Role of voltage-gated Ca(2+) channel dysfunction in gastric vagal afferent neuropathy following spinal cord injury.

Upper gastrointestinal dysfunction is one of the most common comorbidities of spinal cord injury (SCI) and significantly impairs overall health and quality of life. Despite the need for targeted treatment options, the causal mechanisms underlying upper gastrointestinal dysfunction after injury remains unknown. Previous studies have demonstrated gastric vagal afferents are less sensitive to stimuli after SCI, which may be due to changes in voltage-gated Ca(2+) (Ca(V)) channels in gastric-projecting nodose ganglia (NG) neurons, as they contribute to action potential initiation along vagal afferents and neurotransmitter release at central synapses. Therefore, the purpose of this study was to investigate whether altered function of Ca(V) channels in gastric NG neurons develops after upper thoracic SCI using whole cell patch-clamp electrophysiology. Although no change in the biophysical properties of Ca(V) channels were observed 3-days postinjury, there was a significant (P = 0.0006) reduction in the Ca(2+) current density in gastric NG neurons isolated from 3-wk SCI animals as compared with controls (16.41 ± 2.41 pA/pF vs. 39.92 ± 5.63 pA/pF). When evaluating the Ca(V) channel expression profile, we found the Ca(V)2.2 blocker ω-conotoxin produced the largest Ca(2+) current inhibition in the 3-day SCI (60.0 ± 6.6%, n = 13), 3-wk SCI (59.4 ± 6.7%, n = 15), and control groups (3-day: 67.4 ± 8.1%, n = 11; 3-wk: 58.3 ± 5.0%). However, the effect of ω-agatoxin was significantly (P = 0.0225) higher in the 3-wk SCI group compared with the 3-day SCI group. These findings suggest Ca(V) channel currents are reduced following 3-wk SCI in gastric NG neurons, offering necessary insights into the cellular mechanisms underlying vagal afferent hyposensitivity postinjury.NEW & NOTEWORTHY This study demonstrated that voltage-gated Ca(2+) channel currents are diminished in gastric vagal afferent neurons 3 wk following experimental spinal cord injury. In addition, there is an increased contribution of P/Q-type channels 3-wk postinjury, though N-type channels still provide the majority of Ca(2+) currents. These results provide necessary insight into the cellular mechanism underlying the pathophysiological reduction of gastric vagal afferent sensitivity after injury, which may benefit future studies investigating therapeutic interventions for the neurogenic gut.