The impact of persistent-inflammation on peripheral GABAA receptor regulation of visceral nociception

Pain is the primary complaint of patients suffering from inflammatory bowel disease (IBD). Based on recent evidence indicating that peripheral GABAA receptor (GAR) inhibition plays an important role in establishing colonic afferent excitability and consequently nociceptive threshold, we hypothesized that the increase in pain associated with persistent inflammation in IBD is due, at least in part, to a decrease in peripheral GAR inhibition. To test this hypothesis, we evaluated the impact of persistent inflammation on peripheral GAR modulation of visceral nociception. Persistent inflammation was induced with five days of dextran sodium sulfate (DSS) in the drinking water. Visceral sensitivity was assessed with the visceromotor response (VMR) evoked with balloon distention of the colon. The VMR was assessed in the vehicle (control) and DSS- treated mice before and after intracolonic administration of GAR agonist muscimol, positive allosteric modulator (PAM, diazepam), or antagonists (bicuculline and gabazine). Activation of high-affinity GAR with low concentrations of muscimol increased the VMR in DSS-treated, but not control mice. However, high concentrations of muscimol decreased the VMR in both vehicle and DSS-treated mice. Diazepam, a low-affinity GAR PAM, decreased the VMR in both DSS-treated and control mice. In contrast, while bicuculline increased the VMR in control mice, it decreased the VMR in DSS-treated mice. Gabazine had no effect on the VMR at a concentration blocking only low-affinity GAR in either DSS-treated or control mice but produced divergent changes in the VMR in DSS-treated and control mice at a concentration blocking both the low and high-affinity GAR: the VMR was increased in control mice but decreased in DSS-treated mice. The data suggest that activation of low-affinity GAR and/or blocking high-affinity GAR may be effective therapeutic strategies for the management of pain associated with IBD. NIH grant R01 DK10796.