5‐HT2 receptor activation modulates phrenic motor output following chronic cervical spinal cord injury

Abstract

C2 spinal hemisection (C2Hx) results in loss of ipsilateral phrenic bursting due to interruption of bulbospinal respiratory pathways. Time‐dependent return of spinal serotonin (5‐HT) innervation correlates with the partial recovery of phrenic output that is seen over weeks to months following C2Hx. Both 5‐HT2A and 2C receptors are present on phrenic motoneurons. 5‐HT2A receptors on phrenic motoneurons are upregulated following spinal cord injury, and studies in other motor pools have shown that constitutive 5‐HT2C receptor activity develops after spinal cord injury. Accordingly, we hypothesized that pharmacological blockade of these receptors would modulate phrenic motor activity after chronic C2Hx. Bilateral phrenic activity was recorded in anesthetized, vagotomized and ventilated rats. The 5‐HT2A/C receptor antagonist ketanserin (1 mg/kg, i.v.) significantly reduced phrenic burst amplitude bilaterally in C2Hx but not uninjured rats. The relative decrease of phrenic bursting was significantly greater in the ipsilateral phrenic nerve. Additionally, we tested a 5‐HT2C inverse agonist (cyproheptadine, 1 mg/kg, i.v.) and observed a slight increase of bilateral phrenic motor output in C2Hx animals. These results suggest that endogenous activation of 5‐HT2A receptors can maintain phrenic activity, while constitutively active 5‐HT2C receptors may blunt phrenic motor recovery after chronic C2Hx.