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Difference between revisions of "Pain Pathophysiology"
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(Created page with "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 deitie...") |
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Although morphine is not able to exert its efficacy in neuropathic pain, a wide range of evidence suggests that it is not completely resistant, but only shows reduced sensitivity, and higher doses are needed to achieve the same response <ref>Mayer DJ, Mao J, Price DD. The development of morphine tolerance and dependence is associated with translocation of protein kinase C. Pain 1995; 61: 365-374.</ref>. Mayer and colleagues demonstrated that a nerve injury induced 8 days before the morphine test caused the dose-response curve to shift towards higher doses, by a factor of 6, meaning six times higher doses were needed to achieve the same response as in the control. Of particular interest is the fact that pretreatment with an NMDA receptor inhibitor (MK-801) prevents desensitization to morphine <ref>Mayer DJ, Mao J, Price DD. The development of morphine tolerance and dependence is associated with translocation of protein kinase C. Pain 1995; 61: 365-374.</ref>. | Although morphine is not able to exert its efficacy in neuropathic pain, a wide range of evidence suggests that it is not completely resistant, but only shows reduced sensitivity, and higher doses are needed to achieve the same response <ref>Mayer DJ, Mao J, Price DD. The development of morphine tolerance and dependence is associated with translocation of protein kinase C. Pain 1995; 61: 365-374.</ref>. Mayer and colleagues demonstrated that a nerve injury induced 8 days before the morphine test caused the dose-response curve to shift towards higher doses, by a factor of 6, meaning six times higher doses were needed to achieve the same response as in the control. Of particular interest is the fact that pretreatment with an NMDA receptor inhibitor (MK-801) prevents desensitization to morphine <ref>Mayer DJ, Mao J, Price DD. The development of morphine tolerance and dependence is associated with translocation of protein kinase C. Pain 1995; 61: 365-374.</ref>. | ||
Studies on the molecular processes of opioid regulation, tolerance, and dependence have shown that nitric oxide (NO) is closely linked to these mechanisms: not only do opioids influence NO release, but NO itself also participates in the processes of tolerance and dependence. In the first case, it has been shown that chronic pain activates NMDA receptors, allowing calcium entry, which activates Nitric Oxide Synthase (NOS) and, downstream, guanylate cyclase. The increase in cGMP causes thermal and mechanical hyperalgesia, and tactile allodynia. On the other hand, chronic activation of μ-opioid receptors causes PKC translocation, which phosphorylates NMDA receptors, increasing calcium levels and activating NOS; in this case, NO induces tolerance and dependence. This theory has been confirmed by studies in rodents that have demonstrated significant reductions in hyperalgesia, allodynia, and tolerance following the administration of NOS inhibitors such as Agmatine and N(G)-nitro-L-arginine methyl ester (L-NAME). Interestingly, these desensitization mechanisms do not occur with endomorphins, indicating the existence of different pathways for these molecules <ref>Mayer DJ, Mao J, Price DD. The development of morphine tolerance and dependence is associated with translocation of protein kinase C. Pain 1995; 61: 365-374.</ref>. | Studies on the molecular processes of opioid regulation, tolerance, and dependence have shown that nitric oxide (NO) is closely linked to these mechanisms: not only do opioids influence NO release, but NO itself also participates in the processes of tolerance and dependence. In the first case, it has been shown that chronic pain activates NMDA receptors, allowing calcium entry, which activates Nitric Oxide Synthase (NOS) and, downstream, guanylate cyclase. The increase in cGMP causes thermal and mechanical hyperalgesia, and tactile allodynia. On the other hand, chronic activation of μ-opioid receptors causes PKC translocation, which phosphorylates NMDA receptors, increasing calcium levels and activating NOS; in this case, NO induces tolerance and dependence. This theory has been confirmed by studies in rodents that have demonstrated significant reductions in hyperalgesia, allodynia, and tolerance following the administration of NOS inhibitors such as Agmatine and N(G)-nitro-L-arginine methyl ester (L-NAME). Interestingly, these desensitization mechanisms do not occur with endomorphins, indicating the existence of different pathways for these molecules <ref>Mayer DJ, Mao J, Price DD. The development of morphine tolerance and dependence is associated with translocation of protein kinase C. Pain 1995; 61: 365-374.</ref>. | ||
**BDNF: neuromodulator** | |||
During development, brain-derived neurotrophic factor (BDNF) supports the survival of a neuronal population in both the central and peripheral nervous systems. In maturity, BDNF appears to act as an important modulator of synaptic plasticity. BDNF is synthesized by primary sensory neurons (presynaptic neurons) whose expression is regulated in models of inflammatory and neuropathic pain. The high-affinity receptor for BDNF, tropomyosine receptor kinase B (TrkB), is expressed by postsynaptic neurons in the dorsal horn of the spinal cord. Stimulation of presynaptic nociceptive afferent fibers induces the release of BDNF and the consequent activation of TrkB receptors, leading to postsynaptic excitability. Electrophysiological recordings in vitro show that BDNF increases discharge potential induced by stimulation of C fibers in ventral roots. Additionally, behavioral data indicate that BDNF exerts antagonism by attenuating both the second phase of hyperalgesia induced by formalin (in animals treated with NGF) and the thermal hyperalgesia induced by carrageenan antigen: this suggests that BDNF is involved in some aspects of central sensitization under conditions of peripheral inflammation. In conclusion, BDNF meets many of the criteria needed to be defined as a neurotransmitter/neuromodulator in small-diameter nociceptive neurons <ref>Pezzet S, Malcangio M, McMahon SB. BDNF: a neuromodulator in nociceptive pathways? Brain Res Rew 2002; 40: 240-249.</ref>. | |||
**Wind-up and neuropathic pain** | |||
In recent years, numerous experimental models of neuropathic pain have been developed, and the multiple changes characterizing spinal neurons have been studied, yet very few have emphasized the wind-up phenomenon. Dorsal horn neurons in animals with experimental mononeuropathy exhibit normal wind-up to electrical stimulation of C fibers. Some have shown reduced sensitivity to wind-up after dizocilpine administration, an NMDAR inhibitor. | |||
In a group of 16 patients with neuropathic pain from spinal cord injury, repeated stimulation with a von Frey filament revealed wind-up-like pain more commonly in denervated and painful skin areas than in denervated but non-painful areas <ref>Eide et al. Somatosensory findings in patients with spinal cord injury and central dysesthesia pain. J Neurol Neurosurg Psychiat 1996; 60: 411-415.</ref>. | |||
Similarly, Price and colleagues report temporal summation with repeated von Frey filament stimulation in some patients with areas of mechanical hyperalgesia or tactile allodynia; these patients also demonstrated greater intensity of wind-up-like pain <ref>Price et al. Sensory testing of pathophysiological mechanisms of pain in patients with reflex sympathetic dystrophy. Pain 1992; 49:163-173.</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** | |||
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>. | |||
Heme oxygenase is an enzyme that catalyzes the formation of biliverdin and iron and carbon monoxide monoxides through the heme structure. In humans, two isoforms have been identified: HO-1 and HO-2, the latter of which is present in both neurons and glial cells in the CNS <ref>Snyder SH, Jaffrey SR, Zakhary R. Nitric oxide and carbon monoxide: parallel roles as neural messengers. Brain Res Rev 1998; 26:167-175.</ref>. | |||
Both of these enzymes produce highly toxic substances (nitric oxide and carbon monoxide) but play a role as neuromediators in the CNS <ref>Liang D et al. Heme oxygenase type 2 modulates behavioral and molecular changes during chronic exposure to morphine. Neuroscience 2003; 121: 999-1005.</ref>. These two mediators are described in the literature for their influence on opioid dependence and tolerance phenomena, as well as hyperalgesia. | |||
Similar results have been reported using various techniques: Liang and colleagues first used NOS and HO-2 inhibitors and then molecular biology techniques to demonstrate that these enzymes independently modulate the molecular changes that occur during chronic opioid exposure, tolerance, and the resulting behavioral alterations. Activation of the NOS system by chronic morphine stimulation limits the analgesic capacity of the opioid; additionally, NOS knock-out rodents exhibit reduced hyperalgesia. Similarly, HO-2 knock-out rodents show reduced mechanical allodynia after withdrawal from chronic morphine therapy; while wild-type rodents (not genetically altered) exhibit two- to three-fold increased expression of NOS, NMDAR, and prodynorphin. Morphine administration increases cGMP levels in spinal neurons, and cGMP analogs cause hyperalgesia. Administration of NOS and HO-2 inhibitors significantly reduces cGMP production induced by morphine and the resulting hyperalgesia <ref>Liang D et al. Heme oxygenase type 2 modulates behavioral and molecular changes during chronic exposure to morphine. Neuroscience 2003; 121: 999-1005.</ref> <ref>Li X et Clark JD. Spinal cord nitric oxide synthase and heme oxygenase limit morphine-induced analgesia. Molecular Brain Research 2001; 95: 96-102.</ref>. | |||
These data collectively demonstrate that NOS and HO alter opioid action and open new therapeutic strategies. | |||
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 == | |||
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). | |||
The induction of c-jun by NGF seems to have dual properties, both in axonal regeneration and in programmed cell death. Studies on the bcl-2 oncogene have shown that its intense expression protects neurons from cell death following axotomy, while the Bax protein promotes apoptosis. In reality, these proteins interact in regulating these processes, so the expression ratio between Bax and Bcl-2 determines whether apoptosis progresses. The c-Jun protein is a regulator of the expression of Bax and Bcl-2 and is itself controlled by jun kinase (JNK): phosphorylation of c-Jun facilitates apoptosis, whereas the non-phosphorylated form promotes neuronal regeneration <ref>Grilli M, Memo M. Apoptosis: Unraveling the mystery of programmed cell death in the nervous system. Prog Neurobiol 1999; 59: 287-312.</ref><ref>Ham J, Babij C, Whitfield J. Activation of c-Jun N-terminal kinase in dorsal root ganglion neurons following axotomy. J Neurosci 1997; 17: 6464-6472.</ref>. | |||
Some data suggest that, in chronic pain, specific genes involved in apoptosis are active, contributing to critical changes in cell survival and the establishment of chronic pain states <ref>Ham J, Babij C, Whitfield J. Activation of c-Jun N-terminal kinase in dorsal root ganglion neurons following axotomy. J Neurosci 1997; 17: 6464-6472.</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>. | |||
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