Gupta Rohit A, Higham James P, Pearce Abigail, Urriola-Muñoz Paulina, Barker Katie H, Paine Luke, Ghooraroo Joshua, Raine Tim, Hockley James R F, Rahman Taufiq, St John Smith Ewan, Brown Alastair J H, Ladds Graham, Suzuki Rie, Bulmer David C
Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, United Kingdom.
Department of Gastroenterology, Addenbrookes Hospital, Cambridge University Teaching Hospitals, Cambridge, United Kingdom.
Pain. 2025 Mar 1;166(3):596-613. doi: 10.1097/j.pain.0000000000003399. Epub 2024 Oct 3.
The development of nonopioid analgesics for the treatment of abdominal pain is a pressing clinical problem. To address this, we examined the expression of G i/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 G i/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.
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。为了解决这一问题，我们研究了G i/o偶联受体（通常抑制伤害感受器激活）在结肠感觉神经元中的表达。这使得孤儿受体GPR35被鉴定为一种内脏镇痛药物靶点，因为它与瞬时受体电位锚蛋白1（TRPA1，肠道中有害机械转导的介质）显著共表达。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，可促进不同G i/o亚基的激活。用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，并预防TRPA1介导的机械敏化。这些效应在GPR35 -/-小鼠的组织中消失，并显示是通过抑制TRPA1诱发的P物质（SP）释放介导的。这一观察结果突出了SP的促痛觉作用及其对TRPA1介导的结肠伤害感受器激活和敏化的作用。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依赖的方式消除。我们的数据表明，GPR35激动剂通过抑制TRPA1介导的SP释放来预防结肠伤害感受器的激活和敏化。这些发现突出了GPR35激动剂提供非阿片类镇痛用于治疗腹痛的潜力。
