Sensory neuron-specific receptor activation elicits central and peripheral nociceptive effects in rats

Abstract

The sensory neuron-specific G protein coupled receptors (SNSRs) have been described as a family of receptors whose expression in small diameter sensory neurons in the trigeminal and dorsal root ganglia suggests an implication in nociception. To date, the physiological function(s) of SNSRs remain unknown. Hence, the aim of the present study was to determine the effects of rat SNSR1 activation on nociception in rats. The pharmacological characterization of rat SNSR1 was initially performed in vitro to identify a specific ligand, which could be used subsequently in the rat for physiological testing. Among all ligands tested, ␥2-MSH was the most potent at activating rat SNSR1. Structure-activity relationship studies revealed that the active moiety recognized by rat SNSR1 was the C-terminal part of ␥2-MSH. The radiolabeled C-terminal part of ␥2-MSH, ␥2-MSH-6 -12, bound with high affinity to membranes derived from rat skin and spinal cord, demonstrating the presence of receptor protein at both the proximal and distal terminals of dorsal root ganglia. To investigate the physiological role of SNSR, specific ligands to rat SNSR1 were tested in behavioral assays of pain sensitivity in rats. Selective rat SNSR1 agonists produced spontaneous pain behavior, enhanced heat and mechanical sensitivity when injected intradermally, and heat hypersensitivity when injected centrally, consistent with the localization of rat SNSR1 protein at central and peripheral sites. Together, these results clearly indicate that the SNSR1 plays a role in nociception and may provide novel therapeutic opportunities for analgesia. Gprotein-coupled receptors constitute one of the largest gene family of proteins that have been exploited successfully as drug targets (1). With the near completion of the human genome project, bioinformatic analyses have revealed the existence of Ϸ145 orphan receptors (1, 2). In recent years, the ''reverse pharmacology approach'' has generated Ͼ40 ligand-receptor pairings (1, 3), and the subsequent investigation of these newly discovered ligand-receptor pairings should help in understanding and elucidating their potential physiological and pathophysiological roles.We cloned a previously undescribed family of G protein-coupled receptors that we named the sensory neuron-specific receptors (SNSRs) because of their unique mRNA distribution in small nociceptive sensory neurons in dorsal root (DRG) and trigeminal ganglia (4). The SNSRs are phylogenetically related to the Mas oncogene receptor and belong to the Mas-related genes or Mrg family described for mouse and human by Dong et al. (5). Based on several analyses, this subfamily of receptors is comprised of four to six members in human (MrgX1-4 or SNSR1-6) and 32 receptors in mouse classified into three major subfamilies Mrg A, B, and C (4-7). Initially, only one SNSR gene was identified in rat (4); recently, Zylka et al. (8) have demonstrated that more than one rat SNSR͞ Mrg subtype exists. These receptors have been subclassified in a similar scheme as described for human a...

Human Sensory Neuron-specific Mas-related G Protein-coupled Receptors-X1 Sensitize and Directly Activate Transient Receptor Potential Cation Channel V1 via Distinct Signaling Pathways

“…Regarding the MRGPR-X1 subtype, one rodent receptor activated by BAM8 -22 was identified in mice and rats (MRGPR-C) (1, 2). However, apart from common high affinity binding to BAM8 -22, rodent MRGPR-C and human MRGPR-X1 exhibit fundamental differences in their affinity to other endogenous peptides, as previously reported (4,52,53). Furthermore, in contrast to rodent MRGPR-C, human MRGPR-X1 resist ␤-arrestin-dependent, agonist-promoted endocytosis (4), not only affecting signal duration but also directing GPCR-promoted signaling toward distinct signaling pathways (54).…”

Agonists of the Mas-Related Gene (Mrgs) Orphan Receptors as Novel Mediators of Mast Cell-Sensory Nerve Interactions

“…In addition, the RF-amides increase peripheral pain responses consistent with nociceptor modulation (29). Some of these molecules may stimulate nociceptors by interacting with acid-sensing ion channels (30), but the algogenic effect of RF-amides in rats, was not inhibited by pharmacological blockers of acid-sensing ion channels.…”

MrgD Activation Inhibits KCNQ/M-Currents and Contributes to Enhanced Neuronal Excitability

“…In addition, that rodents (MrgA-H) and humans (MrgD, MrgX) contain more than one Mrg, which may form heterodimers, suggests that the readouts from painful stimuli mediated by Mrgs may be complex. In vivo evidence for Mrgs in pain is limited, but one report found that activation of SNSR1 (MrgC) by its ligand, ␥2-MSH, was pronociceptive (Grazzini et al, 2004). Finally, a change in MrgD levels in response to chronicconstriction injury, a model of inflammatory and neuropathic pain, was noted by Shinohara et al (2004), but an increase or decrease in MrgD levels was not reported.…”