Targeting G<sub>i/o</sub>-coupled GPCRs to inhibit nociceptors: Insights from the serotonin receptor Htr1b and triptans.
basic_science · Level V
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- Record sourced from PubMed, PMID 42532046.
- Also identified by DOI 10.1016/j.xcrm.2026.102949.
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Abstract
Pain perception is initiated upon activation of nociceptors of the dorsal root ganglia (DRG) and trigeminal ganglia. We identify G-protein-coupled receptors (GPCRs) expressed in CGRP<sup>+</sup> mouse and human DRG neurons and find that agonists of several identified G<sub>i/o</sub>-coupled and orphan GPCRs attenuate neuronal excitability. Experiments focusing on the G<sub>i/o</sub>-coupled serotonin receptor Htr1b, which is expressed in mouse and human CGRP<sup>+</sup> DRG neurons, reveal that Htr1b/1d agonists, the triptans sumatriptan and zolmitriptan, attenuate CGRP<sup>+</sup> neuron excitability in vitro and exhibit analgesia across several pain models, including neuropathic pain. Conditional genetic deletion experiments show 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 identifies the GPCR Gpr19 as an additional promising target for treating pain. These findings establish a preclinical screening platform for identifying analgesic candidates and reveal nociceptor GPCRs that may be targeted to treat pain.