Na_V1.7 mRNA and Protein Expression in Resident Neurons of the Human Spinal Dorsal Horn

The voltage-gated sodium channel Na_V1.7 is a pain target supported by human genetics, and many compounds have been developed to inhibit Na_V1.7 but have disappointed in clinical trials due to cardiovascular effects. Because some recent reports suggest that pharmacological inhibition of Na_V1.7 in the rodent spinal dorsal horn can achieve pain relief, we sought to better understand Na_V1.7 expression in the human spinal cord. We report that Na_V1.7 mRNA is expressed in putative projection neurons (NK1R+, GPR83+) in the human spinal dorsal horn, predominantly in lamina I and II, as well as in deep dorsal horn neurons. Na_V1.7 mRNA was also detected in preganglionic parasympathetic and sympathetic neurons, motor neurons in the ventral horn, and ependymal cells lining the central canal. Na_V1.7 protein was predominantly found in the central axons of sensory neurons terminating in lamina I-II and colocalized, in part, with presynaptic markers like Bassoon and CGRP. Postsynaptically, Na_V1.7 protein was detectable in the soma of motor neurons but was more elusive in dorsal horn populations due to the abundance of presynaptic signal. However, Na_V1.7 protein was detected in the axon initial segment of some resident 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_V1.7 expression may play an unappreciated role in pain phenotypes observed in humans with genetic SCN9A mutations.