Mas-related G-protein–coupled receptors inhibit pathological pain in mice
An important objective of pain research is to identify novel drug targets for the treatment of pathological persistent pain states, such as inflammatory and neuropathic pain. Mas-related G-protein–coupled receptors (Mrgprs) represent a large family of orphan receptors specifically expressed in small-diameter nociceptive primary sensory neurons. To determine the roles of Mrgprs in persistent pathological pain states, we exploited a mouse line in which a chromosomal locus spanning 12 Mrgpr genes was deleted (KO). Initial studies indicated that these KO mice show prolonged mechanical- and thermal-pain hypersensitivity after hind-paw inflammation compared with wild-type littermates. Here, we show that this mutation also enhances the windup response of dorsal-horn wide dynamic-range neurons, an electrophysiological model for the triggering of central pain sensitization. Deletion of the Mrgpr cluster also blocked the analgesic effect of intrathecally applied bovine adrenal medulla peptide 8–22 (BAM 8–22), an MrgprC11 agonist, on both inflammatory heat hyperalgesia and neuropathic mechanical allodynia. Spinal application of bovine adrenal medulla peptide 8–22 also significantly attenuated windup in wild-type mice, an effect eliminated in KO mice. These data suggest that members of the Mrgpr family, in particular MrgprC11, may constitute an endogenous inhibitory mechanism for regulating persistent pain in mice. Agonists for these receptors may, therefore, represent a class of antihyperalgesics for treating persistent pain with minimal side effects because of the highly specific expression of their targets.
© 2010 by the National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by David J. Anderson, July 29, 2010 (sent for review May 10, 2010). Published online before print August 19, 2010. We thank Claire Levine, MS, for editing the manuscript and Yixun Geng for assistance with the mice. D.J.A and X.D. are investigators at the Howard Hughes Medical Institute. The work was supported by the Johns Hopkins Blaustein Pain Research Fund Award (to Y.G. and X.D.), an Alfred P. Sloan Neuroscience grant (to X.D.), and a Whitehall Foundation grant (to X.D.). This work was also supported by National Institutes of Health Grants NS26363 (to S.N.R.), NS048499 (to D.J.A.), and NS054791 and NS58481 (to X.D.). Author contributions: Y.G., Q.L., S.N.R., D.J.A., and X.D. designed research; Y.G., Q.L., and Z.T. performed research; Y.G., Q.L., Z.T., S.N.R., D.J.A., and X.D. analyzed data; and Y.G., Q.L., S.N.R., D.J.A., and X.D. wrote the paper.
Published - Guan2010p11415P_Natl_Acad_Sci_Usa.pdf