Role of A-delta low threshold mechanoreceptors and tropomyosin receptor kinase B plasticity in at-level aversive pain after spinal cord injury.

The mechanisms of neuropathic pain after spinal cord injury (SCI) are not fully understood, although spinal and peripheral processes are involved. Maladaptive tropomyosin receptor kinase-B (TrkB) signaling has been implicated in pain hypersensitivity after SCI. A-delta-low threshold mechanoreceptors (Aδ-LTMRs) innervate the hairy skin and normally signal directional touch and are identified by their preferential TrkB expression. This study investigated whether Aδ-LTMRs play a role in at-level pain after thoracic contusion SCI. Using a modified light-dark chamber conditioned place aversion (CPA) paradigm, we assessed chamber preferences and transitions between chambers in response to mechanical stimulation, and optogenetic stimulation of Aδ-LTMRs in the trunk skin of adult TrkBCre mice of both sexes. Respiratory rates (RRs) were monitored at baseline and during truncal stimulation. The expression of brain-derived neurotrophic factor (BDNF), TrkB and pERK1/2 in the lesioned spinal cord and skin, and histological changes in Aδ-LTMRs in trunk skin were assessed. In addition, electrophysiological studies examined changes in Aδ-LTMRs membrane and firing properties, and response to bath-applied 7, 8-dihydroxyflavone (7,8-DHF), a TrkB agonist. The results showed that whereas brush stimulation evoked an aversive response at 4 weeks post-SCI that was accompanied by increased RRs, targeted stimulation of Aδ-LTMRs produced an aversive response 7 weeks post-SCI. SCI increased BDNF, TrkB and pERK1/2 expression in the skin, and augmented 7,8-DHF-induced inward current in Aδ-LTMRs. Together, these results suggest that plasticity of Aδ-LTMR, including an increase in TrkB signaling in the periphery, contribute to at-level affective pain following chronic SCI in adult mice.