•Mrgpr gene family gathers more than 50 members in rodents and humans.•Mrgprs are mainly expressed in nociceptive neurons and specialized immune cells.•Mrgprs are essential player in pain, itch and ...neuroimmune interactions.•Some Mrgprs are still orphan receptors with unknown ligand and pathophysiological role.•Mrgprs represent promising future therapeutic targets in pain, itch and chronic inflammatory diseases.
Interplay between physiological systems in the body plays a prominent role in health and disease. At the cellular level, such interplay is orchestrated through the binding of specific ligands to their receptors expressed on cell surface. G protein-coupled receptors (GPCR) are seven-transmembrane domain receptors that initiate various cellular responses and regulate homeostasis. In this review, we focus on particular GPCRs named Mas-related G protein-coupled receptors (Mrgprs) mainly expressed by sensory neurons and specialized immune cells. We describe the different subfamilies of Mrgprs and their specific ligands, as well as recent advances in the field that illustrate the role played by these receptors in neuro-immune biological processes, including itch, pain and inflammation in diverse organs.
Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those ...derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1
Tac1
nociceptor-MRGPRB2
mast cell sensory clusters represents a key early event in the development of allergic skin reactions.
Recent studies revealed the existence of unique functional links between mast cells and nociceptors in the skin. Here, we propose that mast cells and nociceptors form a single regulatory unit in both ...physiology and disease. In this model, MrgprB2/X2 signaling is a primary mechanism by which mast cells functionally interact with nociceptors to form specialized neuroimmune clusters that regulate pain, inflammation, and itch.
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder that is characterized by chronic abdominal pain concurrent with altered bowel habit. Polyunsaturated fatty acid (PUFA) metabolites ...are increased in abundance in IBS and are implicated in the alteration of sensation to mechanical stimuli, which is defined as visceral hypersensitivity. We sought to quantify PUFA metabolites in patients with IBS and evaluate their role in pain. Quantification of PUFA metabolites by mass spectrometry in colonic biopsies showed an increased abundance of 5-oxoeicosatetraenoic acid (5-oxoETE) only in biopsies taken from patients with IBS with predominant constipation (IBS-C). Local administration of 5-oxoETE to mice induced somatic and visceral hypersensitivity to mechanical stimuli without causing tissue inflammation. We found that 5-oxoETE directly acted on both human and mouse sensory neurons as shown by lumbar splanchnic nerve recordings and Ca
imaging of dorsal root ganglion (DRG) neurons. We showed that 5-oxoETE selectively stimulated nonpeptidergic, isolectin B4 (IB4)-positive DRG neurons through a phospholipase C (PLC)- and pertussis toxin-dependent mechanism, suggesting that the effect was mediated by a G protein-coupled receptor (GPCR). The MAS-related GPCR D (Mrgprd) was found in mouse colonic DRG afferents and was identified as being implicated in the noxious effects of 5-oxoETE. Together, these data suggest that 5-oxoETE, a potential biomarker of IBS-C, induces somatic and visceral hyperalgesia without inflammation in an Mrgprd-dependent manner. Thus, 5-oxoETE may play a pivotal role in the abdominal pain associated with IBS-C.
Quiescent phases of inflammatory bowel disease (IBD) are often accompanied by chronic abdominal pain. Although the transient receptor potential vanilloid 1 (TRPV1) ion channel has been postulated as ...an important mediator of visceral hypersensitivity, its functional role in postinflammatory pain remains elusive. This study aimed at establishing the role of TRPV1 in the peripheral sensitization underlying chronic visceral pain in the context of colitis. Wild-type and TRPV1-deficient mice were separated into three groups (control, acute colitis, and recovery), and experimental colitis was induced by oral administration of dextran sulfate sodium (DSS). Recovery mice showed increased chemically and mechanically evoked visceral hypersensitivity 5 wk post-DSS discontinuation, at which point inflammation had completely resolved. Significant changes in nonevoked pain-related behaviors could also be observed in these animals, indicative of persistent discomfort. These behavioral changes correlated with elevated colonic levels of substance P (SP) and TRPV1 in recovery mice, thus leading to the hypothesis that SP could sensitize TRPV1 function. In vitro experiments revealed that prolonged exposure to SP could indeed sensitize capsaicin-evoked currents in both cultured neurons and TRPV1-transfected human embryonic kidney (HEK) cells, a mechanism that involved TRPV1 ubiquitination and subsequent accumulation at the plasma membrane. Importantly, although TRPV1-deficient animals experienced similar disease severity and pain as wild-type mice in the acute phase of colitis, TRPV1 deletion prevented the development of postinflammatory visceral hypersensitivity and pain-associated behaviors. Collectively, our results suggest that chronic exposure of colon-innervating primary afferents to SP could sensitize TRPV1 and thus participate in the establishment of persistent abdominal pain following acute inflammation.
Inflammatory visceral pain is endogenously controlled by enkephalins locally released by mucosal CD4
T lymphocytes in mice. The present study aimed at identifying opioid receptor(s) expressed on ...nociceptive sensory nerves involved in this peripheral opioid-mediated analgesia.
The peripheral analgesia associated with the accumulation of CD4
T lymphocytes within the inflamed colonic mucosa was assessed in conditional knockout mice specifically deleted for either of the two opioid receptors for enkephalins (i.e., µ (MOR) and δ (DOR) receptors) in Na
1.8-expressing sensory neurons in the dextran sulfate sodium (DSS)-induced colitis model.
Endogenous analgesia is lost in conditional knockout mice for DOR, but not MOR at the later phase of the DSS-induced colitis. The absence of either of the opioid receptors on sensory nerves had no impact on both the colitis severity and the rate of T lymphocytes infiltrating the inflamed colonic mucosa.
The key role of DOR on primary afferents in relieving intestinal inflammatory pain opens new therapeutic opportunities for peripherally restricted DOR analgesics to avoid most of the side effects associated with MOR-targeting drugs used in intestinal disorders.
Opioids remain the gold standard for the treatment of moderate to severe pain. However, their analgesic properties come with important side effects, including pruritus, which occurs frequently after ...systemic or neuraxial administration. Although part of the opioid-induced itch is mediated centrally, recent evidence shows that the opioid receptor system in the skin also modulates itch. The goal of our study was to identify the peripherally located transducer mechanisms involved in opioid-induced pruritus. Scratching behaviors in response to an intradermal injection of the mu-opioid receptor (MOR) agonist D-Ala2, N-MePhe4, Gly-ol-enkephalin (DAMGO) was quantified in mast cell-, PAR2- and TRPV1-deficient mice or following ablation of TRPV1+ sensory neurons. We found that mast cells-/-, PAR-2-/-, or TRPV1-/- mice still exhibit DAMGO-induced itch responses. However, we show that ablation of TRPV1+ neurons or acute TRPV1 activation by capsaicin abolishes DAMGO-induced itch. Overall, our work shows that peripheral DAMGO-induced itch is dependent on the presence of TRPV1-expressing pruriceptors, but not the TRPV1 channel itself. Activation of these fibers by capsaicin prevents the opioid-induced itch.
Immune activation may underlie the pathogenesis of irritable bowel syndrome (IBS), but the evidence is conflicting. We examined whether peripheral CD4+ T-cells from IBS patients demonstrated immune ...activation and changes in cytokine production. To gain mechanistic insight, we examined whether immune activation correlated with psychological stress and changing symptoms over time. IBS patients (n = 29) and healthy volunteers (HV; n = 29) completed symptom and psychological questionnaires. IBS patients had a significant increase in CD4+ T-cells expressing the gut homing marker integrin β7 (p = 0.023) and lymphoid marker CD62L (p = 0.026) compared to HV. Furthermore, phytohaemagglutinin stimulated CD4+ T-cells from IBS-D patients demonstrated increased TNFα secretion when compared to HV (p = 0.044). Increased psychological scores in IBS did not correlate with TNFα production, while stress hormones inhibited cytokine secretion from CD4+ T-cells of HV in vitro. IBS symptoms, but not markers of immune activation, decreased over time. CD4+ T-cells from IBS-D patients exhibit immune activation, but this did not appear to correlate with psychological stress measurements or changing symptoms over time. This could suggest that immune activation is a surrogate of an initial trigger and/or ongoing parallel peripheral mechanisms.
Pain is a main symptom of inflammatory diseases and often persists beyond clinical remission. Although we have a good understanding of the mechanisms of sensitization at the periphery during ...inflammation, little is known about the mediators that drive central sensitization. Recent reports have identified hematopoietic colony-stimulating factors as important regulators of tumor- and nerve injury-associated pain. Using a mouse model of colitis, we identify the proinflammatory cytokine granulocyte-colony–stimulating factor (G-CSF or Csf-3) as a key mediator of visceral sensitization. We report that G-CSF is specifically up-regulated in the thoracolumbar spinal cord of colitis-affected mice. Our results show that resident spinal microglia express the G-CSF receptor and that G-CSF signaling mediates microglial activation following colitis. Furthermore, healthy mice subjected to intrathecal injection of G-CSF exhibit pronounced visceral hypersensitivity, an effect that is abolished by microglial depletion. Mechanistically, we demonstrate that G-CSF injection increases Cathepsin S activity in spinal cord tissues. When cocultured with microglia BV-2 cells exposed to G-CSF, dorsal root ganglion (DRG) nociceptors become hyperexcitable. Blocking CX3CR1 or nitric oxide production during G-CSF treatment reduces excitability and G-CSF–induced visceral pain in vivo. Finally, administration of G-CSF–neutralizing antibody can prevent the establishment of persistent visceral pain postcolitis. Overall, our work uncovers a DRG neuron–microglia interaction that responds to G-CSF by engaging Cathepsin S-CX3CR1-inducible NOS signaling. This interaction represents a central step in visceral sensitization following colonic inflammation, thereby identifying spinal G-CSF as a target for treating chronic abdominal pain.
Pain and inflammation are inherently linked responses to injury, infection, or chronic diseases. Given that acute inflammation in humans or mice enhances the analgesic properties of opioids, there is ...much interest in determining the inflammatory transducers that prime opioid receptor signaling in primary afferent nociceptors. Here, we found that activation of the transient receptor potential vanilloid type 1 (TRPV1) channel stimulated a mitogen-activated protein kinase (MAPK) signaling pathway that was accompanied by the shuttling of the scaffold protein β-arrestin2 to the nucleus. The nuclear translocation of β-arrestin2 in turn prevented its recruitment to the μ-opioid receptor (MOR), the subsequent internalization of agonist-bound MOR, and the suppression of MOR activity that occurs upon receptor desensitization. Using the complete Freund's adjuvant (CFA) inflammatory pain model to examine the role of TRPV1 in regulating endogenous opioid analgesia in mice, we found that naloxone methiodide (Nal-M), a peripherally restricted, nonselective, and competitive opioid receptor antagonist, slowed the recovery from CFA-induced hypersensitivity in wild-type, but not TRPV1-deficient, mice. Furthermore, we showed that inflammation prolonged morphine-induced antinociception in a mouse model of opioid receptor desensitization, a process that depended on TRPV1. Together, our data reveal a TRPV1-mediated signaling pathway that serves as an endogenous pain-resolution mechanism by promoting the nuclear translocation of β-arrestin2 to minimize MOR desensitization. This previously uncharacterized mechanism may underlie the peripheral opioid control of inflammatory pain. Dysregulation of the TRPV1-β-arrestin2 axis may thus contribute to the transition from acute to chronic pain.
PDF
