Role of voltage-gated Ca²⁺ 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 post-injury, there was a significant (p=0.0006) reduction in the Ca 2+ current density in gastric NG neurons isolated from 3-week SCI animals as compared to 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-week SCI (59.4±6.7%, n=15), and control groups (3-day: 67.4 ±8.1%, n=11; 3-week: 58.3 ± 5.0%). However, the effect of ω-agatoxin was significantly (p= 0.0225) higher in the 3-week SCI group compared to the 3-day SCI group. These findings suggest Ca V channel currents are reduced following 3-week SCI in gastric NG neurons, offering necessary insights into the cellular mechanisms underlying vagal afferent hyposensitivity post-injury.