Pain is a common and debilitating symptom of inflammatory bowel disease (IBD). Based on evidence that peripheral GABAA receptor (GAR) inhibition plays an important role in establishing colonic afferent excitability and nociceptive threshold, we hypothesized that the increase in pain associated with IBD is due, at least in part, to a decrease in peripheral GAR-mediated inhibition.Acute colitis was induced with five days of dextran sodium sulfate (DSS, 3%) in the drinking water. Visceral sensitivity was assessed with the visceromotor response (VMR) evoked with balloon distention of the colon in control and DSS-treated mice before and after intracolonic administration of GAR agonist muscimol, the high-affinity GAR preferring agonist THIP, the GAR positive allosteric modulator (PAM) diazepam, or the GAR antagonists gabazine and bicuculline.Low concentrations of muscimol or THIP increased the VMR in DSS-treated, but not in control mice. However, high concentrations of muscimol decreased the VMR in both control and DSS-treated mice. Diazepam decreased the VMR in both DSS-treated and control mice. In contrast, at a concentration of gabazine that blocks only low-affinity GAR, there was no effect on the VMR in either DSS-treated or control mice, but at concentrations of the antagonist that block low- and high-affinity GAR, the VMR was increased in control mice, and decreased in DSS-treated mice. Furthermore, bicuculline increased the VMR in control mice, but decreased it in DSS-treated mice.These data suggest that activating of low-affinity GAR and/or blocking high-affinity GAR may be effective therapeutic strategies for the management of pain in IBD.Copyright © 2021 International Association for the Study of Pain.
