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.
Show 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 nociceptors 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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