Effect of Mas‐related gene (Mrg) receptors on hyperalgesia in rats with CFA‐induced inflammation via direct and indirect mechanisms

Abstract

Background and Purpose Mas oncogene‐related gene (Mrg) receptors are exclusively distributed in small‐sized neurons in trigeminal and dorsal root ganglia (DRG). We investigated the effects of MrgC receptor activation on inflammatory hyperalgesia and its mechanisms. Experimental Approach A selective MrgC receptor agonist, bovine adrenal medulla peptide 8‐22 (BAM8‐22) or melanocyte‐stimulating hormone (MSH) or the μ‐opioid receptor (MOR) antagonist CTAP was administered intrathecally (i.t.) in rats injected with complete Freund's adjuvant (CFA) in one hindpaw. Thermal and mechanical nociceptive responses were assessed. Neurochemicals were measured by immunocytochemistry, Western blot, ELISA and RT‐PCR. Key Results CFA injection increased mRNA for MrgC receptors in lumbar DRG. BAM8‐22 or MSH, given i.t., generated instant short and delayed long‐lasting attenuations of CFA‐induced thermal hyperalgesia, but not mechanical allodynia. These effects were associated with decreased up‐regulation of neuronal NOS (nNOS), CGRP and c‐Fos expression in the spinal dorsal horn and/or DRG. However, i.t. administration of CTAP blocked the induction by BAM8‐22 of delayed anti‐hyperalgesia and inhibition of nNOS and CGRP expression in DRG. BAM8‐22 also increased mRNA for MORs and pro‐opiomelanocortin, along with β‐endorphin content in the lumbar spinal cord and/or DRG. MrgC receptors and nNOS were co‐localized in DRG neurons. Conclusions and Implications Activation of MrgC receptors suppressed up‐regulation of pronociceptive mediators and consequently inhibited inflammatory pain, because of the activation of up‐regulated MrgC receptors and subsequent endogenous activity at MORs. The uniquely distributed MrgC receptors could be a novel target for relieving inflammatory pain.

Activation of Mas Oncogene-Related G Protein–Coupled Receptors Inhibits Neurochemical Alterations in the Spinal Dorsal Horn and Dorsal Root Ganglia Associated with Inflammatory Pain in Rats

“…1). Similar to our previous observation (Jiang et al, 2013), intrathecal BAM8-22 significantly attenuated CFA-induced hyperalgesia at 20 minutes after administration (4.5 6 0.3 seconds; P , 0.001; n 5 7).…”

“…Our previous study showed that after the treatment with intrathecal BAM8-22 on day 1, the intrathecal BAM8-22 administered on day 2 produced instant and delayed (24 hours later) inhibitions of CFA-induced hyperalgesia in a dose-dependent manner (Jiang et al, 2013). A slightly different protocol was used in the present study.…”

“…Our previous study demonstrated that intrathecal administration of the highly selective MrgC receptor agonist BAM8-22 (Guan et al, 2010) at a dose of 30 nmol produced an immediate antihyperalgesic effect lasting approximately 40 minutes (Jiang et al, 2013). We first repeated a behavioral study and observed that intrathecal BAM8-22 inhibited CFA-induced hyperalgesia at 20 minutes.…”

“…MrgC receptors exert protective actions in the inflammatory pain state, as evidenced by the studies showing that MrgC cluster knock-out animals display an enhanced windup responding to C fiber inputs and/or increased pain behavior following an intraplantar injection of formalin (Guan et al, 2010), complete Freund's adjuvant (CFA), and carrageenan . Moreover, MrgC receptor mRNA in DRG is upregulated and the activation of these receptors recruits m-opioid bioactivity in the spinal cord and DRG in inflammatory pain (Jiang et al, 2013). Therefore, the investigation of MrgC receptors has important clinical implications.…”

“…We have shown that an intrathecal administration of BAM8-22 produces immediate short and delayed longlasting attenuations of CFA-induced hyperalgesia. The delayed inhibition by MrgC receptors is attributed to the recruitment of opioid receptor activity as it can be abolished by the m-opioid receptor antagonist CTAP (Jiang et al, 2013). However, the mechanism underlying the immediate effect of MrgC receptors on inflammatory pain is not clear.…”