These findings establish a preclinical screening platform for identifying analgesic candidates and reveal nociceptor GPCRs that may be targeted to treat pain.
Abstract
Summary 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 Gi/o-coupled and orphan GPCRs attenuate neuronal excitability. Experiments focusing on the Gi/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.
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BACKGROUND
Neuropathic pain, a debilitating chronic condition, remains a major clinical challenge due to its complex pathogenesis and limited treatment options. Protein tyrosine phosphatase 1B (PTP1B), a key regulator of tyrosine phosphorylation, has been implicated in various diseases, yet its specific role and mechan...
Xiao-Qin Li, Shu-Jin Wu, Rui-Li Sun et al.· Regional anesthesia and pain...· 0 citations
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