Signaling by heptahelical G protein-coupled receptors (GPCR) regulates many vital body functions. Consequently, dysfunction of GPCR signaling leads to pathologic states, and approximately 30% of all ...modern clinical drugs target GPCR. One decade ago, an entire new GPCR family was discovered, which was recently named MAS-related G protein-coupled receptors (MRGPR) by the HUGO Gene Nomenclature Committee. The MRGPR family consists of ∼40 members that are grouped into nine distinct subfamilies (MRGPRA to -H and -X) and are predominantly expressed in primary sensory neurons and mast cells. All members are formally still considered "orphan" by the Committee on Receptor Nomenclature and Drug Classification of the International Union of Basic and Clinical Pharmacology. However, several distinct peptides and amino acids are discussed as potential ligands, including β-alanine, angiotensin-(1-7), alamandine, GABA, cortistatin-14, and cleavage products of proenkephalin, pro-opiomelanocortin, prodynorphin, or proneuropeptide-FF-A. The full spectrum of biologic roles of all MRGPR is still ill-defined, but there is evidence pointing to a role of distinct MRGPR subtypes in nociception, pruritus, sleep, cell proliferation, circulation, and mast cell degranulation. This review article summarizes findings published in the last 10 years on the phylogenetic relationships, pharmacology, signaling, physiology, and agonist-promoted regulation of all MRGPR subfamilies. Furthermore, we highlight interactions between MRGPR and other hormonal systems, paying particular attention to receptor multimerization and morphine tolerance. Finally, we discuss the challenges the field faces presently and emphasize future directions of research.
Single intradermal injections of nerve growth factor (NGF) evoke prolonged but temporally distinct sensitization patterns to somatosensory stimuli. Focal administration of the non-histaminergic ...pruritogen cowhage but not histamine resulted in elevated itch at day 21 after NGF administration. Here, we injected bovine adrenal medulla peptide 8-22 (BAM8-22), β-alanine (β-ALA) and endothelin-1 (ET-1) into NGF-treated skin of 11 healthy volunteers and investigated the corresponding itch/pain and flare reactions. β-ALA was the weakest pruritogen, while BAM8-22 and ET-1 were equally potent as histamine. NGF did not sensitize itch or flare reactions induced by any compound, but injection and evoked pain were increased at day 21 and 49. The involvement of histamine H1 receptors in itch was explored in eight subjects after oral cetirizine. ET-1-induced itch and flare were significantly reduced. BAM8-22 and β-ALA itch were not affected, but flare responses after BAM8-22 reduced by 50%. The results indicate that a single NGF injection does not sensitize for experimentally induced itch but increases pain upon pruritogen injection. In healthy humans, pruritic and algetic processing appear differentially regulated by NGF. However, in patients suffering chronic itch, prolonged elevation of NGF-levels under inflammatory conditions may contribute to elevated itch.
In humans, intradermal administration of β-alanine (ALA) and bovine adrenal medulla peptide 8-22 (BAM8-22) evokes the sensation of itch. Currently, it is unknown which human dorsal root ganglion ...(DRG) neurons express the receptors of these pruritogens, MRGPRD and MRGPRX1, respectively, and which cutaneous afferents these pruritogens activate in primate. In situ hybridization studies revealed that MRGPRD and MRGPRX1 are co-expressed in a subpopulation of TRPV1+ human DRG neurons. In electrophysiological recordings in nonhuman primates (
), subtypes of polymodal C-fiber nociceptors are preferentially activated by ALA and BAM8-22, with significant overlap. When pruritogens ALA, BAM8-22, and histamine, which activate different subclasses of C-fiber afferents, are administered in combination, human volunteers report itch and nociceptive sensations similar to those induced by a single pruritogen. Our results provide evidence for differences in pruriceptive processing between primates and rodents, and do not support the spatial contrast theory of coding of itch and pain.
Stimuli that elicit itch are detected by sensory neurons that innervate the skin. This information is processed by the spinal cord; however, the way in which this occurs is still poorly understood. ...Here we investigated the neuronal pathways for itch neurotransmission, particularly the contribution of the neuropeptide somatostatin. We find that in the periphery, somatostatin is exclusively expressed in Nppb
neurons, and we demonstrate that Nppb
somatostatin
cells function as pruriceptors. Employing chemogenetics, pharmacology and cell-specific ablation methods, we demonstrate that somatostatin potentiates itch by inhibiting inhibitory dynorphin neurons, which results in disinhibition of GRPR
neurons. Furthermore, elimination of somatostatin from primary afferents and/or from spinal interneurons demonstrates differential involvement of the peptide released from these sources in itch and pain. Our results define the neural circuit underlying somatostatin-induced itch and characterize a contrasting antinociceptive role for the peptide.
TRPM3 is a calcium-permeable cation channel expressed in a range of sensory neurons that can be activated by heat and the endogenous steroid pregnenolone sulfate (PS). During inflammation, the ...expression and function of TRPM3 are both augmented in somatosensory nociceptors. However, in isolated dorsal root ganglion (DRG) neurons application of inflammatory mediators like prostaglandins and bradykinin (BK) inhibit TRPM3. Therefore, the aim of this study was to examine the effect of preceding activation of cultured 1 day old mouse DRG neurons by the inflammatory mediator BK on TRPM3-mediated calcium responses. Calcium signals were recorded using the intensity-based dye Fluo-8. We found that TRPM3-mediated calcium responses to PS were enhanced by preceding application of BK in cells that responded to BK with a calcium signal, indicating BK receptor (BKR) expression. The majority of cells that co-expressed TRPM3 and BKRs also expressed TRPV1, however, only a small fraction co-expressed TRPA1, identified by calcium responses to capsaicin and supercinnamaldehyde, respectively. Signaling and trafficking pathways responsible for sensitization of TRPM3 following BK were characterized using inhibitors of second messenger signaling cascades and exocytosis. Pharmacological blockade of protein kinase C, calcium-calmodulin-dependent protein kinase II and diacylglycerol (DAG) lipase did not affect BK-induced sensitization, but inhibition of DAG kinase did. In addition, release of calcium from intracellular stores using thapsigargin also resulted in TRPM3 sensitization. Finally, BK did not sensitize TRPM3 in the presence of exocytosis inhibitors. Collectively, we show that preceding activation of DRG neurons by BK sensitized TRPM3-mediated calcium responses to PS. Our results indicate that BKR-mediated activation of intracellular signaling pathways comprising DAG kinase, calcium and exocytosis may contribute to TRPM3 sensitization during inflammation.
Itch is an unpleasant skin sensation that can be triggered by exposure to many chemicals, including those released by mast cells. The natriuretic polypeptide b (Nppb)-expressing class of sensory ...neurons, when activated, elicits scratching responses in mice, but it is unclear which itch-inducing agents stimulate these cells and the receptors involved. Here, we identify receptors expressed by Nppb neurons and demonstrate the functional importance of these receptors as sensors of endogenous pruritogens released by mast cells. Our search for receptors in Nppb neurons reveals that they express leukotriene, serotonin, and sphingosine-1-phosphate receptors. Targeted cell ablation, calcium imaging of primary sensory neurons, and conditional receptor knockout studies demonstrate that these receptors induce itch by the direct stimulation of Nppb neurons and neurotransmission through the canonical gastrin-releasing peptide (GRP)-dependent spinal cord itch pathway. Together, our results define a molecular and cellular pathway for mast cell-induced itch.
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•Chemogenetic activation of mast cells induces itch responses•Receptors for mast cell mediators are specifically expressed by Nppb neurons•Serotonin, leukotriene, and sphingosine-1-phosphate stimulate Nppb neurons•Mast cell activation via GRP spinal cord signaling elicits itch behavior
Solinski et al. describe a cellular and molecular pathway that couples mast cell activation to itch behavior. They show that mast cell mediators, serotonin, leukotriene-C4, and sphingosine-1 phosphate directly stimulate Nppb sensory neurons via Htr1f, Cysltr2, and S1pr1 receptors, and this results in itch responses that are elicited through a canonical spinal cord-GRP pathway.
Piezo2 is a mechanically activated ion channel required for touch discrimination, vibration detection, and proprioception. Here, we discovered that Piezo2 is extensively spliced, producing different ...Piezo2 isoforms with distinct properties. Sensory neurons from both mice and humans express a large repertoire of Piezo2 variants, whereas non-neuronal tissues express predominantly a single isoform. Notably, even within sensory ganglia, we demonstrate the splicing of Piezo2 to be cell type specific. Biophysical characterization revealed substantial differences in ion permeability, sensitivity to calcium modulation, and inactivation kinetics among Piezo2 splice variants. Together, our results describe, at the molecular level, a potential mechanism by which transduction is tuned, permitting the detection of a variety of mechanosensory stimuli.
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•Piezo2 undergoes alternative splicing•Sensory neurons express multiple Piezo2 variants; non-neuronal tissues express one•Different classes of touch neurons express different Piezo2 splice forms•Alternative splicing confers functional differences on Piezo2
Szczot et al. find that the mechanoreceptor Piezo2 is extensively alternatively spliced, generating multiple distinct isoforms. Their findings indicate that these splice products have specific tissue and cell type expression patterns and exhibit differences in receptor properties.
Slowly depolarizing currents applied for one minute have been shown to activate C-nociceptors and provoke increasing pain in patients with neuropathy. This study examined the effect of transcutaneous ...slowly depolarizing currents on pruritus in patients with atopic dermatitis. C-nociceptor-specific electrical stimulation was applied to areas of eczema-affected and non-affected skin in 26 patients with atopic dermatitis. Single half-sine wave pulses (500 ms, 0.2–1 mA) induced itch in 9 patients in eczema-affected areas of the skin (numerical rating scale 5 ± 1), but pain in control skin (numerical rating scale 6±1).Sinusoidal stimuli (4 Hz, 10 pulses, 0.025–0.4 mA) evoked itch in only 3 patients in eczema-affected areas of the skin but on delivering pulses for one minute (0.05–0.2 mA) 48% of the patients (
n
= 12) reported itch with numerical rating scale 4 ± 1 in areas of eczema-affected skin. The number of patients reporting itch in eczema-affected areas of the skin increased with longer stimulation (
p
< 0.005). These results demonstrate a reduced adaptation of peripheral C-fibres conveying itch in patients with atopic dermatitis. Sensitized spinal itch processing had been suggested before in atopic dermatitis patients, and this could be present also in our patients who therefore might benefit from centrally acting antipruritic therapy.
Administration of chemicals (pruritogens) into the skin evokes itch based on signal transduction mechanisms that generate action potentials mainly in mechanically sensitive and
sensitive primary ...afferent C-fibers (pruriceptors). These signals from peripheral neurons are processed in spinal and supra-spinal centers of the central nervous system and finally generate the sensation of itch. Compared to chemical stimulation, electrical activation of pruriceptors would allow for better temporal control and thereby a more direct functional assessment of their activation. Here, we review the electrical stimulation paradigms which were used to evoke itch in humans in the past. We further evaluate recent attempts to explore electrically induced itch in atopic dermatitis patients. Possible mechanisms underlying successful pruritus generation in chronic itch patients by transdermal slowly depolarizing electrical stimulation are discussed.
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