Sodium channel blockers for the treatment of neuropathic pain

Drugs that block voltage-gated sodium channels are efficacious in the management of neuropathic pain. Accordingly, this class of ion channels has been a major focus of analgesic research both in academia and in the pharmaceutical/biotechnology industry. In this article, we review the history of the use of sodium channel blockers, describe the current status of sodium channel drug discovery, highlight the challenges and hurdles to attain sodium channel subtype selectivity, and review the potential usefulness of selective sodium channel blockers in neuropathic pain.     

Voltage-gated sodium channel blockers as immunomodulators

Several Voltage-Gated Sodium Channels (VGSC) are widely expressed on lymphocytes and macrophages but their role in immune function is still debated. Nevertheless, Na(+) influx through VGSC is required for lymphocytes activation and proliferation, since these responses are blocked by Na(+)-free medium or by VGSC blockers. These effects may be mediated by the reduced intracellular Na(+) levels, which in turn may impair the activity of Na(+)/Ca(++) exchanger resulting in reduced intracellular Ca(++) levels during lymphocyte activation. Furthermore, in Jurkat cell line VGSC appear to be involved in cell volume regulation, migration in artificial matrix and cell death by apoptosis. VGSC play a role in macrophage function as well, and VGSC blockers impair both phagocytosis and inflammatory responses. Several VGSC blockers have shown immunomodulatory properties in mice models, skewing the immune response toward a Th2-mediated response, while suppressing Th1-mediated responses, and VGSC already used in clinical practice are known to modulate immunoglobulin (Ig) levels both in mice and in humans. These effects suggest that VGSC blockers may find clinical application in the treatment of autoimmune and inflammatory disease. However, many of these drugs induce a number of severe side effects. The relevance of VGSC function in immune regulation suggest that the testing of newly patented VGSC blockers for their effect on immunity may be worthwhile.     

Neurotrophin-3 significantly reduces sodium channel expression linked to neuropathic pain states

Neuropathic pain resulting from chronic constriction injury (CCI) is critically linked to sensitization of peripheral nociceptors. Voltage gated sodium channels are major contributors to this state and their expression can be upregulated by nerve growth factor (NGF). We have previously demonstrated that neurotrophin-3 (NT-3) acts antagonistically to NGF in modulation of aspects of CCI-induced changes in trkA-associated nociceptor phenotype and thermal hyperalgesia. Thus, we hypothesized that exposure of neurons to increased levels of NT-3 would reduce expression of Na_v1.8 and Na_v1.9 in DRG neurons subject to CCI. In adult male rats, Na_v1.8 and Na_v1.9 mRNAs are expressed at high levels in predominantly small to medium size neurons. One week following CCI, there is reduced incidence of neurons expressing detectable Na_v1.8 and Na_v1.9 mRNA, but without a significant decline in mean level of neuronal expression, and similar findings observed immunohistochemically. There is also increased accumulation/redistribution of channel protein in the nerve most apparent proximal to the first constriction site. Intrathecal infusion of NT-3 significantly attenuates neuronal expression of Na_v1.8 and Na_v1.9 mRNA contralateral and most notably, ipsilateral to CCI, with a similar impact on relative protein expression at the level of the neuron and constricted nerve. We also observe reduced expression of the common neurotrophin receptor p75 in response to CCI that is not reversed by NT-3 in small to medium sized neurons and may confer an enhanced ability of NT-3 to signal via trkA, as has been previously shown in other cell types. These findings are consistent with an analgesic role for NT-3.     

Calcium channel blockers and pain therapy

This review focuses on the advances in the development of N-type calcium channel blockers as analgesic agents over the last 2 years. Firstly, it highlights the clinical progress with SNX-111 (Ziconotide; Elan Pharmaceuticals, Smithfield, RI) and then secondly, it outlines the various approaches being taken by researchers to design orally active, selective, small molecule modulators without the perceived disadvantages associated with SNX-111.     

Voltage-gated sodium channel expression in rat spiral ganglion neurons

The spiral ganglion neurons (SGN) provide the afferent innervation of the hair cells in the organ of Corti and relay auditory information from the inner ear to the brain. Voltage-gated sodium channels (Na_V) initiate and propagate action potentials that encode this sensory information but little is known regarding the subtypes expressed in these cells. We have used RT-PCR and immunohistochemistry to study the compliment and anatomical distribution of Na_V channels in rodent SGN. Na_V1.1, Na_V1.6 and Na_V1.7 were all detected at the mRNA level. Fluorescence or streptavidin–horseradish peroxidase immunohistochemistry extended these findings, demonstrating predominant localisation of Na_V1.6 and Na_V1.7 on SGN cell bodies and Na_V1.1 on axonal processes. Dual labelling with peripherin demonstrated higher Na_V1.6 and Na_V1.7 expression on Type I rather than Type II neurons. These results provide evidence for selective expression and variations in the distribution of VGSC in the rodent SGN, which may guide further studies into afferent function in the auditory pathway and therapeutic approaches for diseases such as hearing loss and tinnitus.     

Na(+) channel blockers for the treatment of pain: context is everything, almost

Motor neuron death as seen in amyotrophic lateral sclerosis (ALS) is likely to be a non-cell autonomous process. One cell type that may be involved in the pathogenesis of the disease is the astrocyte. Under normal conditions, astrocytes affect survival of motor neurons by releasing growth factors and removing glutamate from the synaptic cleft. In addition, they determine some of the functional characteristics of motor neurons. In turn, motor neurons affect the functional characteristics of astrocytes. Recent evidence suggests that activation of astrocytes in a degenerative disease like ALS leads to a disturbance of this crosstalk between astrocytes and motor neurons, and that this may contribute to the death of motor neurons. As a consequence, understanding the interactions between motor neurons and astrocytes in health and disease may have important therapeutic implications.     

A role for the TTX-resistant sodium channel Nav 1.8 in NGF-induced hyperalgesia, but not neuropathic pain

The tetrodotoxin-resistant voltage-gated sodium channel Nav 1.8 is expressed only in nociceptive sensory neurons. This channel has been proposed to contribute significantly to the sensitization of primary sensory neurons after injury. We have studied the nociceptive behaviours of mice carrying a null mutation in the Nav 1.8 gene (Nav 1.8 -/-) in models of peripheral inflammation as well as a model of neuropathic pain. The results from the present studies reveal that Nav 1.8 is a necessary mediator of NGF-induced thermal hyperalgesia but is not essential for PGE2-evoked hypersensitivity. Neuropathic pain behaviours were unchanged in Nav 1.8 -/- mice indicating that this channel is not involved in the alteration of sensory thresholds following peripheral nerve injury.     

Lacosamide for the treatment of diabetic neuropathic pain

Lacosamide is a novel chemical entity with anticonvulsant and analgesic properties that is being developed to treat epilepsy and neuropathic pain conditions. Lacosamide has shown efficacy in many animal models of chronic pain and in several short- and long-term Phase II/III clinical trials in humans with diabetic neuropathic pain. The mechanism of action of lacosamide differs from other drugs used to treat neuropathic pain in that it selectively enhances sodium channel slow inactivation without affecting fast inactivation, and may modulate collapsin-response mediator protein 2. The pharmacokinetic properties of lacosamide include a fast rate of absorption, little or no interaction with cytochrome P450 isoenzymes, limited effect of age and gender on plasma levels and low potential for drug-drug interactions.     

Pharmacologic treatment of neuropathic pain

There is currently no consensus concerning the optimal therapeutic strategy for neuropathic pain, despite an increasing number of clinical trials demonstrating successful pain relief with several drugs. Treatments have generally been selected on the basis of evidence for efficacy in randomized placebo-controlled trials conducted in disease-based groups of patients, notably in postherpetic neuralgia and diabetic polyneuropathy. These studies plead in favour of the overall efficacy of tricyclic antidepressants, standard and newer antiepileptics, opioids, tramadol, systemic and topical local anaesthetics, and some NMDA receptor antagonists; whereas evidence for efficacy is less for selective serotonin reuptake inhibitors, antiarrhythmics (mexiletine), and capsaicin. Pharmacological tests, notably therapeutic infusions, have been proposed for predicting the effectiveness of long-term treatments, but are not routinely performed. An analysis of the various neuropathic symptoms, aimed at selecting treatments targeted at mechanisms, may ultimately help the choice of different pharmacologic agents.     

神经病理性疼痛外科治疗

由周围和(或)中枢神经系统原发性和(或)继发性损害、功能障碍或短暂性功能紊乱引起的疼痛,称为神经病理性疼痛,表现为以痛觉过敏、异常性疼痛和自发性疼痛为特点的综合征。神经病理性疼痛的外科治疗经历了较长的发展过程,在疼痛治疗中占有重要地位。本文主要对近年来关于神经病理性疼痛外科治疗研究进展,当前主要外科治疗手术技术(神经调控技术、神经损毁术及神经减压术等)进行概述。     

Invasive brain stimulation for the treatment of neuropathic pain

Neurostimulation therapy is indicated for neuropathic pain that is refractory to medical treatment, and includes stimulation of the dorsal spinal cord, deep brain structures, and the precentral motor cortex. Spinal cord stimulation is validated in the treatment of selected types of chronic pain syndromes, such as failed back surgery syndrome. Deep brain stimulation (DBS) has shown promise as a treatment for peripheral neuropathic pain and phantom limb pain. Compared with DBS, motor cortex stimulation (MCS) is currently more frequently used, mainly because it is more easily performed, and has a wider range of indications (including central poststroke pain). Controlled trials have demonstrated the efficacy of MCS in the treatment of various types of neuropathic pain, although these trials included a limited number of patients and need to be confirmed by large, controlled, multicenter studies. Despite technical progress in neurosurgical navigation, results from studies of MCS are variable, and validated criteria for selecting good candidates for implantation are lacking. However, the evidence in favor of MCS is sufficient to include it in the range of therapeutic options for refractory neuropathic pain. In this Review, the respective efficacies and mechanisms of action of DBS and MCS are discussed.     

Gene therapy applications for the treatment of neuropathic pain

Neuropathic pain is notoriously difficult to treat; currently available pharmaceutical drugs result in moderate analgesia in approximately a third of patients. As our understanding of the biological processes involved in the establishment and maintenance of neuropathic pain increases, so does the development of novel treatment options. Significant advancements have been made in the past few years in gene transfer, a very powerful potential therapy that can be used to directly target affected areas of the neuraxis or body tissues involved in neuropathic pain. Candidate gene products include directly analgesic proteins as well as proteins that interfere with pain-associated biochemical changes in nerve or other tissues underlying the disease process.     

神经病理性疼痛治疗进展

目前,神经病理性疼痛(NP)的治疗进展主要表现为对传统镇痛药物作用的重新评价及微创介入治疗的广泛应用.近年来,对周围神经损伤所致病理性疼痛的分子和细胞学机制,特别是对初级感觉神经元和脊髓损伤的研究积累了丰富的资料,周围神经损伤、脊髓背根神经节(DRG)胞体损伤及背根神经损伤等动物模型的建立,为认识神经病理性疼痛的机制和筛选治疗药物提供了有力的工具.