Mas-related G-protein–coupled receptors inhibit pathological pain in mice

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2010; 107(36):15933-8. DOI: 10.1073/pnas.1011221107
Source: PubMed


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.

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Available from: Xinzhong Dong, Feb 05, 2014
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    • "The approach utilized in this study readily detected these effects. Other group suggested that members of the Mrgpr family, in particular, MrgprC11, may constitute an endogenous inhibitory mechanism for regulating persistent pain in mice [8]. Our results indicate that A779 and losartan potentiate carrageenan-induced hyperalgesia in rats. "
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    ABSTRACT: We investigated the mechanisms underlying the endogenous control of nociception at the peripheral level during inflammation. We hypothesized that angiotensin receptors could modulate pain at the peripheral level via endogenous processes because angiotensin receptors are present in peripheral nerve terminals. We evaluated the role of the angiotensin receptors system (RAS) in the modulation of inflammatory and neuropathic pain states. Mas receptor KO mice exhibited major inflammatory pain compared to wild-type mice. Similar results were observed when rats were injected with the Mas receptor antagonist A779 or the AT1 receptor antagonist, losartan after inflammatory stimulation by carrageenan. However, these antagonists were not effective in animals with neuropathic-induced pain (e.g., sciatic nerve constriction). Therefore, RAS seems to play an important role in inflammatory but not neuropathic pain.
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    • "Although it remains to be confirmed by pharmacokinetic measurements, it is possible that small volumes of drug (eg, 10 lL, dissolved in saline) are quickly diluted by the cerebrospinal fluid after intrathecal infusion. Furthermore , intrathecal MrgC agonists induce analgesia at lower doses without signs of irritation (eg, BAM8-22: 0.5 mM, JHU58: 0.05 mM, 10 lL) [17] [22]. Intriguingly, JHU58 also inhibited HVA I Ca at a concentration (0.1 nM) much lower than that needed to induce calcium transients (>3 lM) in DRG neurons. "

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    • "Furthermore, BAM8–22 inhibits the upregulation of inflammatory mediators, such as CGRP, in the spinal cord (Jiang et al., 2013), and it changes the signaling of m-opioid receptors, enhancing and maintaining their antinociceptive activity even in the presence of morphines, which normally would induce tolerance (Cai et al., 2007b; Chen et al., 2010; Wang et al., 2013a). Thus, Mrgprs binding BAM8–22, such as mMrgprX1, rMrgprX1, and hMRGPRX1, exert different effects in the skin, where they elicit itch and pain (Liu et al., 2009; Sikand et al., 2011), and in the spinal cord, where they exert mainly hypoalgesic but also, albeit less potently, hyperalgesic actions (Guan et al., 2010). These actions are more pronounced in inflammatory conditions , probably because the expression of BAM22 (Cai et al., 2007a) and of rMrgprX1 (Jiang et al., 2013) are upregulated in DRGs in inflammation, e.g., induced by intrapaw injection of complete Freund's adjuvant; however , there are also conflicting data in the same model (Ndong et al., 2009), and a downregulation of rMrgprX1 has been observed after spinal nerve ligation (Gustafson et al., 2005). "
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    ABSTRACT: The Mas-related G protein-coupled receptors (Mrgprs or Mas-related genes) comprise a subfamily of receptors named after the first discovered member, Mas. For most Mrgprs, pruriception seems to be the major function based on the following observations: 1) they are relatively promiscuous in their ligand specificity with best affinities for itch-inducing substances; 2) they are expressed in sensory neurons and mast cells in the skin, the main cellular components of pruriception; and 3) they appear in evolution first in tetrapods, which have arms and legs necessary for scratching to remove parasites or other noxious substances from the skin before they create harm. Because parasites coevolved with hosts, each species faced different parasitic challenges, which may explain another striking observation, the multiple independent duplication and expansion events of Mrgpr genes in different species as a consequence of parallel adaptive evolution. Their predominant expression in dorsal root ganglia anticipates additional functions of Mrgprs in nociception. Some Mrgprs have endogenous ligands, such as β-alanine, alamandine, adenine, RF-amide peptides, or salusin-β. However, because the functions of these agonists are still elusive, the physiologic role of the respective Mrgprs needs to be clarified. The best studied Mrgpr is Mas itself. It was shown to be a receptor for angiotensin-1-7 and to exert mainly protective actions in cardiovascular and metabolic diseases. This review summarizes the current knowledge about Mrgprs, their evolution, their ligands, their possible physiologic functions, and their therapeutic potential.
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