Abstract
Chronic and neuropathic pain constitute significant health problems affecting millions of individuals each year. Pain sensations typically originate in sensory neurons of the peripheral nervous system which relay information to the central nervous system (CNS). Pathological pain sensations can arise as result of changes in excitability of these peripheral sensory neurons. Voltage-gated sodium channels are key determinants regulating action potential generation and propagation; thus, changes in sodium channel function can have profound effects on neuronal excitability and pain signaling. At present, most of the clinically available sodium channel blockers used to treat pain are non-selective across sodium channel isoforms and can contribute to cardio-toxicity, motor impairments, and CNS side effects. Numerous strides have been made over the last decade in an effort to develop more selective and efficacious sodium channel blockers to treat pain. The purpose of this review is to highlight some of the more recent developments put forth by research universities and pharmaceutical companies alike in the pursuit of developing more targeted sodium channel therapies for the treatment of a variety of neuropathic pain conditions.
Highlights
The International Association for the Study of Pain (ISAP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage.” The ability to experience painful stimuli is essential for an organism’s survival by alerting the individual to engage in protective behaviors to prevent further tissue damage or to seek appropriate actions to ameliorate the painful condition
We will highlight (1) the development of sodium channel blockers targeted at isoforms preferentially expressed in peripheral sensory neurons involved in the initiation and transduction of pain sensations, (2) techniques for limiting the action of sodium channel blockers to the periphery, and (3) the development of sodium channel modulators that target specific patterns of sodium channel activity associated with problematic pain
Voltage-gated sodium channels are emerging as exciting targets for the treatment of neuropathic pain, albeit several challenges must be overcome
Summary
The International Association for the Study of Pain (ISAP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage.” The ability to experience painful stimuli is essential for an organism’s survival by alerting the individual to engage in protective behaviors to prevent further tissue damage or to seek appropriate actions to ameliorate the painful condition. Nerve injury can result in changes in sodium channel trafficking, gene expression, and/or channel kinetics, all of which contribute to neuronal membrane remodeling and hyperexcitability associated with neuropathic pain (Devor, 2006). Used medications for the treatment of neuropathic pain which have demonstrable actions against sodium channels include tricyclic antidepressants (TCAs: amitriptyline and nortriptyline), local anesthetics (lidocaine, mexiletine), and anticonvulsants (carbamazepine, lamotrigine, phenytoin). We will highlight (1) the development of sodium channel blockers targeted at isoforms preferentially expressed in peripheral sensory neurons involved in the initiation and transduction of pain sensations, (2) techniques for limiting the action of sodium channel blockers to the periphery, and (3) the development of sodium channel modulators that target specific patterns of sodium channel activity associated with problematic pain
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