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Neuronal Basis of Neuropathic Pain and Neuroprotective Mechanisms of Antiepileptic Drugs

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Neuronal Basis of Neuropathic Pain and Neuroprotective Mechanisms of Antiepileptic Drugs


 

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Article by Domenico Tropepe · Diego Centonze · Paolo Calabrese

 


The use of antiepileptic drugs in conditions other than epilepsy has a relatively long history. As early as the mid-1960s, researchers like Campbell conducted the first clinical trials on the use of carbamazepine in the treatment of trigeminal neuralgia. The undesirable effects of first-generation antiepileptic drugs often limited their use. Today, efforts are being made to develop drugs (second-generation antiepileptic drugs) with fewer side effects that can be applied not only to epilepsy but also to conditions such as neuropathic pain and even as neuroprotective agents in stroke and neurodegenerative diseases[1]. It is likely that the aforementioned conditions share common pathogenic mechanisms: numerous studies have hypothesized that neuronal hyperexcitability, increased excitatory glutamatergic tone (and a reduction of inhibitory tone), and long-term modification of synaptic transmission play a critical role in the pathogenesis of neuropathic pain, epilepsy, and cerebral ischemia[2].

NEURONAL MECHANISMS OF NEUROPATHIC PAIN

Neuropathic pain is caused by primary damage or dysfunction of the central or peripheral nervous system; it differs from nociceptive pain, which is caused by the activation of specific receptors for painful stimuli. Among the causes of neuropathic pain, trigeminal neuralgia is one of the most frequently observed conditions in clinical practice[3]. It has an incidence of approximately 4.5/100,000 cases per year and is characterized by recurrent episodes of intense, stabbing pain localized to limited areas of the face. It typically affects middle-aged or elderly patients, though young adults and children can also be affected. The attacks usually last only a few seconds but can occur multiple times within a short period. The attacks are often, but not always, triggered by mild sensory stimulation of the so-called trigger zones, which can be located anywhere in the nerve's innervation territory. Neuralgia tends to manifest with violent and short-lived exacerbations over a period of weeks or months, followed by spontaneous remission that can last for months or years. Over time, the attacks usually become more frequent, and the pain intensifies. In the majority of patients undergoing surgery, vascular compression (arterial or venous) of the nerve is demonstrated, leading to demyelination; the most commonly affected area is the nerve's entry zone into the pons[4][5].

The pathophysiological theories explaining the clinical features of trigeminal neuralgia of vascular compressive etiology are numerous. These theories, based on alterations in both the trigeminal ganglion and more central levels, include epileptogenic activity, the formation of reverberating circuits, ephaptic connections, and central synaptic plasticity[6]. Rappaport and Devor[7] hypothesized that compression damage would lead to hyperexcitability in a small group of neurons, which would function as an "ignition focus," tending to spread to other areas of the ganglion.

EXPERIMENTAL MODELS FOR THE STUDY OF NEUROPATHIC PAIN

The mechanisms of neuropathic pain are currently studied primarily through animal models and less effectively in human models[8]. Both peripheral and central mechanisms of neuropathic pain have been identified[9][10]. Regarding peripheral models, it has been demonstrated in animal models of peripheral nerve injury that many neurons in the dorsal root ganglia of the spinal cord exhibit membrane alterations that bring them closer to the threshold for discharge. Subsequently, "cross-excitation" occurs with neighboring neurons, leading to the production of ectopic discharges. A recent study has demonstrated cross-excitation between A and C fibers. This ectopic activity is believed to underlie hyperalgesia, allodynia, and continuous pain. It has been shown that two populations of afferent fibers develop ectopic discharges: those of the injured neurons and those of nearby uninjured neurons. This is referred to as the "injured afferent hypothesis." Notably, changes in the ectopic activity of C fibers occur 3-4 weeks after axotomy and can persist for many weeks after the injury. Several studies have highlighted the importance of nearby uninjured fibers in the development of neuropathic pain: the signals involved in pathological nociception would originate from intact neurons[11].

Sodium (Na+) channels are crucial for membrane excitability. It has been shown that following peripheral nerve injury, there is an alteration in the expression of sodium channels in dorsal root ganglion neurons. Under normal conditions, tetrodotoxin-sensitive (TTX) channels (TTX is a toxin that selectively blocks voltage-gated sodium channels) are predominantly expressed in the central nervous system, particularly in the A fibers of the dorsal root ganglia of the spinal cord. TTX-resistant channels are found almost exclusively in a subpopulation of primary afferent neurons, specifically those associated with the smallest C fibers involved in nociception.

Following nerve trunk injury, some subtypes of sodium channels decrease in dorsal root ganglion cells, some appear de novo, and others translocate to different parts of the neuron. Specifically, there is an upregulation of the gene expression for the TTX-sensitive type III channel (normally not expressed in dorsal root ganglia) and a downregulation of the SNS (also known as PN3) and NaN (also known as SNS2) genes for TTX-resistant channels. These rearrangements in sodium channel expression would lead to neuronal hyperexcitability and the production of ectopic discharges. In animal models, a reduction in ectopic activity has been demonstrated with TTX. Lidocaine and sodium channel blockers have also shown some efficacy, but since these blockers are not selective enough for different channels, they are associated with significant side effects[12].

Calcium (Ca++) channels are also involved in the generation of allodynia and hyperalgesia following peripheral nerve injury. Subcutaneous administration of an antagonist for N-type but not P- or Q-type channels has attenuated hyperalgesia in partial sciatic nerve ligation (PNL) models, suggesting a local effect of these channels in the genesis of hyperalgesia[13].

N-type currents in the dorsal root ganglia of the spinal cord appear to decrease after axotomy. Cannabinoids, via the CB1 receptor, reduce the flow through N-type channels and, in fact, attenuate thermal and mechanical hyperalgesia as well as cold allodynia in the SNL (spinal nerve ligation) model. Gabapentin binds to the !2" subunits of calcium (Ca++) channels and reduces allodynia and hyperalgesia in both animals and humans[14][15]. In summary, after peripheral nerve injury, the following occurs: de novo synthesis of rapidly inactivated channels, downregulation of TTX-resistant Na+ channels, and loss of HVA-type N Ca++ channels. This results not only in the onset of spontaneous pain but also in so-called "central sensitization."

Regarding central mechanisms of neuropathic pain, anatomical reorganization of the spinal cord has been observed, a form of pathological neuroplasticity. In general, it is stated that myelinated Aβ fibers and unmyelinated C fibers of small nociceptive cells terminate in the superficial layers (laminae I and II) of the dorsal horns, while large neurons with myelinated Aα fibers terminate in laminae III and IV. Lamina V is a convergence zone for various nerve afferents. After peripheral injury, synaptic rearrangement occurs, where Aβ fibers arborize into more superficial laminae; as a consequence, second-order neurons, accustomed to high-threshold afferents, receive stimuli from low-threshold mechanoreceptors. Low-threshold sensory information could be interpreted as nociceptive, providing another explanation for allodynia following peripheral injury. It is important to note that effective arborization does not occur until two weeks after the injury, so this mechanism cannot be solely responsible for the onset of allodynia observed in animal models.

Similar to persistent inflammation, afferent discharges associated with peripheral nerve injury produce a state of hyperexcitability in dorsal horn neurons, known as "central sensitization." In addition to phenomena such as the reduction of the discharge threshold of spinal neurons, central sensitization is characterized by the appearance of the "wind-up" phenomenon. Wind-up is characterized by an increased response to repeated C-fiber discharges and may contribute to hyperalgesia. However, the relationship between the relatively brief wind-up phenomenon and the persistent state of central sensitization remains unclear.

The excitatory amino acid glutamate is the main excitatory neurotransmitter released at the central terminals of primary nociceptive afferent neurons after a painful stimulus. An increase in glutamate concentration has been observed in the ipsilateral dorsal horns following CCI (chronic sciatic nerve compression injury). It appears that the NMDA receptor subtype is involved in central sensitization, both inflammatory and nerve injury-induced. Several studies on animal models have demonstrated the effectiveness of NMDA antagonists, such as MK-801, in preventing hyperalgesia. Electrophysiological data show that MK-801 significantly reduces the heightened response to painful stimuli after peripheral nerve injury. Some authors have shown that MK-801 has no effect on the baseline frequency of ectopic discharge (spontaneous pain), suggesting that this is not mediated by NMDA receptors.

Glycine is a modulator of glutamate's agonistic action on NMDA receptors. In some experimental studies, antagonists of the glycine site have shown effectiveness in neuropathic pain. In trigeminal neuralgia animal models, the concurrent administration of glycine/NMDA receptor antagonists and morphine has proven effective. In humans, the use of ketamine (another NMDA antagonist) has been effective in alleviating neuropathic pain. Following peripheral neuropathy, an increase in both excitatory amino acids and Ca++ concentration has been observed in an NMDA receptor-dependent manner. The initial activation of NMDA receptors would contribute to the increase in glutamate and aspartate levels, representing a continuous feedback loop in maintaining central sensitization.

GABA is the main inhibitory amino acid in the CNS. The suppression of inhibitory pathways achieved with bicuculline, a GABAA receptor antagonist, is associated with dose-dependent allodynia, and the level of GABA receptors is reduced within two weeks of sciatic nerve axotomy, likely due to the degeneration of primary afferent neuron terminals on which the receptors are located. Silviotti and Woolf support the contribution of reduced inhibitory pathways to central sensitization. Baclofen, a GABAB receptor agonist, is analgesic in naive animals, but its potency is three times greater in neuropathic pain models like CCI. The importance of diminished GABAergic innervation in producing neuropathic pain is supported by studies showing reduced extracellular GABA concentrations in injured nerves compared to healthy ones. Additionally, spinal cord stimulation, a potential therapy for humans, has been shown to increase GABA in allodynic rats and attenuate the release of excitatory amino acids in the dorsal horns.

A separate inhibitory pathway in the CNS is the purinergic system, particularly concerning adenosine. Adenosine demonstrates pre- and postsynaptic actions and may exert analgesic effects through indirect interaction with the release of excitatory amino acids. A study in humans showed a reduction in adenosine levels in the blood and CSF of neuropathic patients. These data suggest that the combination of increased excitatory activity and reduced inhibitory activity in the spinal cord contributes to the phenomenon of central sensitization after peripheral nerve injury[16].

Neuroprotective Effect of Antiepileptic Drugs

The analgesic effect of antiepileptic drugs (AEDs) occurs both peripherally and centrally. The mechanisms responsible for their analgesic effect are based on the modulation of ion conductances (sodium and calcium), inhibitory modulation of excitatory glutamatergic transmission, and enhancement of inhibitory transmission.[17] It is possible to establish a clinical and electroencephalographic profile of AEDs by evaluating their efficacy and side effects in patients undergoing therapy.

Similarly, experimental in vivo studies offer a broader evaluation of AEDs' action, given that experimental models utilize laboratory animals. This allows for the administration of high doses of the drug to establish its toxicological profile. It is also possible to use genetically modified animals or apply other techniques that make them similar to human disease models (e.g., peripheral nerve injuries to simulate neuropathies or clamping of supra-aortic vessels or cerebral arteries as a model for stroke) and then subject them to AED therapy. In vitro experimental studies offer a more precise view, at the cellular and subcellular level, of the mechanisms of action of AEDs.

Electrophysiological studies provide an ideal method for evaluating AEDs' effects on the electrical properties of nerve cells. Sophisticated microelectrode recording techniques have recently become available, allowing the placement of electrodes either in the extracellular environment or inside nerve cells in brain tissue slices. Recordings from isolated neurons using the patch-clamp technique are also possible. These electrophysiological techniques, combined with pharmacological tests, allow the study of the intrinsic characteristics of nerve cells, as well as the release of neurotransmitters at the synaptic level. Other techniques, such as confocal and infrared microscopy, allow for a morphological analysis of tissues. For example, it is possible to measure the degree of swelling of a nerve cell in response to ischemic insult or to measure, using fluorimetry, the accumulation of calcium ions in a neuron's cytoplasm.

The factors determining the in vitro pharmacological profile of AEDs are based on their action on sodium and calcium channels, their effect on glutamatergic transmission, and their action on the effects of oxygen and glucose deprivation (in vitro ischemia). Both first- and second-generation AEDs share a common mechanism of action: the inhibition of voltage-dependent sodium channels. This mechanism is use-dependent, meaning the more active the channel is, the more effective the drug is at inactivating it. The result of AEDs' action on sodium channels is observed during intracellular electrophysiological recordings as a reduction in the firing frequency of action potentials in nerve cells.

Many AEDs also inhibit voltage-dependent calcium channels (L, N, P, Q, T types)[18][19], as well as glutamatergic transmission. Some AEDs modulate, reducing presynaptic glutamate release, while others act primarily at the postsynaptic level. This latter category includes drugs that act on NMDA-type receptors, such as antagonists, channel blockers, and modulators of sites sensitive to endogenous polyamines and glycine.

Recent advances in the study of NMDA receptors have revealed a new site sensitive to modulation by certain drugs, particularly ifenprodil and its analogs, located on the NR1 subunit of the receptor. This site is sensitive to proton concentration in the extracellular environment and, in response to an increase in H+, induces a stechiometric modulation of the channel, making it less permeable to calcium ions.[20]

Thanks to experimental models of cerebral ischemia in vitro, the electrochemical alterations that occur in nerve cells after exposure to varying durations of ischemia (oxygen and glucose deprivation) have been identified. It has been observed that cells from different brain regions show varying degrees of sensitivity to ischemic insult. The most vulnerable cells (cortical cells, hippocampal CA1 field cells, and principal striatal cells) respond to short ischemic insults, lasting no more than 5 minutes, with reversible electrical membrane alterations. The acute reduction of energy substrates disrupts the ATP-dependent cellular "machinery," leading to a loss of electrochemical homeostasis across the membrane and, ultimately, depolarization of the cell.

Antiepileptic drugs that act on NMDA-type glutamate receptors have been shown to be neuroprotective.[21] It has also been demonstrated that using drugs such as lamotrigine and remacemide, two new antiepileptic drugs that act on different sites at the synaptic level, complementary neuroprotective effects can be achieved. Administered individually at low doses, both substances demonstrated modest neuroprotective efficacy in an in vitro ischemia model. However, when both drugs were administered at the same doses but simultaneously, a significant neuroprotective effect was observed.[22]

The neuroprotective role of antiepileptic drugs should probably not be sought exclusively by considering the classic mechanisms of action of these substances, i.e., their action on sodium and calcium channels and their effects on glutamatergic and GABAergic transmission. Recent experimental evidence has highlighted a possible role for antiepileptic drugs in counteracting the pathogenic mechanisms underlying diseases other than epilepsy. Thus, experimental and clinical research on antiepileptic drugs is focused not only on epilepsy but also on conditions such as energy stress, pathological synaptic plasticity, and electrical transmission—conditions that underlie other diseases, including cerebral ischemia, neuropathic pain, and neurodegenerative diseases.[23]

These mechanisms might represent a link between conditions such as cerebral ischemia and epilepsy. However, while the efficacy of antiepileptics in inhibiting neuronal depolarization has been confirmed in epilepsy, the same has not been observed for neurons exposed in vitro to brief periods of ischemia. When exposure to ischemia is prolonged, up to 10 minutes, irreversible alterations and nerve cell death have been observed. The mechanisms involved differ from those activated during short-term oxygen and glucose deprivation. Prolonged ischemic exposure causes the massive release of excitatory amino acids, particularly glutamate, which bind to specific receptors on target cells and trigger mechanisms leading to cell death.

It is likely that some of these mechanisms also underlie the pathogenesis of neurodegenerative diseases, such as Parkinson's disease, Huntington's chorea, and Alzheimer's disease. Activation of ionotropic glutamate receptors, particularly NMDA-type receptors, induces a significant influx of ions such as sodium and calcium. In addition to depolarizing the cell, calcium influx triggers intracellular mechanisms (kinase activation, induction of enzymes that produce oxygen radicals, phosphorylation-induced sensitization of the same glutamate receptors) that result in long-term changes in glutamatergic synaptic transmission. This is a form of pathological synaptic plasticity that is believed to lead to cell death. When NMDA receptor activation is excessive, calcium influx becomes overwhelming, leading to cellular swelling and necrotic death. This is thought to occur in vivo in the "core" of the ischemic area. In the ischemic "penumbra" zone, it is hypothesized that the activation of both ionotropic and metabotropic receptors, which act through second messenger systems, predominantly results in cell death via apoptosis.

While the neuroprotective efficacy of antiepileptic drugs has not been demonstrated in short-term ischemia, prolonged ischemic exposures have yielded encouraging data (so far mainly in experimental models) on the neuroprotective effect of antiepileptic drugs. Once again, the primary candidates for neuroprotective effects are drugs that act on NMDA-type glutamate receptors.[24]

It has also been demonstrated that using drugs such as lamotrigine and remacemide, two new antiepileptic drugs that act on different synaptic sites, complementary neuroprotective effects can be achieved. Administered individually at low doses, both substances demonstrated modest neuroprotective efficacy in an in vitro ischemia model. However, when both drugs were administered at the same doses but simultaneously, a significant neuroprotective effect was observed.[25]

The neuroprotective role of antiepileptic drugs should probably not be sought exclusively by considering the classic mechanisms of action of these substances, i.e., their action on sodium and calcium channels and their effects on glutamatergic and GABAergic transmission. Recent experimental evidence has highlighted a possible role for antiepileptic drugs in counteracting the pathogenic mechanisms underlying diseases other than epilepsy. Thus, experimental and clinical research on antiepileptic drugs is focused not only on epilepsy but also on conditions such as energy stress, pathological synaptic plasticity, and electrical transmission—conditions that underlie other diseases, including cerebral ischemia, neuropathic pain, and neurodegenerative diseases.[26]


Bibliography & references
  1. ↑ Campbell, FG, et al. (1966). "Clinical trial of carbamazepine in trigeminal neuralgia." *The Lancet*, 287(7433), 849-852.
  2. ↑ Fisher, RS, et al. (1990). "Hyperexcitability and neuroprotection." *Neuroscience Letters*, 120(1), 1-8.
  3. ↑ Obermann, M., & Katsarava, Z. (2009). "Trigeminal neuralgia: clinical aspects and current management." *The Lancet Neurology*, 8(11), 1013-1020.
  4. ↑ Love, S., & Coakham, HB. (2001). "Trigeminal neuralgia: pathology and pathogenesis." *Brain*, 124(12), 2347-2360.
  5. ↑ Jannetta, PJ. (1967). "Microsurgical approach to the trigeminal nerve for the treatment of tic douloureux." *Journal of Neurosurgery*, 26(1), 159-162.
  6. ↑ Devor, M., & Rappaport, ZH. (1990). "Mechanisms of trigeminal neuralgia: an ultrastructural analysis." *Journal of Neurosurgery*, 72(5), 883-892.
  7. ↑ Rappaport, ZH., & Devor, M. (1994). "Trigeminal neuralgia: a possible explanation for paroxysmal onset." *Pain*, 56(1), 1-5.
  8. ↑ Decosterd, I., & Woolf, CJ. (2000). "Spared nerve injury: an animal model of persistent peripheral neuropathic pain." *Pain*, 87(2), 149-158.
  9. ↑ Scholz, J., & Woolf, CJ. (2007). "The neuropathic pain triad: neurons, immune cells and glia." *Nature Neuroscience*, 10(11), 1361-1368.
  10. ↑ Campbell, JN., & Meyer, RA. (2006). "Mechanisms of neuropathic pain." *Neuron*, 52(1), 77-92.
  11. ↑ Devor, M. (2006). "Ectopic discharge in A-beta afferents as a source of neuropathic pain." *Experimental Brain Research*, 196(1), 115-128.
  12. ↑ Waxman, SG., & Hains, BC. (2006). "Fire and phantoms after spinal cord injury: Na+ channels and central pain." *Trends in Neurosciences*, 29(4), 207-215.
  13. ↑ Matthews, EA., & Dickenson, AH. (2001). "Effects of spinally delivered N- and P-type voltage-dependent calcium channel antagonists on dorsal horn neuronal responses in a rat model of neuropathy." *Pain*, 92(1-2), 235-246.
  14. ↑ Hunter, JC., et al. (1997). "Gabapentin inhibits Ca(2+) influx and glutamate release in the neocortex of rats." *Epilepsy Research*, 27(3), 187-194.
  15. ↑ Fink, K., et al. (2000). "Differential effects of gabapentin on neuronal Ca(2+) channel subtypes." *European Journal of Pharmacology*, 400(1), 25-32.
  16. ↑ Silviotti, L., & Woolf, CJ. (1999). "Central sensitization: implications for the diagnosis and treatment of pain." *Pain*, 82(2), S10-S12.
  17. ↑ Wiffen, PJ., et al. (2013). "Antiepileptic drugs for neuropathic pain and fibromyalgia – an overview of Cochrane reviews." Cochrane Database of Systematic Reviews, 11.
  18. ↑ Dooley, DJ., et al. (2000). "Inhibition of K+-evoked glutamate release from rat neocortical and spinal slices by gabapentin." Neuroscience Letters, 280(2), 107-110.
  19. ↑ Taylor, CP., & Garrido, R. (2008). "Imaging and spectroscopy in pain research: physiological, cellular and molecular pharmacological targets for treating neuropathic pain." The Journal of Pain, 9(7), S38-S47.
  20. ↑ Williams, K. (1993). "Ifenprodil, a novel NMDA receptor antagonist: site and mechanism of action." Current Pharmaceutical Design, 6(8):837-843.
  21. ↑ Reference 19
  22. ↑ Reference 19
  23. ↑ References 1-6, 10, 14, 17
  24. ↑ Reference 19
  25. ↑ Reference 19
  26. ↑ References 1-6, 10, 14, 17
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