Itch Sensation Research Articles

Nociceptin/Orphanin FQ Peptide Receptor-Related Ligands as Novel Analgesics.

Despite similar distribution patterns and intracellular events observed in the nociceptin/ orphanin FQ peptide (NOP) receptor and other opioid receptors, NOP receptor activation displays unique pharmacological profiles. Several researchers have identified a variety of peptide and nonpeptide ligands to determine the functional roles of NOP receptor activation and observed that NOP receptor- related ligands exhibit pain modality-dependent pain processing. Importantly, NOP receptor activation results in anti-nociception and anti-hypersensitivity at the spinal and supraspinal levels regardless of the experimental settings in non-human primates (NHPs). Given that the NOP receptor agonists synergistically enhance mu-opioid peptide (MOP) receptor agonist-induced anti-nociception, it has been hypothesized that dual NOP and MOP receptor agonists may display promising functional properties as analgesics. Accumulating evidence indicates that the mixed NOP/opioid receptor agonists demonstrate favorable functional profiles. In NHP studies, bifunctional NOP/MOP partial agonists (e.g., AT-121, BU08028, and BU10038) exerted potent anti-nociception via NOP and MOP receptor activation; however, dose-limiting adverse effects associated with the MOP receptor activation, including respiratory depression, itch sensation, physical dependence, and abuse liability, were not observed. Moreover, a mixed NOP/opioid receptor agonist, cebranopadol, presented promising outcomes in clinical trials as a novel analgesic. Collectively, the dual agonistic actions on NOP and MOP receptors, with appropriate binding affinities and efficacies, may be a viable strategy to develop innovative and safe analgesics.

The pseudo-allergic/neurogenic route of mast cell activation via MRGPRX2: discovery, functional programs, regulation, relevance to disease, and relation with allergic stimulation

Mast cells (MCs) form operating units with sensory nerves and can contribute to sensations of itch and pain. However, it remained enigmatic for decades how MCs are actually activated in the absence of atopy. MRGPRX2 was discovered only recently but has already changed our view of MC biology. As the receptor of multiple endogenous and exogenous ligands, including substance P and various drugs, MRGPRX2 can be viewed as the missing link underlying clinically relevant MC degranulation in the context of drug-triggered pseudo-allergy and autonomous (eg, neuronal) MC activation in disease. Its existence explains previous findings that remained inexplicable for a long time. The confinement of MRGPRX2 to MCs, and even only to the subgroup of MCTC-type MCs, makes research in this field exciting from a theoretical as well as from a translational or pharmacological perspective alike. In this review, I will first give a brief overview of MCs, their subsets and modes of activation, then briefly touch on the history of MRGPRX2 discovery, summarize some recent advances regarding ligands, functional aspects and regulation by extracellular cues, and recapitulate the emerging role of the MRGPRX2 system in health and disease. Finally, a concise comparison between MRGPRX2 and FcεRI will be presented, contrasting key characteristics of the 2 dominant ways of MC activation. There is a huge disproportion in our understanding of FcεRI-triggered versus MRGPRX2-triggered events, but since research into the latter is in full swing, some of the missing pieces of the puzzle are likely to be filled in soon.

Molecular Signature of Pruriceptive MrgprA3+ Neurons

Itch, initiated by the activation of sensory neurons, is associated frequently with dermatological diseases. MrgprA3+ sensory neurons have been identified as one of the major itch-sensing neuronal populations. Mounting evidence has demonstrated that peripheral pathological conditions induce physiological regulation of sensory neurons, which is critical for the maintenance of chronic itch sensation. However, the underlying molecular mechanisms are not clear. Here, we performed RNA sequencing of genetically labeled MrgprA3+ neurons under both naïve and allergic contact dermatitis conditions. Our results revealed the unique molecular signature of itch-sensing neurons and the distinct transcriptional profile changes that result in response to dermatitis. We found enrichment of nine Mrgpr family members and two histamine receptors in MrgprA3+ neurons, suggesting that MrgprA3+ neurons are a direct neuronal target for histamine and Mrgpr agonists. In addition, PTPN6 and PCDH12 were identified as highly selective markers of MrgprA3+ neurons. We also discovered that MrgprA3+ neurons respond to skin dermatitis in a way that is unique from other sensory neurons by regulating a combination of transcriptional factors, ion channels, and key molecules involved in synaptic transmission. These results significantly increase our knowledge of itch transmission and uncover potential targets for combating itch.

Anteromedial thalamic nucleus to anterior cingulate cortex inputs modulate histaminergic itch sensation

Itch is an unpleasant feeling that triggers scratching behavior. Much progress has been made in identifying the mechanism of itch at the peripheral and spinal levels, however, itch circuits in the brain remain largely unexplored. We previously found that anterior cingulate cortex (ACC) to dorsal medial striatum (DMS) inputs modulated histamine-induced itch sensation, but how itch information was transmitted to ACC remained unclear. Here, we demonstrated that the anteromedial thalamic nucleus (AM) was activated during histaminergic itch, and there existed reciprocal neuronal projections between AM and ACC. Disconnection between AM and ACC resulted in a significant reduction of histaminergic, but not nonhistaminergic, itch-related scratching behavior. Optogenetic activation of AM-ACC, but not ACC-AM, projections evoked histaminergic itch sensation. Thus, our studies firstly reveal that AM is critical for histaminergic itch sensation and AM-ACC projections modulate histaminergic itch-induced scratching behavior.

GRP receptor and AMPA receptor cooperatively regulate itch-responsive neurons in the spinal dorsal horn

Gastrin-releasing peptide (GRP) receptor-expressing (GRPR)+ neurons have a central role in the spinal transmission of itch. Because their fundamental regulatory mechanisms are not yet understood, it is important to determine how such neurons are excited and integrate itch sensation. In this study, we investigated the mechanisms for the activation of itch-responsive GRPR+ neurons in the spinal dorsal horn (SDH). GRPR+ neurons expressed the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) containing the GluR2 subunit. In mice, peripherally elicited histaminergic and non-histaminergic itch was prevented by intrathecal (i.t.) administration of the AMPAR antagonist NBQX, which was consistent with the fact that firing of GRPR+ neurons in SDH under histaminergic and non-histaminergic itch was completely blocked by NBQX, but not by the GRPR antagonist RC-3095. Because GRP+ neurons in SDH contain glutamate, we investigated the role of GRP+ (GRP+/Glu+) neurons in regulating itch. Chemogenetic inhibition of GRP+ neurons suppressed both histaminergic and non-histaminergic itch without affecting the mechanical pain threshold. In nonhuman primates, i.t. administration of NBQX also attenuated peripherally elicited itch without affecting the thermal pain threshold. In a mouse model of diphenylcyclopropenone (DCP)-induced contact dermatitis, GRP, GRPR, and AMPAR subunits were upregulated in SDH. DCP-induced itch was prevented by either silencing GRP+ neurons or ablation of GRPR+ neurons. Altogether, these findings demonstrate that GRP and glutamate cooperatively regulate GRPR+ AMPAR+ neurons in SDH, mediating itch sensation. GRP–GRPR and the glutamate–AMPAR system may play pivotal roles in the spinal transmission of itch in rodents and nonhuman primates.

Neural similarities and differences between pain and itch: Reception, transmission and modulation

Both pain and itch are important protective sensations of the human body, which could induce reflective behaviors such as withdraw and scratch when facing danger. Pain and itch have some similarities in the process of sensory information transmission and modulation, but whether the two sensations share the same neural pathway is still controversial. Most of the existing research focuses on a single level (e.g., neurons, fibers, or brain regions) to explore the relationship between two sensations. Here, we discussed the similarities and differences of neural mechanisms between pain and itch perceptions from bottom-up and top-down pathways of the peripheral and central nervous system based on recent neuroimaging and electrophysiological studies. First, we reviewed the neural coding mechanisms of pain and itch on the peripheral nervous system and central nervous system. Existing research based on the peripheral nervous system shows that the itch reception and nociception induced by different stimuli, such as heat pain, mechanically pain, histamine dependent and independent itch, selectively transmit through different primary afferent nerves, including Aδ and C fibers. Furthermore, we summarized the roles of the spinothalamic tract and the spinoparabrachial pathway in the sensory information transmission of pain and itch sensations separately at the spinal cord level. Then we compared the specific brain regions related to these two sensations, including the insula, amygdala, cingulate cortex, primary and secondary sensory cortex, which composed a “matrix” responsible for producing the perception of itch and pain but with different features. Second, we introduced the descending pain modulation system with critical regions of the periaqueductal gray (PAG) and the rostral ventromedial medulla (RVM), and we compared the different modulation mechanisms of pain and itch perceptions in the central nervous system. Meanwhile, we explained the pain and itch analgesic mechanism in the view of bidirectional modulation involved the reward system, which usually considered merely the opposite of aversive somatosensory system. The existing research conclusion showed that the neural mechanisms of pain and itch are not purely independent, overlapping, or antagonistic, but have very complex interactions. To reveal the underlying mechanisms of complex interactions, more precise neurological techniques (e.g., high-resolution head-neck combined imaging) are needed for future studies. To distinguish the mechanisms of pain and itch sensations are very important to the targeted clinical treatment. Our review summarized their similarities and differences, which could provide some new insights to explore the useful treatment directions.

Neural Mechanisms of Itch.

Itch is a unique sensation that helps organisms scratch away external threats; scratching itself induces an immune response that can contribute to more itchiness. Itch is induced chemically in the peripheral nervous system via a wide array of receptors. Given the superficial localization of itch neuron terminals, cells that dwell close to the skin contribute significantly to itch. Certain mechanical stimuli mediated by recently discovered circuits also contribute to the itch sensation. Ultimately, in the spinal cord, and likely in the brain, circuits that mediate touch, pain, and itch engage in cross modulation. Much of itch perception is still a mystery, but we present in this review the known ligands and receptors associated with itch. We also describe experiments and findings from investigations into the spinal and supraspinal circuitry responsible for the sensation of itch.

Efficacy of pregabalin for the treatment of chronic pruritus of unknown origin, assessed based on electric current perception threshold

Chronic pruritus of unknown origin (CPUO) is defined as itching lasting more than 6 weeks in the absence of discernible skin lesions. Pregabalin is used to treat patients with CPUO. In this study, we aimed to investigate differences in the perception threshold of itch sensation between patients with CPUO and healthy individuals and to evaluate the efficacy of pregabalin for CPUO. At baseline, week 2, and week 4 after treatment initiation, the visual analogue scale (VAS) score was measured to assess pruritus severity, and electric current perception threshold (CPT) was measured at 250 and 5 Hz using a NEUROMETER CPT/C stimulator. Twenty healthy individuals and 41 patients with CPUO were enrolled in this study. The patients with CPUO were categorised as those who responded to antihistamines (Antihistamine group), were not improved by antihistamines (Pregabalin group), and were not improved by antihistamines and pregabalin (Refractory group). The baseline CPT values were not significantly different between patients with CPUO and healthy control. Pruritus was improved in 7 of 10 patients in the Pregabalin group after treatment with pregabalin, showing decreased CPT at 5 Hz. The sensitive C-fibres presented a high threshold to detect itch sensation, and this sensitivity decreased in response to treatment with pregabalin.

Quantitative Characterization of the Neuropeptide Level Changes in Dorsal Horn and Dorsal Root Ganglia Regions of the Murine Itch Models.

Chronic itch can be extremely devastating and, in many cases, difficult to treat. One challenge in treating itch disorders is the limited understanding of the multitude of chemical players involved in the communication of itch sensation from the peripheral to the central nervous system. Neuropeptides are intercellular signaling molecules that are known to be involved in the transmission of itch signals from primary afferent neurons, which detect itch in the skin, to higher-order circuits in the spinal cord and brain. To investigate the role of neuropeptides in transmitting itch signals, we generated two mouse models of chronic itch-Acetone-Ether-Water (AEW, dry skin) and calcipotriol (MC903, atopic dermatitis). For peptide identification and quantitation, we analyzed the peptide content of dorsal root ganglia (DRG) and dorsal horn (DH) tissues from chronically itchy mice using liquid chromatography coupled to tandem mass spectrometry. De novo-assisted database searching facilitated the identification and quantitation of 335 peptides for DH MC903, 318 for DH AEW, 266 for DRG MC903, and 271 for DRG AEW. Of these quantifiable peptides, we detected 30 that were differentially regulated in the tested models, after accounting for multiple testing correction (q ≤ 0.1). These include several peptide candidates derived from neuropeptide precursors, such as proSAAS, protachykinin-1, proenkephalin, and calcitonin gene-related peptide, some of them previously linked to itch. The peptides identified in this study may help elucidate our understanding about these debilitating disorders. Data are available via ProteomeXchange with identifier PXD015949.

CXCL12/CXCR4 signaling induced itch and pain sensation in a murine model of allergic contact dermatitis.

Allergic contact dermatitis is a skin inflammatory disease manifested with itch and pain symptom around the inflamed area. Chemokines such as CXCL12 are involved in the pathophysiology of allergic contact dermatitis, but little has been known about the effect of CXCL12/CXCR4 signaling for nociceptive sensation accompanying allergic contact dermatitis. Our study showed that CXCL12 and CXCR4 were upregulated in trigeminal ganglion with the progression of allergic contact dermatitis through western blotting and immunofluorescence. CXCL12 and CXCR4 were mainly upregulated in small-diameter neurons, which were co-localized with nociceptive markers in trigeminal ganglion. CXCR4 and CXCL12 were also expressed in trigeminal ganglion neurons retrograded from the skin lesion. Intradermal injection of CXCL12 enhanced the itch- and pain-like behavior which could be relieved by AMD3100, a CXCR4 antagonist, without changes of mast cells. Our findings suggested that blockade of CXCL12/CXCR4 signaling pathway might be beneficial to relieve itch and pain sensation accompanying allergic contact dermatitis.

No significant relation of proinflammatory slanDCs with uremic pruritus

The pathogenesis of the pruritus associated with chronic kidney disease-(CKD-aP) is not completely understood. Endocrine, metabolic, neuropathic, and inflammatory disorders were suspected to be the origin of CKD-aP. Based on the hypothesis which suggests that deregulated systemic inflammation may play a crucial role in CKD-a, we investigated the potential relation of an inflammatory monocyte subset (slanDCs) with CKD-aP. Itch questionnaire, visual analogue scale (VAS)-scoring, and Dermatology Life Quality Index (DQLI) were applied for the characterization of itch sensation. VAS-scoring was re-evaluated after 6 months. Monocytes were flow-cytometrically categorized into classical, intermediate, and non-classical subsets. slanDCs are part of the non-classical monocyte subpopulation. Sixty-six hemodialysis patients (CKD5-D) were screened of whom 43 met the study inclusion criteria. In all, 46.5% of patients were scored pruritus-positive (CKD-aP+). CKD-aP severity level of patients was moderate at the start of the study (VAS 5.3 ± 2.5) and remained unchanged after 6 months (VAS: 5.2 ± 1.9, P < 0.757). Thirty percent of patients were affected with mild, 30.0% with moderate, and 35.0% with severe itchiness. In contrast to all other factors tested solely slanDC showed a weak correlation to VAS-score (r = 0.41, P = 0.07). slanDC frequencies between CKD5-D patients with and without itch sensation, however, were not significantly different. Endocrine problems appeared to influence CKD-aP. CKD-aP + patients had significantly higher L-thyroxin supplementation than CKD-aP- (50.0% vs 8.7%, P < 0.005). A binary logistic regression model confirmed the significance of L-thyroxin medication on chronic itch problems of our CKD5-D patients ( P < 0.007). There is no clear evidence that slanDCs are related to uremic pruritus. Therefore, other factors underlie the pathophysiology of CKD-aP.

Molecular Genetics of Kappa Opioids in Pain and Itch Sensations.

The opioid peptides and their receptors have been linked to multiple key biological processes in the nervous system. Here we review the functions of the kappa opioid receptor (KOR) and its endogenous agonists dynorphins (Goldstein A, Tachibana S, Lowney LI, Hunkapiller M, Hood L, Proc Natl Acad Sci U S A 76:6666-6670, 1979) in modulating itch and pain (nociception). Specifically, we discuss their roles relative to recent findings that tell us more about the cells and circuits which are impacted by this opioid and its receptor and present reanalysis of single-cell sequencing data showing the expression profiles of these molecules. Since the KOR is relatively specifically activated by peptides derived from the prodynorphin gene and other opioid peptides that show lower affinities, this will be the only interactions we consider (Chavkin C, Goldstein A, Nature 291:591-593, 1981; Chavkin C, James IF, Goldstein A, Science 215:413-415, 1982), although it was noted that at higher doses peptides other than dynorphins might stimulate KOR (Lai J, Luo MC, Chen Q, Ma S, Gardell LR, Ossipov MH, Porreca F, Nat Neurosci 9:1534-1540, 2006). This review has been organized based on anatomy with each section describing the effect of the kappa opioid system in a specific location but let us not forget that most of these circuits are interconnected and are therefore interdependent.

Corrigendum to "CXCL12/CXCR4 signaling induced itch and pain sensation in a murine model of allergic contact dermatitis".

Corrigendum to "CXCL12/CXCR4 signaling induced itch and pain sensation in a murine model of allergic contact dermatitis".

An unusual two-stage infection following a scolopendra bite

Background:Scolopendrae represent the best-known genus of centipedes. They are nocturnal general feeders with strong mandibles and venomous fangs which leave visible puncture marks at the bite site. The bite accidents occur during the warm rainy season and mostly take place on the extremities. Following the bite, the most common symptoms are mild: limited localized erythema, pain, swelling, local itching and burning sensation. However, more severe local and systemic sequelae can not be excluded.Method:we report the case of a 63-year-old man with fever and a widespread edema of the right hand and forearm, happened as a consequence of a Scolopendra Subspinipes bite. During the weeks following the bite, he developed a severe unusual superinfection via hematogenous dissemination, which required a double surgical debridement and a targeted intravenous antibiotic therapy.Results:the complete clinical recovery took over two months.Conclusions:Many victims of Scolopendra envenomation do not seek medical attention since most symptoms will resolve spontaneously. The case presented falls within the spectrum of those rare cases which escalate due to bacterial superinfection.

Role Of Ayurveda In Paediatric skin disease - A Case Study.

Background: Ayurveda categorises all skin disease under the ambit of Kushtha Roga which has been further classified into major (Maha) and minor (Kshudra) varieties. Skin manifestations are also considered to be a major group of disorders in children. As explained in the lexicons (Samhita), all the skin disorders have involvement of all the three body humours (Tridosha) but the type of manifestation depends on the predominance of any particular Dosha among them. Aim: To evaluate the role of Ayurveda treatment modalities in a paediatric case of Atopic Dermatitis. Materials and Methods: Male child aged 13 years suffering from excessive dryness of skin since early age, dry brownish pink patches with itching and burning sensation especially over face and elbow area since 2 months presented to OPD of Kaumarabhritya of authors institution. The child was facing social stigma, which stopped him to mingle with his peers. On the basis of clinical presentation, the condition was diagnosed as Vataj Kushta. Both External and internal therapies were administered which included of carminative, digestive, palliative and rejuvenative medicines along with oleation therapy (internal and external) for a period of 1 year with regular follow up of every 15 to 20 days in between. A course of Virechana (purgation) therapy was also administered during the process. Clinical assessment was done during both pre-and post-treatment period with the parameters of patches and skin and other clinical feature and quality of life parameters Observations and results: Change over skin was observed after one month of treatment and complete recovery of normal skin was achieved after Virechana. Skin texture and colour became normal after 2nd follow up. Conclusion: The present case study revealed the efficacy of Ayurveda therapy including both external and internal medications in curing the atopic dermatitis (Vatottar Kushtha). The quality of life of the child was also improved as he started mingling with peer and attending social gathering due to reduction of the complaint.

Identification of the molecule required for transmission of IL-31–induced itch sensation in the spinal cord

Identification of the molecule required for transmission of IL-31–induced itch sensation in the spinal cord

Discovery of a new MrgprA3 agonist and evaluation of its effect for itch sensation

Discovery of a new MrgprA3 agonist and evaluation of its effect for itch sensation

Cinnamaldehyde elicits itch behavior via TRPV1 and TRPV4 but not TRPA1.

Introduction:Cinnamaldehyde (CA) elicits itch sensation in humans. We investigated if CA elicits scratching behavior in mice and determined the roles for TRPV1, TRPA1, and TRPV4.Materials and Methods:Scratching behavior elicited by intradermal injection of CA was assessed in wildtype (WT) mice and knockout (KO) mice lacking TRPV1, TRPA1, TRPV4, or deficient in mast cells. We also assessed scratching and wet dog shakes elicited by low-threshold mechanical stimulation of skin treated topically with CA or vehicle. Using calcium imaging we tested if CA activates dorsal root ganglion (DRG) neurons of each genotype.Results:Intradermal cheek injection of CA elicited dose-dependent hindlimb scratch bouts, with fewer forelimb wipes and facial groom bouts that were not dose-dependent. CA elicited significantly fewer scratch bouts in TRPV1 and TRPV4 KO mice, but not TRPA1KOs, compared with WTs. There were no sex differences across genotypes. The histamine H1 antagonist cetirizine did not affect CA-evoked scratching, which was normal in mast cell deficient mice, indicating lack of histamine involvement. Scores for alloknesis were significantly greater following topical application of CA compared with vehicle. Post-CA alloknesis scores were significantly higher in TRPV4KOs of both sexes and in female TRPV1 and TRPA1KOs, compared with WTs. Low threshold mechanical stimuli also elicited significantly more wet dog shakes in mice treated topically with 20% CA, with significantly fewer in TRPV1, TRPA1, and TRPV4KOs compared with WTs. In calcium imaging studies, CA excited 24% of WT DRG cells, significantly fewer (11.5%) in cells from TRPV4KOs, and none in TRPA1KOs. Responses of cells of all genotypes exhibited significant sensitization to repeated CA stimulation. Sensitization was significantly enhanced by IL-4, which itself excited 16% of WT DRG cells and none from TRPA1KOs.Discussion:The results indicate that TRPA1 is dispensable for CA-evoked scratching, which depends partly on TRPV1 and TRPV4.

Upcoming topical TRPV1 anti-pruritic compounds

Transient receptor potential vanilloid type 1 (TRPV1) is found on sensory neurons, keratinocytes, sebocytes, and dendritic cells. Activated TRPV1 channels are believed to help propagate the itch sensation. Therefore, there has been great interest in targeting TRPV1 to treat pruritus. Since oral formulations aimed at TRPV1 have led to adverse effects such as hyperthermia, there has been emphasis on developing novel topical agents. Several companies are investigating topical TRPV1 anti-pruritic compounds and the initial data has been very promising. These drugs have the potential to be important treatment options for the management of itch. This paper reviews topical products in current development for pruritus that target TRPV1 channels.

Physiology and Pathophysiology of Itch.

Itch is a topic to which everyone can relate. The physiological roles of itch are increasingly understood and appreciated. The pathophysiological consequences of itch impact quality of life as much as pain. These dynamics have led to increasingly deep dives into the mechanisms that underlie and contribute to the sensation of itch. When the prior review on the physiology of itching was published in this journal in 1941, itch was a black box of interest to a small number of neuroscientists and dermatologists. Itch is now appreciated as a complex and colorful Rubik's cube. Acute and chronic itch are being carefully scratched apart and reassembled by puzzle solvers across the biomedical spectrum. New mediators are being identified. Mechanisms blur boundaries of the circuitry that blend neuroscience and immunology. Measures involve psychophysics and behavioral psychology. The efforts associated with these approaches are positively impacting the care of itchy patients. There is now the potential to markedly alleviate chronic itch, a condition that does not end life, but often ruins it. We review the itch field and provide a current understanding of the pathophysiology of itch. Itch is a disease, not only a symptom of disease.