Na(V)1.7 mRNA and protein expression in putative projection neurons of the human spinal dorsal horn

Na(V)1.7, a membrane-bound voltage-gated sodium channel, is preferentially expressed along primary sensory neurons, including their peripheral & central nerve endings, axons, and soma within the dorsal root ganglia and plays an integral role in amplifying membrane depolarization and pain neurotransmission. Loss- and gain-of-function mutations in the gene encoding Na(V)1.7, SCN9A, are associated with a complete loss of pain sensation or exacerbated pain in humans, respectively. As an enticing pain target supported by human genetic validation, many compounds have been developed to inhibit Na(V)1.7 but have disappointed in clinical trials. The underlying reasons are still unclear, but recent reports suggest that inhibiting Na(V)1.7 in central terminals of nociceptor afferents is critical for achieving pain relief by pharmacological inhibition of Na(V)1.7. We report for the first time that Na(V)1.7 mRNA is expressed in putative projection neurons (NK1R+) in the human spinal dorsal horn, predominantly in lamina 1 and 2, as well as in deep dorsal horn neurons and motor neurons in the ventral horn. Na(V)1.7 protein was found in the central axons of sensory neurons terminating in lamina 1–2, but also was detected in the axon initial segment of resident spinal dorsal horn neurons and in axons entering the anterior commissure. Given that projection neurons are critical for conveying nociceptive information from the dorsal horn to the brain, these data support that dorsal horn Na(V)1.7 expression may play an unappreciated role in pain phenotypes observed in humans with genetic SCN9A mutations, and in achieving analgesic efficacy in clinical trials.