Colonic Neuromuscular Transmission Failure in Female Rats after Spinal Cord Injury

Abstract

Introduction Along with lost mobility, spinal cord injury (SCI) impacts visceral control of the autonomic nervous system; eliciting critical challenges to quality of life. Gastrointestinal (GI) complaints in the SCI population include decreased colonic motility and subsequent disruptions in evacuation. Although SCI damages the central nervous system, the enteric nervous system located intrinsic to the GI tract is not damaged by the initial trauma. The enteric neuromuscular control of colonic slow-wave propagation is a balance of excitatory and inhibitory inputs to smooth muscle cells that are recorded electrophysiologically as junction potentials (EJPs and IJPs, respectively). IJPs consist of a fast (purinergic; fIJP) and subsequent slow (nitrergic; sIJP) component. Our previous research has demonstrated diminished EJPs and sIJPs in male SCI rats. The higher prevalence of GI abnormalities in females underscores the differential control of motility in health and disease. This study aims to expand our mechanistic understanding of colonic dysmotility in female rat models of acute SCI. Methods Female rats received a surgical control or severe T3 contusion SCI. After 3 days recovery, ex vivo distal colon samples of the circular and longitudinal smooth muscle were dissected for electrophysiological recording and immunohistochemical analysis. For electrophysiology experiments, smooth muscle cells were recorded in response to pharmacologic treatments that isolate the EJPs and IJP components. Results Our data reveals that, in contrast to comparable regions of male rats’ distal colon, female rats have minimal sIJP (i.e., nitrergic) responses. With no significant difference between acute control and SCI responses, this suggests that female neuromuscular transmission is less dependent on nitrergic signaling. Control female sIJPs are significantly smaller than control male rats and resemble the sIJPs in SCI male rats. The resting membrane potential and fIJP component appears unchanged by SCI, with values consistent to male rats. Conclusion All of the current data illustrates sex-differences in colonic physiology and pathophysiology after SCI. Addressing gender differences would improve clinical post-injury care for these individuals. Significance To date, the mechanism for colon dysmotility after SCI remains uncertain and this project provides novel insight to female neurogenic bowel. The colonic neuromuscular junction is the final common pathway for proper motor function and abnormalities have implications for peripheral and central neurostimulation therapies. Our observed differences from neuromuscular transmission in the male rat, reinforces the importance of developing gender specific treatment. Future studies will evaluate female EJP dysfunction and specific agonist pharmacodynamics.