The development of nonopioid analgesics for the treatment of abdominal pain is a pressing clinical problem. To address this, we examined the expression of Gi/o-coupled receptors, which typically inhibit nociceptor activation, in colonic sensory neurons. This led to the identification of the orphan receptor GPR35 as a visceral analgesic drug target because of its marked coexpression with transient receptor potential ankyrin 1 (TRPA1), a mediator of noxious mechanotransduction in the bowel. Building on in silico docking simulations, we confirmed that the mast cell stabiliser, cromolyn (CS), and phosphodiesterase inhibitor, zaprinast, are agonists at mouse GPR35, promoting the activation of different Gi/o subunits. Pretreatment with either CS or zaprinast significantly attenuated TRPA1-mediated colonic nociceptor activation and prevented TRPA1-mediated mechanosensitisation. These effects were lost in tissue from GPR35-/- mice and were shown to be mediated by inhibition of TRPA1-evoked substance P (SP) release. This observation highlights the pronociceptive effect of SP and its contribution to TRPA1-mediated colonic nociceptor activation and sensitisation. Consistent with this mechanism of action, we confirmed that TRPA1-mediated colonic contractions evoked by SP release were abolished by CS pretreatment in a GPR35-dependent manner. Our data demonstrate that GPR35 agonists prevent the activation and sensitisation of colonic nociceptors through the inhibition of TRPA1-mediated SP release. These findings highlight the potential of GPR35 agonists to deliver nonopioid analgesia for the treatment of abdominal pain.

中文翻译：

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GPR35 激动剂通过抑制 P 物质的释放来抑制 TRPA1 介导的结肠伤害感受。


开发用于治疗腹痛的非阿片类镇痛药是一个紧迫的临床问题。为了解决这个问题，我们检查了结肠感觉神经元中 Gi/o 偶联受体的表达，这种受体通常抑制伤害感受器的激活。这导致孤儿受体 GPR35 被鉴定为内脏镇痛药物靶点，因为它与瞬时受体电位锚蛋白 1 （TRPA1） 显着共表达，TRPA1 是肠道中有害机械转导的介质。基于计算机对接模拟，我们证实肥大细胞稳定剂色甘酸钠 （CS） 和磷酸二酯酶抑制剂扎普司特是小鼠 GPR35 的激动剂，促进不同 Gi/o 亚基的激活。CS 或扎普司特预处理可显著减弱 TRPA1 介导的结肠伤害感受器激活，并阻止 TRPA1 介导的机械增敏。这些作用在 GPR35-/-小鼠的组织中丢失，并且被证明是通过抑制 TRPA1 诱发的物质 P （SP） 释放介导的。这一观察强调了 SP 的伤害感受作用及其对 TRPA1 介导的结肠伤害感受器激活和致敏的贡献。与这种作用机制一致，我们证实 SP 释放诱发的 TRPA1 介导的结肠收缩被 CS 预处理以 GPR35 依赖性方式消除。我们的数据表明，GPR35 激动剂通过抑制 TRPA1 介导的 SP 释放来阻止结肠伤害感受器的激活和致敏。这些发现强调了 GPR35 激动剂提供非阿片类镇痛治疗腹痛的潜力。