Role of rat sensory neuron-specific receptor (rSNSR1) in inflammatory pain: Contribution of TRPV1 to SNSR signaling in the pain pathway

Abstract

Sensory neuron-specific receptors (SNSRs) belong to a large family of GPCRs, known as Mrgs (Mas-related genes), many of which are preferentially expressed in primary afferent nociceptors. Selective SNSR agonists produce pain-like behaviors in rats, showing that SNSR activation is sufficient to produce pain. However, it is unknown whether SNSR activation is necessary for pain either in the normal condition or in pathological pain states. Here we used small interfering RNA (siRNA) to acutely knockdown rat SNSR1 and test the hypothesis that this receptor mediates pain responses. Administration of siRNA to the lumbar spinal cord in rats dose-dependently knocked down rSNSR1 mRNA and protein and abolished heat hyperalgesia evoked by intradermal administration of specific rSNSR1 agonists. In rats with levels of rSNSR1 knockdown sufficient to block responses to the SNSR1 agonists, there was no effect on normal pain responses, but there was a significant reduction of heat hyperalgesia in an inflammatory pain model (Complete Freund's Adjuvant), supporting a role for rSNSR1 in inflammatory pain. Further in vivo studies revealed that SNSR1 knockdown had no effect on responses to intradermal capsaicin, a selective TRPV1 agonist. In contrast, a selective TRPV1 antagonist abolished heat hyperalgesia produced by an SNSR agonist, suggesting that TRPV1 receptors mediate rSNSR1-evoked responses. We also found that rSNSR1-like immunoreactivity, like TRPV1, is localized in the superficial dorsal horn of the spinal cord. We propose that rSNSR1 represents a new member of the receptors expressed on chemosensitive nociceptors responsible for detecting the "inflammatory soup" of mediators generated by tissue damage.

Mas and Its Related G Protein–Coupled Receptors, Mrgprs

“…These animals exhibit unaltered nociceptive thresholds at baseline, showing that normal pain processing is not dependent on the Mrgprs deleted in the cluster. The same was true in rats with downregulation of the rMrgprX1 gene by local siRNA injection in the spinal cord (Ndong et al, 2009). However, the cluster-knockout mice and the rMrgprX1-siRNA-injected rats exhibited prolonged pain sensitivity after hind paw inflammation (Ndong et al, 2009;Guan et al, 2010).…”

“…Activators of mMrgprX1, rMrgprX1, and hMRGPRX1, such as BAM8-22, have been shown to induce both hyperalgesia and hypoalgesia (Grazzini et al, 2004;Ndong et al, 2009;Guan et al, 2010;Jiang et al, 2013). Recent experiments with the cluster knockout mice lacking 12 Mrgprs, including mMrgprX1 ( Fig.…”

Pharmacology and Signaling of MAS-Related G Protein–Coupled Receptors

“…Pain-enhancing effects. Intraplantar injections of the MRGPRC-specific peptides BAM8-22 or Tyr 6 -g 2 -MSH6-12 into juvenile or adult rats dose dependently resulted in acute nocifensive behavior, thermal hyperalgesia, and mechanical allodynia (Grazzini et al, 2004;Ndong et al, 2009). Likewise, intrathecal injection of MRGPRC agonists into juvenile or adult rats and Kunming mice also induced acute pain-like behavior and thermal hyperalgesia (Grazzini et al, 2004;Chang et al, 2009;Wei et al, 2010).…”

“…Several publications identified heat-sensitive TRPV1 ion channels as major downstream targets of MRGPRC responsible for its pain-enhancing effects (Honan and McNaughton, 2007;Hager et al, 2008;Ndong et al, 2009;Wilson et al, 2011). In rat primary sensory neurons, BAM8-22 sensitized TRPV1 for its agonist capsaicin (CAP) via a PKC-dependent pathway (Honan and McNaughton, 2007).…”

“…In rats, MRGPRC-mediated thermal hyperalgesia was abrogated by a specific TRPV1 inhibitor (Ndong et al, 2009), and coexpression of TRPV1 with murine MRGPRC in NG108 cells resulted in augmented calcium signals by BAM8-22 (Wilson et al, 2011). Thus, TRPV1 has been defined as a common target for cellular signaling induced by MRGPRC, which might be of high physiologic significance because coexpression of TRPV1 with MRGPRC in rodent primary sensory neurons was frequently observed (Lembo et al, 2002;Hager et al, 2008;Liu et al, 2009).…”