Research ReportRegulation of two rat mas-related genes in a model of neuropathic pain
Introduction
The Mrg (mas-related gene) family is a complex group of genes which exhibit considerable interspecies differences, both in the number and homology of Mrgs found in a given species [1], [5], [12], [16], [17]. Interspecies differences may have resulted from positive selection for nociceptive functional diversification [4] as has been seen for taste receptors [14]. To further complicate the nomenclature, several Mrgs have been described as sensory-neuron-specific receptors (SNSR), based on their preferential localization in neurons of the dorsal root ganglia [5], [12]. While many are still classified as orphan receptors, a number of these receptors have been “de-orphaned” in the past several years by the identification of ligands which activate their cognate receptor(s). These receptor/ligand pairs include the activation of human MrgX2 by cortistatin and proadrenomedullin-derived peptides [10], [13], activation of human MrgX1 (aka SNSR4), SNSR3, and rat rMrgC by BAM22 (bovine adrenal medulla peptide) [6], [12], activation of MrgA1, MrgA4, and MrgC11 by a variety of RF-amide neuropeptides [5], [8], and activation of the rat version of MrgA10 by adenine [1].
In spite of the considerable complexity presented by the interspecies differences in this gene family, the expression of a subset of these genes in sensory neurons of the dorsal root ganglia makes them a compelling target for pain research. Chronic pain syndromes in particular represent a large unmet medical need, and the search for novel mechanisms may provide innovative therapeutics devoid of the side effects known for currently available remedies. In the present study, we have examined the effects of spinal nerve ligation on the expression of two members of the rat Mrg family, termed here rMrgA and rMrgC, in dorsal root ganglia. Our results indicate that these two genes are more widely expressed than previously demonstrated and, more importantly, that both are downregulated in a neuropathic pain model.
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Experimental animals
Experiments were carried out on male Sprague–Dawley rats (Charles River, Calco, Italy) weighing 150–175 g at time of surgery. Rats were housed in groups of 6 per cage and supplied with food and water ad libitum, under a 12 h day/night cycle at a constant room temperature of 21 °C. The animals were kept 2 days under these conditions before surgery. All experimental procedures involving rat manipulation were performed according to Schering-Plough ACUC guidelines, in compliance with both the
Note on nomenclature
In our review of the literature, it became clear that following the “SNSR” nomenclature would be counterproductive. First, as shown below, the two liganded members of the rat Mrg family are not sensory-neuron-specific. Second, the existing Mrg nomenclature covers all of the known family members and provides an interspecies point of reference for all. A ClustalW multiple sequence alignment [3] of the two rat receptors of interest and their closest mouse and human relatives resulted in the
Discussion
In the present study, the tissue distribution of two related rat Mrg receptors has been elucidated, and we have demonstrated that the expression of these genes in the DRG is regulated in response to a neuropathic stimulus. The results of the quantitative PCR studies suggest that rMrgC and rMrgA are more widely distributed than previously documented, although both are present in the DRG and trigeminal ganglion. In addition, the qPCR results indicate that the expression of both genes is
Acknowledgments
The authors would like to acknowledge the support of Dr. Marvin Bayne, Dr. John Hunter, and Dr. Catherine Strader in performing these studies.
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Cited by (11)
Effects of the mas-related gene (Mrg) C receptor agonist BAM6-22 on nociceptive reflex activity in naive, monoarthritic and mononeuropathic rats after intraplantar and intrathecal administration
2016, European Journal of PharmacologyCitation Excerpt :This result is in agreement with previous reports demonstrating that spinal MrgC receptor agonists inhibited neuropathy-induced mechanical hypersensitivity in mice and rats (Guan et al., 2010; He et al., 2014b). As for inflammation, also peripheral nerve injury was reported to change MrgC receptor expression in rats (Gustafson et al., 2005; He et al., 2014a). From the perspective of potential therapeutic application, first studies exploring the role of MrgC receptors in nociception suggested that MrgC receptor antagonists might be effective analgesics as peripherally and centrally administered MrgC receptor agonists elicited pronociceptive effects in naïve rats (Cao et al., 2003; Grazzini et al., 2004).
Temporal changes in MrgC expression after spinal nerve injury
2014, NeuroscienceCitation Excerpt :It is also unclear whether nerve injury induces time-dependent changes in MrgC expression that differ between injured and uninjured DRG. A previous study showed that spinal nerve ligation (SNL) decreased MrgC mRNA levels in injured DRG, but not in adjacent uninjured DRG, at day 14 post-SNL (Gustafson et al., 2005). Yet, it remains unclear if the decreased mRNA in injured DRG recovers at later time points (e.g., maintenance/recovery phase of neuropathic pain) and whether MrgC mRNA is upregulated in uninjured DRG.
Involvement of NMDA receptor in nociceptive effects elicited by intrathecal [Tyr<sup>6</sup>] γ2-MSH(6-12), and the interaction with nociceptin/orphanin FQ in pain modulation in mice
2009, Brain ResearchCitation Excerpt :Despite their pharmacological differences, mas-related genes (sensory neuron-specific receptors) have been shown to be located in small diameter sensory neurons of the trigeminal nerve, dorsal root ganglia (Dong et al., 2001), suggesting an important role of the receptors in nociception. Actually, several members of Mrg receptors have been suggested to be involved in pain transmission (Cai et al., 2007; Choi and Lahn, 2003; Cox et al., 2008; Gustafson et al., 2005; Hager et al., 2008; Honan and McNaughton, 2007; Zeng et al., 2004). Grazzini et al. (2004) proved that activation of rMrgC by intrathecal [Tyr6] γ2-MSH(6-12) or BAM(8-22) evoked pronociceptive effects (decrease in the tail withdrawal latency), and activation of rMrgC by peripheral [Tyr6] γ2-MSH(6-12) elicited pain behaviors, heat hyperalgesia, and mechanical allodynia.
Murine central and peripheral nervous system transcriptomes: Comparative gene expression
2006, Brain ResearchCitation Excerpt :Instead, many of these GPCRs may be involved in chemical nociception or trophic survival of axons. For illustration, the mas-related gene (Mrg) family includes a number of G-protein-coupled receptors that are specific or relatively specific to sensory neurons of the PNS (Gustafson et al., 2005). Several of these Mrgs are activated by peptides.
Mas and its related G protein–coupled receptors, Mrgprs
2014, Pharmacological Reviews