CGRP+ fibers sprout within gastrocnemius muscle following complete spinal cord injury in rodents

Abstract

Following spinal cord injury nociceptive afferents exhibit functional and anatomical plasticity within the spinal dorsal horn. This plasticity is, at least in part, maladaptive, contributing to secondary complications related to neuropathic pain, autonomic dysreflexia, and spasticity. While previous studies have shown that nociceptors, particularly CGRP⁺ C-fibers, are also capable of sprouting peripherally following pathologies of chronic inflammation, muscle disuse, and denervation, the peripheral plasticity of C-fibers following spinal cord injury remains largely uninvestigated. Here, we show that CGRP⁺ nerve fibers, likely nociceptors, display expanded innervation within the gastrocnemius muscle, particularly near blood vessels and within the calcaneal tendon. Furthermore, CGRP⁺ sensory axons exhibit a fundamental change in their innervation pattern near motor axons, innervating independently of, rather than along, motor trunks. These changes occurred alongside significantly reduced size and expression of CGRP by motor axon terminals following spinal transection. We also report positive correlations between volume of CGRP⁺ fibers in the gastrocnemius muscle and muscle atrophy, hypersensitivity, intraspinal plasticity, and activation of glia within the lumbar spinal cord. Importantly, bulk RNA sequencing of muscle revealed upregulation of genes indicative of biological processes occurring at 6 weeks post-SCI that may contribute to sensory plasticity including inflammation, immune cell infiltration, and apoptosis. Taken together, these data suggest that many nociceptor-dependent complications that are thought to be spinally mediated may be driven or exacerbated by nociceptor plasticity occurring in the periphery.