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

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.