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bioRxiv · 10.64898/2026.04.22.719367

Targeting Gi/o-coupled GPCRs to inhibit nociceptors: insights from the serotonin receptor Htr1b and triptans

Peng, J.·Sanchez, B. T.·Chirila, A. M.·Zeng, X.·DeLisle, M. M.·Qi, L.·Xiao, J.·Lezgiyeva, K.·Low, S. A.·Woolf, C. J.·Sharma, N.·Ginty, D. D.
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Abstract

Pain perception is initiated upon activation of nociceptors of the dorsal root ganglia (DRG) and trigeminal ganglia. We identified G protein-coupled receptors (GPCRs) expressed in CGRP+ mouse and human DRG neurons and found that agonists of several identified Gi/o-coupled and orphan GPCRs attenuated neuronal excitability. Experiments focusing on the Gi/o-coupled serotonin receptor Htr1b, which is expressed in mouse and human CGRP+ DRG neurons, revealed that Htr1b/1d agonists, the triptans sumatriptan and zolmitriptan, attenuated CGRP+ neuron excitability in vitro and exhibited analgesia across several pain models, including neuropathic pain. Conditional genetic deletion experiments showed that triptan-induced analgesia is mediated by Htr1b expressed in A-fiber mechanonociceptors. Also, triptan-associated adverse effects are partially mediated by Htr1b-independent targets. Further testing identified the GPCR Gpr19 as an additional promising target for treating pain. These findings establish a preclinical screening platform for identifying novel analgesics and reveal nociceptor GPCRs that may be targeted to treat pain.

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Peng, J., Sanchez, B. T., Chirila, A. M., Zeng, X., DeLisle, M. M., Qi, L., Xiao, J., Lezgiyeva, K., Low, S. A., Woolf, C. J., Sharma, N., Ginty, D. D.. 2026-04-24. Targeting Gi/o-coupled GPCRs to inhibit nociceptors: insights from the serotonin receptor Htr1b and triptans. https://doi.org/10.64898/2026.04.22.719367

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