactions between the adenosine receptor and other receptors, both metabotropic and ion channels, contribute to the fine regulation of nervous function <ref>Ribeiro JA, Sebastiao AM, de Mendonca A. Adenosine receptor in the nervous system: pathophysiological implications. Prog Neurobio 2003; 68: 377-392</ref>. Adenosine and ATP exert numerous influences on peripheral and spinal pain transmission: | ||
* In peripheral nerve terminals, stimulation of the | *In peripheral nerve terminals, stimulation of the <math>A_1</math> receptor increases intracellular cAMP, resulting in analgesia, while activation of the <math>A_2</math> receptor induces pain or facilitates nerve sensitization. | ||
* At the spinal level, activation of the | *At the spinal level, activation of the <math>A_1</math> adenosine receptor produces analgesia for both nociceptive and neuropathic pain, at doses lower than those with motor effects. Spinal analgesia is mediated by the inhibition of interneurons through hyperpolarization (increased <math>K^+</math> conductance) and presynaptic inhibition of the release of Substance P (SP) and possibly glutamate <ref>Sawiynok J. Adenosine receptor activation and nociception. Eur J Pharmacol 1998; 317: 1-11</ref>. | ||
In the spinal cord, morphine can induce analgesia indirectly by releasing adenosine from capsaicin-sensitive afferents via PKC activation associated with μ-opioid receptors. PKC appears responsible for morphine-induced hypotension and the muscle rigidity associated with fentanyl administration <ref>Ribeiro JA, Sebastiao AM, de Mendonca A. Adenosine receptor in the nervous system: pathophysiological implications. Prog Neurobio 2003; 68: 377-392</ref>. Significant interactions also seem possible with the spinal monoaminergic system: in pain perception tests, the effectiveness of adenosine, or its analogs, in inducing analgesia is dependent on the integrity of the noradrenergic system <ref>Sawiynok J. Adenosine receptor activation and nociception. Eur J Pharmacol 1998; 317: 1-11</ref>. | In the spinal cord, morphine can induce analgesia indirectly by releasing adenosine from capsaicin-sensitive afferents via PKC activation associated with μ-opioid receptors. PKC appears responsible for morphine-induced hypotension and the muscle rigidity associated with fentanyl administration <ref>Ribeiro JA, Sebastiao AM, de Mendonca A. Adenosine receptor in the nervous system: pathophysiological implications. Prog Neurobio 2003; 68: 377-392</ref>. Significant interactions also seem possible with the spinal monoaminergic system: in pain perception tests, the effectiveness of adenosine, or its analogs, in inducing analgesia is dependent on the integrity of the noradrenergic system <ref>Sawiynok J. Adenosine receptor activation and nociception. Eur J Pharmacol 1998; 317: 1-11</ref>. | ||
Recent studies have highlighted the relevance of the | Recent studies have highlighted the relevance of the <math>P2X_3</math>subtype in pain pathways: it is selectively expressed at high levels by nociceptive sensory neurons and plays a role in the presynaptic regulation of glutamate release in the first afferent neuron in DRG <ref>Ding Y et al. ATP, P2X receptors and pain pathways. J Auton Nerv Syst 2000; 81: 289-294</ref>. | ||
=== Glutamate and NMDA === | ===Glutamate and NMDA=== | ||
Glutamate (GLU) is the most important excitatory amino acid present in the nervous system. It exerts its effects through various membrane receptors, both ionotropic (NMDA, AMPA, and kainate) and metabotropic ( | Glutamate (GLU) is the most important excitatory amino acid present in the nervous system. It exerts its effects through various membrane receptors, both ionotropic (NMDA, AMPA, and kainate) and metabotropic (<math>mGLUR_{1-8}</math>), all of which are widely represented. Over the years, evidence has accumulated that NMDA receptors (NMDAR) are involved in the induction and maintenance of both central and peripheral sensitization during pain states, including visceral pain. This is due to its unique characteristics: | ||
* NMDARs control an ion channel with high permeability to monovalent ions and calcium; | * NMDARs control an ion channel with high permeability to monovalent ions and calcium; | ||
* Efficient activation requires the simultaneous binding of GLU and GLY; | *Efficient activation requires the simultaneous binding of GLU and GLY; | ||
* At resting membrane potential, the receptor is blocked by extracellular Mg2+, and both agonist binding and depolarization are required for channel opening. | *At resting membrane potential, the receptor is blocked by extracellular Mg2+, and both agonist binding and depolarization are required for channel opening. | ||
NMDARs are composed of three subunits (NR1, NR2, NR3), with various isoforms that determine their chemical and biophysical properties. | NMDARs are composed of three subunits (NR1, NR2, NR3), with various isoforms that determine their chemical and biophysical properties. | ||
Recent studies have shown that NMDARs are present in both the CNS and peripheral nerves, contributing to pain perception. During inflammatory processes, the number of NMDA receptors on peripheral nerve fibers increases significantly, contributing to peripheral sensitization, while in neuropathic pain, once hyperalgesia has already been established, NMDARs no longer contribute to nociceptor sensitization. | Recent studies have shown that NMDARs are present in both the CNS and peripheral nerves, contributing to pain perception. During inflammatory processes, the number of NMDA receptors on peripheral nerve fibers increases significantly, contributing to peripheral sensitization, while in neuropathic pain, once hyperalgesia has already been established, NMDARs no longer contribute to nociceptor sensitization. | ||
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At the spinal level, NMDARs are also present presynaptically in the afferent terminals of small-caliber fibers, and their activation triggers the release of Substance P (SP). These fibers are part of a positive feedback loop for GLU, in response to sequential stimuli, facilitating and prolonging the transmission of the pain signal through the release of GLU, SP, and Calcitonin Gene-Related Peptide (CGRP). Multiple studies conducted on animal models have demonstrated the presence of NMDARs in both the peripheral and central afferents of visceral nociceptive pathways; notably, in this case, unlike in somatic perceptive pathways, the innocuous visceral stimulus is sensitive to NMDAR antagonists <ref>Ren K. WIND-UP and the NMDA receptor: from animal studies to humans. Pain 1994; 59: 157-158</ref>. | At the spinal level, NMDARs are also present presynaptically in the afferent terminals of small-caliber fibers, and their activation triggers the release of Substance P (SP). These fibers are part of a positive feedback loop for GLU, in response to sequential stimuli, facilitating and prolonging the transmission of the pain signal through the release of GLU, SP, and Calcitonin Gene-Related Peptide (CGRP). Multiple studies conducted on animal models have demonstrated the presence of NMDARs in both the peripheral and central afferents of visceral nociceptive pathways; notably, in this case, unlike in somatic perceptive pathways, the innocuous visceral stimulus is sensitive to NMDAR antagonists <ref>Ren K. WIND-UP and the NMDA receptor: from animal studies to humans. Pain 1994; 59: 157-158</ref>. | ||
=== SP and NKA === | ===SP and NKA=== | ||
International literature reports the involvement of neurokinins in the genesis and transmission of pain, both peripherally and centrally, although they do not appear to play a significant role in neuropathic pain. However, their interactions with the endogenous opioid system, the glutamatergic system, molecular transduction mechanisms, and their involvement in wind-up phenomena warrant a brief discussion. Basbaum, in a 1999 review, noted that deletion of the preprotachykinin A (PPT-A) gene, the precursor of SP and NKA, leads to altered perception of acute pain (thermal, mechanical, and chemical) but not chronic pain, suggesting that these neuromediators do not participate in the genesis of neuropathic pain <ref>Przewlocki R, Przewlocka B. Opioids in chronic pain. Eur J Pharmacol 2001; 429: 79-91</ref>. | International literature reports the involvement of neurokinins in the genesis and transmission of pain, both peripherally and centrally, although they do not appear to play a significant role in neuropathic pain. However, their interactions with the endogenous opioid system, the glutamatergic system, molecular transduction mechanisms, and their involvement in wind-up phenomena warrant a brief discussion. Basbaum, in a 1999 review, noted that deletion of the preprotachykinin A (PPT-A) gene, the precursor of SP and NKA, leads to altered perception of acute pain (thermal, mechanical, and chemical) but not chronic pain, suggesting that these neuromediators do not participate in the genesis of neuropathic pain <ref>Przewlocki R, Przewlocka B. Opioids in chronic pain. Eur J Pharmacol 2001; 429: 79-91</ref>. | ||
Hueda highlights peripheral and spinal molecular mechanisms closely related to the endogenous opioid system. In the periphery, chemical stimulation with BK or His induces Ca2+-mediated SP release; in the spinal cord, Orphanin FQ or kitorphin, through activation of the ORL1 receptor, trigger Gi1 activation and Ca2+ influx, resulting in SP release. SP, in turn, stimulates the activation of Gq/11, which activates PLC and the IP3 cascade, with prolonged calcium influx leading to NaV channel activation and depolarization <ref>Thompson SWN, Woolf CJ, Sivilotti LG. Small caliber afferent inputs produce a heterosynaptic facilitation of the synaptic responses evoked by primary afferent A-fibers in the neonatal rat spinal cord in vitro. J Neurophysiol 1993; 69: 2116-2128</ref>. | Hueda highlights peripheral and spinal molecular mechanisms closely related to the endogenous opioid system. In the periphery, chemical stimulation with BK or His induces Ca2+-mediated SP release; in the spinal cord, Orphanin FQ or kitorphin, through activation of the ORL1 receptor, trigger Gi1 activation and Ca2+ influx, resulting in SP release. SP, in turn, stimulates the activation of Gq/11, which activates PLC and the IP3 cascade, with prolonged calcium influx leading to NaV channel activation and depolarization <ref>Thompson SWN, Woolf CJ, Sivilotti LG. Small caliber afferent inputs produce a heterosynaptic facilitation of the synaptic responses evoked by primary afferent A-fibers in the neonatal rat spinal cord in vitro. J Neurophysiol 1993; 69: 2116-2128</ref>. | ||
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Despite the extensive knowledge on these channels and the role of calcium, numerous studies present conflicting evidence; the complexity of the topic highlights the need for further in-depth research on the role of these channels in mammals, particularly in humans. | Despite the extensive knowledge on these channels and the role of calcium, numerous studies present conflicting evidence; the complexity of the topic highlights the need for further in-depth research on the role of these channels in mammals, particularly in humans. | ||
**CCK and Galanin**. It is well known that cholecystokinin (CCK) reduces the antinociceptive effects of opioids. The presence of CCK has been shown to overlap with the expression of opioids and their receptors throughout the CNS. CCK exerts its action via Gi/Go protein-coupled receptors, attenuating the action of endorphins and morphine. The level of CCK and its receptors, as well as its release, show considerable plasticity following nerve injury and inflammation, conditions associated with chronic pain. Such altered CCK release, along with receptor level changes in some cases, may be the cause of altered opioid sensitivity in various clinical pain conditions. | **CCK and Galanin**. It is well known that cholecystokinin (CCK) reduces the antinociceptive effects of opioids. The presence of CCK has been shown to overlap with the expression of opioids and their receptors throughout the CNS. CCK exerts its action via Gi/Go protein-coupled receptors, attenuating the action of endorphins and morphine. The level of CCK and its receptors, as well as its release, show considerable plasticity following nerve injury and inflammation, conditions associated with chronic pain. Such altered CCK release, along with receptor level changes in some cases, may be the cause of altered opioid sensitivity in various clinical pain conditions. | ||
Neuropathic pain resulting from central or peripheral nervous system injury does not respond well to opioid treatment, likely due to increased activity in the endogenous CCKergic system. CCK receptor antagonists may, therefore, be useful as analgesics in combination with opioids for treating neuropathic pain <ref>Wiesenfeld-Hallin Z, Xu XJ, Hokfelt T. The Role of Spinal Cholecystokinin in Chronic Pain States. Pharmacol Toxicol 2002; 91: 398-403.</ref> <ref>Wiesenfeld-Hallin Z, Xu XJ. Neuropeptides in neuropathic and inflammatory pain with special emphasis on cholecystokinin and galanin. Eur J Pharmacol 2001; 429: 49-59.</ref>. | Neuropathic pain resulting from central or peripheral nervous system injury does not respond well to opioid treatment, likely due to increased activity in the endogenous CCKergic system. CCK receptor antagonists may, therefore, be useful as analgesics in combination with opioids for treating neuropathic pain <ref>Wiesenfeld-Hallin Z, Xu XJ, Hokfelt T. The Role of Spinal Cholecystokinin in Chronic Pain States. Pharmacol Toxicol 2002; 91: 398-403.</ref> <ref>Wiesenfeld-Hallin Z, Xu XJ. Neuropeptides in neuropathic and inflammatory pain with special emphasis on cholecystokinin and galanin. Eur J Pharmacol 2001; 429: 49-59.</ref>. | ||
Galanin is a peptide involved in various functions, including pain perception, and it exerts its function through Gi/Go-coupled metabotropic receptors. It is normally expressed in small DRG neurons in rats, which also contain SP and CGRP, and it appears to be located in some neurons in lamina II. Electrophysiological and behavioral studies in rodents have shown that galanin produces complex effects on spinal pain perception, with a predominant inhibitory effect. Intrathecal administration of galanin enhances the analgesic effects of morphine, particularly when administered together with a CCK2 receptor inhibitor. Galanin reduces spinal hyperexcitability and the pain effects of SP. After peripheral nerve injury, a consistent increase in galanin expression and release can be observed in DRG, but not in dorsal horn interneurons of the spinal cord; additionally, there is no alteration in galanin receptor expression. The probable role of this peptide is tonic activation to suppress painful sensation in injured nerves, suggesting that low levels of galaninergic control may contribute to the development of neuropathic pain <ref>Wiesenfeld-Hallin Z, Xu XJ, Hokfelt T. The Role of Spinal Cholecystokinin in Chronic Pain States. Pharmacol Toxicol 2002; 91: 398-403.</ref>. | Galanin is a peptide involved in various functions, including pain perception, and it exerts its function through Gi/Go-coupled metabotropic receptors. It is normally expressed in small DRG neurons in rats, which also contain SP and CGRP, and it appears to be located in some neurons in lamina II. Electrophysiological and behavioral studies in rodents have shown that galanin produces complex effects on spinal pain perception, with a predominant inhibitory effect. Intrathecal administration of galanin enhances the analgesic effects of morphine, particularly when administered together with a CCK2 receptor inhibitor. Galanin reduces spinal hyperexcitability and the pain effects of SP. After peripheral nerve injury, a consistent increase in galanin expression and release can be observed in DRG, but not in dorsal horn interneurons of the spinal cord; additionally, there is no alteration in galanin receptor expression. The probable role of this peptide is tonic activation to suppress painful sensation in injured nerves, suggesting that low levels of galaninergic control may contribute to the development of neuropathic pain <ref>Wiesenfeld-Hallin Z, Xu XJ, Hokfelt T. The Role of Spinal Cholecystokinin in Chronic Pain States. Pharmacol Toxicol 2002; 91: 398-403.</ref>. | ||
**Opioids**. The main groups of opioid peptides, enkephalins, dynorphins, and β-endorphins, are derived from proenkephalin, prodynorphin, and proopiomelanocortin, respectively. Recently, a new group of peptides called endomorphins (-1 and -2), with atypical structure and high selectivity for the μ-opioid receptor, has been discovered. Another group of endogenous opioids is derived from pronociceptin, acting on the ORL1 receptor. Three members of the opioid receptor family were cloned in the early 1990s: first the δ-receptor in mice (DOR1), followed by the μ (MOR1) and κ (KOR1) receptors. These three receptors belong to the seven-transmembrane domain superfamily, coupled to G proteins, and share significant structural similarities <ref>Zimmermann M. Central nervous mechanisms modulating pain-related information: do they become deficient after lesion of the peripheral or central nervous system? In: Casey, KL (Ed.) Pain and Central Nervous System Disease: The Central Pain Syndromes. Raven Press, New York, 1991; pp.183-199.</ref>. | **Opioids**. The main groups of opioid peptides, enkephalins, dynorphins, and β-endorphins, are derived from proenkephalin, prodynorphin, and proopiomelanocortin, respectively. Recently, a new group of peptides called endomorphins (-1 and -2), with atypical structure and high selectivity for the μ-opioid receptor, has been discovered. Another group of endogenous opioids is derived from pronociceptin, acting on the ORL1 receptor. Three members of the opioid receptor family were cloned in the early 1990s: first the δ-receptor in mice (DOR1), followed by the μ (MOR1) and κ (KOR1) receptors. These three receptors belong to the seven-transmembrane domain superfamily, coupled to G proteins, and share significant structural similarities <ref>Zimmermann M. Central nervous mechanisms modulating pain-related information: do they become deficient after lesion of the peripheral or central nervous system? In: Casey, KL (Ed.) Pain and Central Nervous System Disease: The Central Pain Syndromes. Raven Press, New York, 1991; pp.183-199.</ref>. | ||
These receptors and peptides are significantly involved in antinociception processes and are found in nociceptive pathways. Peripheral inflammation affects central structures and alters opioid activity; on one hand, it increases the activity of some receptor antagonists, while on the other hand, it increases the affinity and number of μ receptors, enhancing the analgesic potency of opioids. This is achieved by altering the expression of certain genes in the dorsal horn of the spinal cord <ref>Zimmermann M. Central nervous mechanisms modulating pain-related information: do they become deficient after lesion of the peripheral or central nervous system? In: Casey, KL (Ed.) Pain and Central Nervous System Disease: The Central Pain Syndromes. Raven Press, New York, 1991; pp.183-199.</ref>. | These receptors and peptides are significantly involved in antinociception processes and are found in nociceptive pathways. Peripheral inflammation affects central structures and alters opioid activity; on one hand, it increases the activity of some receptor antagonists, while on the other hand, it increases the affinity and number of μ receptors, enhancing the analgesic potency of opioids. This is achieved by altering the expression of certain genes in the dorsal horn of the spinal cord <ref>Zimmermann M. Central nervous mechanisms modulating pain-related information: do they become deficient after lesion of the peripheral or central nervous system? In: Casey, KL (Ed.) Pain and Central Nervous System Disease: The Central Pain Syndromes. Raven Press, New York, 1991; pp.183-199.</ref>. | ||
Numerous studies have found evidence of the inefficient inhibition exerted by the endogenous opioid system in neuropathic pain and related hyperalgesia; indeed, both this system and the descending inhibitory system may be inadequate for controlling pain at the spinal level. The spinal pain transmission system is under continuous control from the basal nuclei, particularly the periaqueductal gray matter and the locus coeruleus. Zimmermann and colleagues have shown that in animals with neuropathy, although these inhibitory systems are still functioning, they provide less than 50% of the normal inhibition <ref>Zimmermann M. Central nervous mechanisms modulating pain-related information: do they become deficient after lesion of the peripheral or central nervous system? In: Casey, KL (Ed.) Pain and Central Nervous System Disease: The Central Pain Syndromes. Raven Press, New York, 1991; pp.183-199.</ref>; similarly, Porreca and colleagues have demonstrated tonic facilitation in pain transmission in the dorsal horn of the spinal cord in neuropathic animals, driven by neurons located in the ventromedial medulla <ref>Porreca et al. Inhibition of neuropathic pain by selective ablation of brainstem medullary cells expressing the μ-opioid receptor. J Neurosci 2001; 21: 5281-5288.</ref>. | Numerous studies have found evidence of the inefficient inhibition exerted by the endogenous opioid system in neuropathic pain and related hyperalgesia; indeed, both this system and the descending inhibitory system may be inadequate for controlling pain at the spinal level. The spinal pain transmission system is under continuous control from the basal nuclei, particularly the periaqueductal gray matter and the locus coeruleus. Zimmermann and colleagues have shown that in animals with neuropathy, although these inhibitory systems are still functioning, they provide less than 50% of the normal inhibition <ref>Zimmermann M. Central nervous mechanisms modulating pain-related information: do they become deficient after lesion of the peripheral or central nervous system? In: Casey, KL (Ed.) Pain and Central Nervous System Disease: The Central Pain Syndromes. Raven Press, New York, 1991; pp.183-199.</ref>; similarly, Porreca and colleagues have demonstrated tonic facilitation in pain transmission in the dorsal horn of the spinal cord in neuropathic animals, driven by neurons located in the ventromedial medulla <ref>Porreca et al. Inhibition of neuropathic pain by selective ablation of brainstem medullary cells expressing the μ-opioid receptor. J Neurosci 2001; 21: 5281-5288.</ref>. | ||
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In conclusion, while there is limited evidence of changes in the intensity or quality of wind-up in experimental animal models, it is well observed in patients with neuropathic pain, although it is present in less than 50% of these patients <ref>Thompson SWN, Woolf CJ, Sivilotti LG. Small caliber afferent inputs produce a heterosynaptic facilitation of the synaptic responses evoked by primary afferent A-fibers in the neonatal rat spinal cord in vitro. J Neurophysiol 1993; 69: 2116-2128.</ref>. | In conclusion, while there is limited evidence of changes in the intensity or quality of wind-up in experimental animal models, it is well observed in patients with neuropathic pain, although it is present in less than 50% of these patients <ref>Thompson SWN, Woolf CJ, Sivilotti LG. Small caliber afferent inputs produce a heterosynaptic facilitation of the synaptic responses evoked by primary afferent A-fibers in the neonatal rat spinal cord in vitro. J Neurophysiol 1993; 69: 2116-2128.</ref>. | ||
**Nitric Oxide Synthase (NOS), Heme Oxygenase (HO), and Reactive Oxygen Species (ROS) activity** | ** Nitric Oxide Synthase (NOS), Heme Oxygenase (HO), and Reactive Oxygen Species (ROS) activity** | ||
Local inflammation resulting from peripheral nerve injury plays an important role in neuropathic pain. Levy and Zochodne demonstrated the presence of endothelial and neuronal NOS immunoreactivity near the nerve lesion within 48 hours of the injury; additionally, late reactivity for the inducible isoform of NOS (iNOS) was noted 7 and 14 days after the lesion <ref>Levy D, Zochodne DW. Local nitric oxide synthase activity in a model of neuropathic pain. Eur J Neurosci 1998; 10: 1846-1855.</ref>; these findings were confirmed by Cizkova and collaborators <ref>Cizkova D et al. Neuropathic pain is associated with alterations of nitric oxide synthase immunoreactivity and catalytic activity in dorsal root ganglia and spinal dorsal horn. Brain Res Bull 2002; 58: 161-171.</ref>. | Local inflammation resulting from peripheral nerve injury plays an important role in neuropathic pain. Levy and Zochodne demonstrated the presence of endothelial and neuronal NOS immunoreactivity near the nerve lesion within 48 hours of the injury; additionally, late reactivity for the inducible isoform of NOS (iNOS) was noted 7 and 14 days after the lesion <ref>Levy D, Zochodne DW. Local nitric oxide synthase activity in a model of neuropathic pain. Eur J Neurosci 1998; 10: 1846-1855.</ref>; these findings were confirmed by Cizkova and collaborators <ref>Cizkova D et al. Neuropathic pain is associated with alterations of nitric oxide synthase immunoreactivity and catalytic activity in dorsal root ganglia and spinal dorsal horn. Brain Res Bull 2002; 58: 161-171.</ref>. | ||
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Khalil and Khodr studied the effects of reactive oxygen and nitrogen species on nerve lesion healing in rodents by measuring xanthine oxidase (XO) and lipoperoxidase (LPO) activity: XO was more active in the young population (+400% compared to control), while LPO was higher in the older population (+300% compared to control). In the younger population, healing was more frequent and occurred after the fifth week, whereas in the older population, healing occurred less frequently after the ninth or tenth week, with persistent symptoms. Early or late administration of the antioxidant tirilazad mesylate (20 mg/kg) reduced LPO levels with contrasting effects, depending on the timing of administration: it either prolonged or reduced thermal hyperalgesia, respectively. These results led the authors to conclude that reactive oxygen and nitrogen species may be responsible for delayed healing in older individuals but are still necessary for healing itself: early administration of antioxidants may negatively affect nerve lesion repair <ref>Khalil Z, Khodr B. A role for free radicals and nitric oxide in delayed recovery in aged rats with chronic constriction nerve injury. Free Rad Biol Med 2001; 31: 430-439.</ref>. | Khalil and Khodr studied the effects of reactive oxygen and nitrogen species on nerve lesion healing in rodents by measuring xanthine oxidase (XO) and lipoperoxidase (LPO) activity: XO was more active in the young population (+400% compared to control), while LPO was higher in the older population (+300% compared to control). In the younger population, healing was more frequent and occurred after the fifth week, whereas in the older population, healing occurred less frequently after the ninth or tenth week, with persistent symptoms. Early or late administration of the antioxidant tirilazad mesylate (20 mg/kg) reduced LPO levels with contrasting effects, depending on the timing of administration: it either prolonged or reduced thermal hyperalgesia, respectively. These results led the authors to conclude that reactive oxygen and nitrogen species may be responsible for delayed healing in older individuals but are still necessary for healing itself: early administration of antioxidants may negatively affect nerve lesion repair <ref>Khalil Z, Khodr B. A role for free radicals and nitric oxide in delayed recovery in aged rats with chronic constriction nerve injury. Free Rad Biol Med 2001; 31: 430-439.</ref>. | ||
== Neuronal Apoptosis in Neuropathies == | ==Neuronal Apoptosis in Neuropathies == | ||
Apoptosis is defined as programmed cell death, a phenomenon in which a cell, whether damaged or not, undergoes a series of events, either spontaneously or induced, that culminate in the disintegration of DNA and the compaction of cytological material into elements that can be easily phagocytosed by neighboring cells. Naturally, for it to be termed "programmed," there must be genetic elements regulating the process; among these are the proto-oncogenes jun, fos, bcl-2, and bax. Dysfunction of these genes and their products is involved in the pathogenesis of neoplasms, particularly in cell immortalization (Fig.1). | Apoptosis is defined as programmed cell death, a phenomenon in which a cell, whether damaged or not, undergoes a series of events, either spontaneously or induced, that culminate in the disintegration of DNA and the compaction of cytological material into elements that can be easily phagocytosed by neighboring cells. Naturally, for it to be termed "programmed," there must be genetic elements regulating the process; among these are the proto-oncogenes jun, fos, bcl-2, and bax. Dysfunction of these genes and their products is involved in the pathogenesis of neoplasms, particularly in cell immortalization (Fig.1). | ||
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Following axonal injury, some neurons in the dorsal root ganglia undergo apoptosis, resulting in deafferentation of postsynaptic spinal neurons. These in turn degenerate due to the lack of tonic inhibitory stimulation of apoptosis normally exerted by the presynaptic neuron. The preventive administration of MK-801, a competitive NMDAR antagonist, prevents cell death due to axotomy in nearly all cases <ref>Lopez-Garcia JA, King AE. Neuronal cell death after peripheral nerve injury and the role of NMDAR activation. J Neurosci 1997; 17: 4325-4332.</ref>. | Following axonal injury, some neurons in the dorsal root ganglia undergo apoptosis, resulting in deafferentation of postsynaptic spinal neurons. These in turn degenerate due to the lack of tonic inhibitory stimulation of apoptosis normally exerted by the presynaptic neuron. The preventive administration of MK-801, a competitive NMDAR antagonist, prevents cell death due to axotomy in nearly all cases <ref>Lopez-Garcia JA, King AE. Neuronal cell death after peripheral nerve injury and the role of NMDAR activation. J Neurosci 1997; 17: 4325-4332.</ref>. | ||
Furthermore, Whiteside and Munglani have demonstrated that, following chronic nerve ligation injury, hyperalgesia develops in parallel with neuronal apoptosis. The administration of MK-801 prevents the former and significantly reduces the latter; from this, the authors suggest that apoptosis may contribute to the development and maintenance of hyperalgesia <ref>Whiteside GT, Munglani R. NMDAR antagonism prevents both the hyperalgesia and apoptosis induced by peripheral nerve injury. Pain 2001; 89: 287-294.</ref>. | Furthermore, Whiteside and Munglani have demonstrated that, following chronic nerve ligation injury, hyperalgesia develops in parallel with neuronal apoptosis. The administration of MK-801 prevents the former and significantly reduces the latter; from this, the authors suggest that apoptosis may contribute to the development and maintenance of hyperalgesia <ref>Whiteside GT, Munglani R. NMDAR antagonism prevents both the hyperalgesia and apoptosis induced by peripheral nerve injury. Pain 2001; 89: 287-294.</ref>. | ||
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