Abstract
The development of non-opioid 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 due to its marked co-expression with TRPA1, a mediator of noxious mechanotransduction in the bowel. Building on in silico docking simulations, we confirmed that the mast cell stabiliser, cromolyn, and phosphodiesterase inhibitor, zaprinast, are agonists at the GPR35 receptor, promoting the activation of multiple Gi/o subunits. Pre-treatment with either cromolyn or zaprinast significantly attenuated TRPA1-mediated colonic nociceptor activation and prevented TRPA1-mediated mechanosensitisation. These effects of cromolyn and zaprinast were lost in tissue from GPR35-/- mice and were shown to be mediated by inhibition of TRPA1-evoked substance P (SP) release. This observation highlighted the pro-nociceptive effect of SP and its contribution to TRPA1-mediated colonic nociceptor activation and mechanosensitisation. Consistent with this mechanism of action, we confirmed that TRPA1-mediated colonic contractions evoked by SP release were abolished by cromolyn pre-treatment in a GPR35-dependent manner. Our data demonstrates the ability of GPR35 agonists to prevent the activation and sensitisation of colonic nociceptors through the inhibition of TRPA1-mediated SP release. These findings highlight the potential ability of GPR35 agonists to deliver non-opioid analgesia for the treatment of abdominal pain.
