Peripheral N-methyl-D-aspartate receptors as possible targets for chronic pain treatment

The role of N-methyl-D-aspartate receptors (NMDArs) in pain sensation was initially uncovered in 1987 when the hyperexcitability of spinal cord dorsal horn nociceptive neurons evoked by C-fiber stimulation was found to be blocked by spinal delivery of NMDAr antagonist. Since then, many studies have focused on the role of central NMDArs in pain sensation. It is now apparent that peripheral NMDArs also play a role not only in the initiation but also in the maintenance of chronic pain states, particularly those following peripheral nerve injuries. Peripheral NMDArs are an attractive target for treating chronic pain, because under normal (nonpainful) stimulation NMDArs in dorsal root ganglia (DRG) neurons do not activate; in addition, some of the NMDArs isoforms are predominantly expressed in DRG neurons, and NMDArs have various regulatory sites that are isoform-dependent. This article concentrates on reviewing the possible role of peripheral NMDArs in initiating and maintaining chronic pain states. Of particular interest is the role of NMDArs not only on peripheral DRG neurons but also on their surrounding glia, since neuronal-glial interactions have been shown to contribute to injury-evoked neuronal hyperexcitability. Drugs that would target selectively peripheral NMDArs would improve treatment of chronic pain states. This review is divided into 5 sections: NMDAr structure and function; the role of peripheral NMDArs in pain perception; modulation of NMDArs during pain states; modulation of NMDAr activity by Substance P; and role of glia in DRG neuronal hyperexcitability.