Dorsal horn CGRP-expressing interneurons contribute to nerve injury-induced mechanical hypersensitivity

Primary sensory neurons are generally considered the only source of dorsal horn calcitonin gene-related peptide (CGRP), a neuropeptide critical to the transmission of pain messages. Using a tamoxifen-inducible CGRPCreER transgenic mouse, here we identified a distinct population of CGRP-expressing excitatory interneurons in lamina III of the spinal cord dorsal horn and trigeminal nucleus caudalis. These interneurons have spine-laden, dorsally-directed, dendrites and ventrally-directed axons. Neither innocuous nor noxious stimulation provoked significant Fos expression in these neurons. However, synchronous, electrical non-nociceptive A{beta} primary afferent stimulation of dorsal roots depolarized the CGRP interneurons, consistent with their receipt of a VGLUT1 innervation. In contrast, chemogenetic activation produced a significant mechanical hypersensitivity. Importantly, the CGRP interneurons could be activated after peripheral nerve injury, but only with concurrent innocuous, brush stimulation. These findings suggest that hyperexcitability of dorsal horn CGRP interneurons is an important contributor to the circuits that render touch painful after peripheral nerve damage.