Voltage-Gated Ion Channels in the PNS: Novel Therapies for Neuropathic Pain?

Neuropathic pain arises from injury to the nervous system. Conditions associated with neuropathic pain are diverse, and lesions and/or pathological changes in the central nervous system (CNS) or peripheral nervous system (PNS) can frequently, but not always, be identified. It is difficult to treat, with patients often on multiple, different classes of medications, all with appreciable adverse side effect profiles. Consequently, there is a pressing need for the development of new medications. The development of such therapeutics is predicated on a clear understanding of the relevant molecular and cellular processes that contribute to the development, and maintenance, of the neuropathic pain state. One proposed mechanism thought to contribute to the ontogeny of neuropathic pain is altered expression, trafficking, and functioning of ion channels expressed by primary sensory neurons. Here, we will focus on three voltage-gated ion channel families, CaV, HCN, and NaV, first reviewing the preclinical data and then the human data where it exists.

TrendsNeuropathic pain results from injury to the central and/or peripheral nervous system. Such injury can result in neuronal excitability, the basis of which includes altered expression, trafficking, and functioning of ion channels expressed by primary sensory neurons, including CaV, HCN, and NaV channels.Extensive pharmacological data indicate that it is possible to synthesize novel chemical entities (NCEs) that selectively inhibit channel function within each channel family. In preclinical tests, NCEs that selectively target CaV, HCN, and NaV channels have all demonstrated efficacy in various models of neuropathic pain; replicating those results in humans has been difficult, but NaV blockers (at least) show promise.Improvements in animal and human testing methodologies are needed to identify and develop safe and effective NCEs as antihyperalgesics.