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 identified G protein-coupled receptors (GPCRs) expressed in CGRP ⁺ mouse and human nociceptors and found that agonists of several identified G _i/o -coupled and orphan GPCRs attenuated neuronal excitability. Experiments focusing on the G _i/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.