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 to, at least in part, a decrease in peripheral GAR–mediated inhibition. Acute colitis was induced with 5 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 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol (THIP), the GAR positive allosteric modulator diazepam, or the GAR antagonists gabazine and bicuculline. Low concentrations of muscimol or THIP increased the VMR in DSS-treated mice 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. By 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-affinity 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 or blocking high-affinity GAR may be effective therapeutic strategies for the management of pain in IBD.

疼痛是炎症性肠病 (IBD) 的常见且令人衰弱的症状。基于外周 GABAA 受体 (GAR) 抑制在建立结肠传入兴奋性和伤害性阈值中发挥重要作用的证据，我们假设与 IBD 相关的疼痛增加至少部分是由于外周 GAR 介导的减少。抑制。在饮用水中添加右旋糖酐硫酸钠（DSS，3%）5 天，诱发急性结肠炎。在结肠内给予 GAR 激动剂蝇蕈醇（高亲和力 GAR 首选激动剂 4,5,6,7-）之前和之后，通过对照小鼠和 DSS 处理小鼠的结肠球囊扩张引起的内脏运动反应 (VMR) 来评估内脏敏感性。四氢异恶唑并[5,4-c]吡啶-3-醇 (THIP)、GAR 正变构调节剂地西泮或 GAR 拮抗剂加巴嗪和荷包牡丹碱。低浓度的蝇蕈醇或 THIP 会增加 DSS 处理小鼠的 VMR，但不会增加对照小鼠的 VMR。然而，高浓度的蝇蕈醇降低了对照小鼠和 DSS 处理小鼠的 VMR。地西泮降低了 DSS 治疗小鼠和对照小鼠的 VMR。相比之下，在仅阻断低亲和力 GAR 的加巴嗪浓度下，DSS 治疗小鼠或对照小鼠的 VMR 没有影响，但在阻断低亲和力和高亲和力 GAR 的拮抗剂浓度下，对照组小鼠的 VMR 增加，DSS 处理的小鼠 VMR 减少。此外，荷包牡丹碱增加了对照小鼠的VMR，但降低了DSS处理小鼠的VMR。这些数据表明，激活低亲和力 GAR 或阻断高亲和力 GAR 可能是治疗 IBD 疼痛的有效治疗策略。