| First Author | Peng J | Year | 2026 |
| Journal | Cell Rep Med | Volume | 7 |
| Issue | 8 | Pages | 102949 |
| PubMed ID | 42532046 | Mgi Jnum | J:391206 |
| Mgi Id | MGI:8398591 | Doi | 10.1016/j.xcrm.2026.102949 |
| Citation | Peng J, et al. (2026) Targeting G(i/o)-coupled GPCRs to inhibit nociceptors: Insights from the serotonin receptor Htr1b and triptans. Cell Rep Med :102949 |
| abstractText | 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(+) mouse and human DRG neurons and find that agonists of several identified G(i/o)-coupled and orphan GPCRs attenuate neuronal excitability. Experiments focusing on the G(i/o)-coupled serotonin receptor Htr1b, which is expressed in mouse and human CGRP(+) DRG neurons, reveal that Htr1b/1d agonists, the triptans sumatriptan and zolmitriptan, attenuate CGRP(+) 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. |
