Itch Modulation Research Articles

RETRACTED: A Monoclonal Antibody that Targets a NaV1.7 Channel Voltage Sensor for Pain and Itch Relief

Voltage-gated sodium (NaV) channels control the upstroke of the action potentials in excitable cells. Multiple studies have shown distinct roles of NaV channel subtypes in human physiology and diseases, but subtype-specific therapeutics are lacking and the current efforts have been limited to small molecules. Here, we present a monoclonal antibody that targets the voltage-sensor paddle of NaV1.7, the subtype critical for pain sensation. This antibody not only inhibits NaV1.7 with high selectivity, but also effectively suppresses inflammatory and neuropathic pain in mice. Interestingly, the antibody inhibits acute and chronic itch despite well-documented differences in pain and itch modulation. Using this antibody, we discovered that NaV1.7 plays a key role in spinal cord nociceptive and pruriceptive synaptic transmission. Our studies reveal that NaV1.7 is a target for itch management, and the antibody has therapeutic potential for suppressing pain and itch. Our antibody strategy may have broad applications for voltage-gated cation channels.

Glial Cells are Involved in Itch Processing

Recent discoveries in itch neurophysiology include itch-selective neuronal pathways, the clinically relevant non-histaminergic pathway, and elucidation of the notable similarities and differences between itch and pain. Potential involvement of glial cells in itch processing and the possibility of glial modulation of chronic itch have recently been identified, similarly to the established glial modulation of pain processing. This review outlines the similarities and differences between itch and pain, and how different types of central and peripheral glial cells may be differentially involved in the development of chronic itch akin to their more investigated role in chronic pain. Improvements are needed in the management of chronic itch, and future basic and interventional studies on glial activity modulation would both enhance our understanding of mechanisms underlying the chronification of itch and provide novel opportunities for the prevention or treatment of this debilitating and common condition.

Brain's reward circuits mediate itch relief. a functional MRI study of active scratching.

Previous brain imaging studies investigating the brain processing of scratching used an exogenous intervention mimicking scratching, performed not by the subjects themselves, but delivered by an investigator. In real life, scratching is a conscious, voluntary, controlled motor response to itching, which is directed to the perceived site of distress. In this study we aimed to visualize in real-time by brain imaging the core mechanisms of the itch-scratch cycle when scratching was performed by subjects themselves. Secondly, we aimed to assess the correlations between brain patterns of activation and psychophysical ratings of itch relief or pleasurability of scratching. We also compared the patterns of brain activity evoked by self-scratching vs. passive scratching. We used a robust tridimensional Arterial Spin Labeling fMRI technique that is less sensitive to motion artifacts: 3D gradient echo and spin echo (GRASE) - Propeller. Active scratching was accompanied by a higher pleasurability and induced a more pronounced deactivation of the anterior cingulate cortex and insula, in comparison with passive scratching. A significant involvement of the reward system including the ventral tegmentum of the midbrain, coupled with a mechanism deactivating the periaqueductal gray matter (PAG), suggests that itch modulation operates in reverse to the mechanism known to suppress pain. Our findings not only confirm a role for the central networks processing reward in the pleasurable aspects of scratching, but also suggest they play a role in mediating itch relief.

Differences in peripheral endocannabinoid modulation of scratching behavior in facial vs. spinally-innervated skin

Cannabinoids suppress nocifensive behaviors in rodents. We presently investigated peripheral endocannabinoid modulation of itch- and pain-related behaviors elicited from facial vs. spinally-innervated skin of rats. Intradermal (id) injection of the pruritogen serotonin (5-HT) elicited significantly more hindlimb scratch bouts, and longer cumulative time scratching, when injected in the rostral back compared to the cheek. Pretreatment of skin with inhibitors of degrading enzymes for the endocannabinoids anandamide (URB597) or 2-arachidonoylglycerol (JZL184) significantly reduced scratching elicited by 5-HT in the rostral back. These effects were prevented by co-treatment with antagonists of the CB1 (AM251) or CB2 receptor (AM630), implicating both receptor subtypes in endocannabinoid suppression of scratching in spinally-innervated skin. Conversely, pretreatment with either enzyme inhibitor, or with AM630 alone, increased the number of scratch bouts elicited by id 5-HT injection in the cheek. Moreover, pretreatment with JZL184 also significantly increased pain-related forelimb wipes directed to the cheek following id injection of the algogen, allyl isothiocyanate (AITC; mustard oil). Thus, peripheral endocannabinoids have opposite effects on itch-related scratching behaviors in trigeminally- vs. spinally-innervated skin. These results suggest that increasing peripheral endocannabinoid levels represents a promising therapeutic approach to treat itch arising from the lower body, but caution that such treatment may not relieve, and may even exacerbate, itch and pain arising from trigeminally-innervated skin of the face or scalp.

Opioid Modulation of Facial Itch- and Pain-related Responses and Grooming Behavior in Rats

Intradermal facial injections of pruritogens or algogens elicit distinct behavioral hindlimb scratch or forelimb wiping responses in rodents. We systematically investigated the parameters and opioid modulation of these evoked behaviors and spontaneous facial grooming in rats. Serotonin (5-HT) elicited hindlimb scratch bouts with few wipes. Scratching was attenuated by the µ-opiate antagonist naltrexone but not morphine. In contrast, cheek injection of mustard oil (allyl-isothiocyanate (AITC)) elicited ipsilateral forelimb wipes but little hindlimb scratching. AITC-evoked wiping was significantly attenuated by morphine but not naltrexone. Spontaneous facial grooming by the forepaws was attenuated by naltrexone, whereas morphine did not affect grooming behavior before or after cheek injections of 5-HT or AITC. These data validate that the rodent "cheek" model discriminates between itch- and pain-related behaviors. Naltrexone sensitivity of facial grooming and 5-HT-evoked scratch-ing suggests a common functionality. Forelimb wipes may represent a nocifensive response akin to rubbing an injury to relieve pain.

Pathophysiology of itch and new treatments

Itch represents one of the most bothersome symptoms in allergic disorders and numerous dermatological and systemic diseases. Chronic itch has a dramatic impact on the quality of life. The pathophysiology of itch is diverse and involves a complex network of cutaneous and neuronal cells. Thus, we highlight the current pathophysiological aspects of itch together with new treatment options. Apart from histamine, several mediators and receptors including the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor, neurokinins/neuropeptides such as substance P, gastrin-releasing peptide, cytokines such as interleukin-31, autotaxin and the histamine H4 receptor have been identified for playing a role in the pathophysiology of itch. In the skin, tissue resident cells such as keratinocytes, mast cells and cells of the inflammatory infiltrate including lymphocytes and eosinophils have been described to interact with neuronal cells, for example via the release of neurotrophins, neuropeptides and cytokines, adding novel regulatory pathways for the modulation of itch. Accordingly, promising treatment strategies such as the neurokinin-1 receptor antagonist aprepitant have been introduced for a successful management of itch. In this review, we highlight novel key players in the pathophysiology of itch with subsequent introduction of promising, novel and experimental treatment strategies.

Pruritus: an overview of current concepts

Pruritus is an integral part of the patient's symptoms in numerous dermatological and systemic diseases in humans and animals. Comparable to chronic pain, pruritus can have a dramatic impact on the quality of life of the patient. In recent years, pruritus has been defined as an autonomous, pain-independent sensation, and itch-specific neurons, mediators, spinal neurons and cortical areas have been identified. These observations have not only improved our understanding of the neurobiology of itch but will also lead to improved diagnosis and to the development of new and more efficient therapeutic options. This article reviews the role of itch fibres and their response to various mediators of pruritus including histamine, vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), and substance P (SP), and opioids. Substances that may be involved in the induction or modulation of itch may be termed pruritogenic mediators and examples discussed include proteases, lipid mediators, neuropeptides, opioids and various cytokines. There is no single, generally accepted clinical classification of chronic pruritus. In the past pruritus has been classified on the basis of the neuroanatomical origin and on the potential underlying disease. Therapeutic options for the management of pruritus are discussed including topical and systemic therapies, assuming that trigger factors have been eliminated where possible. Topical agents may include capsaicin, the calcineurin inhibitors tacrolimus and pimecrolimus, and cannabinoid agonists such as N-palmitoyl ethanolamine. Systemic therapies may include antihistamines, anticonvulsants, opiate receptor antagonist or agonists, antidepressants, ciclosporin, and UV light.

Heterotopic pruritic conditioning and itch – Analogous to DNIC in pain?

Pain can be endogenously modulated by heterotopic noxious conditioning stimulation (HNCS) through a mechanism which is known as diffuse noxious inhibitory control (DNIC). Since DNIC can be impaired in patients suffering from chronic pain, a comparable impaired itch inhibition may exist in patients suffering from chronic itch. The aim of the present study was to investigate whether heterotopic pruritic conditioning stimulation (HPCS) would display an impaired modulation of itch in patients suffering from chronic itch compared with healthy subjects. To this end, electrical stimuli were applied before and after histamine application (HPCS) to female patients with psoriasis and healthy female control subjects. Subjects reported the intensity of electrically evoked itch before and after HPCS. In order to replicate earlier findings for DNIC, electrically evoked pain was additionally investigated before and after cold stimulation (HNCS). As expected, the intensity of itch evoked by the electrical stimulus was significantly less after than before HPCS in healthy subjects, and the same was found for the intensity of electrically evoked pain after compared to before HNCS. Contrarily, in the patients levels of electrically evoked itch were significantly higher after than before HPCS, and no significant difference in pain intensity before and after HNCS was observed. In line with pain modulation, results suggest that there is a DNIC analogous mechanism for itch, i.e., diffuse pruritic inhibitory control (DPIC), which is impaired in patients with chronic itch, possibly due to a dysregulation of descending itch modulatory systems.

Zentralnervöse Verarbeitung von Juckreiz

Itch is the major symptom of many allergic or inflammatory skin diseases; yet it is still difficult to measure objectively. This article describes recent progress in central nervous system investigations of the itch sensation. Short-term alternating temperature modulation of histamine-induced itch has recently been introduced, allowing human neuro-imaging studies of high resolution. These studies with functional magnetic resonance imaging demonstrate that itch sensation in healthy volunteers is processed by a network of brain regions contributing to the encoding of sensory, emotional, attentional, evaluative and motivational aspects of pruritus.

Cerebral Processing of Histamine-Induced Itch Using Short-Term Alternating Temperature Modulation – An fMRI Study

Human neuroimaging studies on the physiology of itch have been hampered by the lack of reproducible "on-off" stimuli. Using a previously established biphasic temperature stimulus model, we investigated the cerebral activation pattern of itch processing in 12 healthy volunteers with functional magnetic resonance imaging. Itch was provoked on the right forearm with skin prick application of 1% histamine-dihydrochloride. Local temperature modulation allowed reproducible itch provocation above scratch threshold (defined as 33/100 on a visual analogue scale) during 25 degrees C, whereas itch declined below scratch threshold during the 32 degrees C stimulation period. No itch sensation was reported using 0.9% saline with temperature modulation. Itch sensation above scratch threshold was associated with increased activation of the thalamus, presupplementary motor area, anterior insular, inferior parietal, and dorsolateral prefrontal cortex, and decreased activation of the orbitofrontal, medial frontal, mid-cingulate, and primary motor cortex in comparison to saline. The biphasic temperature model allows rapid modulation of histamine-induced itch. The evoked itch sensation above scratch threshold is processed by a network of brain regions contributing to the encoding of sensory, emotional, attention-dependent, cognitive-evaluative and motivational aspects of itch.

Opioid receptors in skin – link between stress and skin disease?

Opioid peptides and its receptors are highly conserved and crucial for survival in stress situations. Besides their well‐known role in antinociception, they control cell differentiation and proliferation and influence apoptosis in various tissues. We are first to discover their presence in skin and to establish their functions in modulation of chronic itch and wound healing.µ‐Opioid receptor is a key player in induction of chronic itch. This could be confirmed using µ‐opiate receptor knockout mice experiments and clinical studies on patients with chronic itch. We have induced a dry skin dermatitis as a model for chronic itching on knockout and wild type mice. µ‐Opioid receptor knockout mice revealed significant less scratching behavior, less epidermal hypertrophy and different density and quality of epidermal nerve endings compared to the wild type mice. In addition, topically applied opioid receptor antagonists relieved significantly chronic pruritus in a double‐blind, placebo‐controlled, cross‐over study in 40 patients with atopic dermatitis.Several findings suggest that the δ‐opioid receptor and its endogenous ligands (enkephalins) are important in cell differentiation and proliferation. We proved the existence of a functional active δ‐opioid receptor in different skin cells using RT‐PCR, Western blot analysis and migration assays. In addition, δ‐opioid receptor knockout mice revealed a phenotype of thinner epidermis and higher expression of cell differentiation marker cytokeratin 10 (CK 10) compared to wild‐type mice. In a burn wound model, δ‐opioid receptor knockout mice showed significant wound healing delay and a severe epidermal hypertrophy at the wound margin. This can be explained by a change of cell differentiation and migration due to the absence of a functional active δ‐opioid receptor.In summary, these experiments proved that the skin and the nervous system interact with each other in a bi‐directional way, i.e. nervous system releases neuropeptides in stress situations affecting skin homeostasis and sensations and vice versa.Therefore, the opioid receptor system is an excellent model to study the connection between psychological stress and aggravation of different skin diseases.

Imaging of central itch modulation in the human brain using positron emission tomography

The unpleasantness of itching is reduced by cooling. Although previous research suggests the presence of a central itch modulation system, there is little documentation about the modulation system in the brain. In the present study, we investigated the modulating system of the itching sensation in human brains using positron emission tomography and H 2 15O. The significant increases of regional cerebral blood flow caused by histamine stimuli using iontophoresis were observed in the anterior cingulate cortex (BA24), the thalamus, the parietal cortex (BA40 and BA7), the dorsolateral prefrontal cortex (BA46) and the premotor cortex (BA6). We did not observe any changes in the secondary somatosensory cortex (S2) during the itching stimulus, corresponding to the previous imaging studies concerning itching. Activation in these areas related to itching stimuli was decreased by a simultaneous stimulation of itching and cold pain (the dual stimuli), as compared to itching alone. Interestingly, the midbrain, including periaqueductal gray matter (PAG), was only activated during the dual stimuli. PAG is well known to be a modulating noxious stimulus. Here we hypothesize that the activation of PAG may also be related to the itch modulation. These findings indicate that the modified brain activities in the PAG, the cingulate, the frontal and the parietal cortex might be associated with the itch modulation in the central nervous system and that the S2 might not be primarily involved in processing the itching perception in the brain since the activity of S2 was not observed in any concentration of itching stimuli.

PHYSIOLOGY OF ITCHING

ArticlesPHYSIOLOGY OF ITCHINGStephen RothmanStephen RothmanPublished Online:01 Apr 1941https://doi.org/10.1152/physrev.1941.21.2.357MoreSectionsPDF (3 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Download PDF FiguresReferencesRelatedInformation Cited BySpinal Circuits Transmitting Mechanical Pain and Itch8 May 2017 | Neuroscience Bulletin, Vol. 34, No. 1A Review of the Therapeutic Interventions in the Management of Pruritus Ani10 January 2017 | Investigative Dermatology and Venereology Research, Vol. 3, No. 1Hydrogen sulfide donors alleviate itch secondary to the activation of type-2 protease activated receptors (PAR-2) in micePharmacological Research, Vol. 113Cerebral Representation of the Relief of Itch by ScratchingVerena Vierow, Miyuki Fukuoka, Akihiko Ikoma, Arnd Dörfler, Hermann Otto Handwerker, and Clemens Forster1 December 2009 | Journal of Neurophysiology, Vol. 102, No. 6Itch Induced by a Novel Method Leads to Limbic Deactivations— A Functional MRI StudyLina Herde, Clemens Forster, Marion Strupf, and Hermann O. Handwerker1 October 2007 | Journal of Neurophysiology, Vol. 98, No. 4Old scratch1 January 2004 | Hepatology, Vol. 39, No. 3Imaging of central itch modulation in the human brain using positron emission tomographyPain, Vol. 105, No. 1Pruritus - Pathophysiologie, Klinik und Therapie - Eine Ubersicht. Pruritus - pathophysiology, clinical features and therapy - an overviewJournal der Deutschen Dermatologischen Gesellschaft, Vol. 1, No. 2Superficial Dorsal Horn Neurons Identified by Intracutaneous Histamine: Chemonociceptive Responses and Modulation by MorphineSteven L. Jinks, and E. Carstens1 August 2000 | Journal of Neurophysiology, Vol. 84, No. 2Responses of Rat Spinal Dorsal Horn Neurons to Intracutaneous Microinjection of Histamine, Capsaicin, and Other IrritantsE. Carstens1 May 1997 | Journal of Neurophysiology, Vol. 77, No. 5Conditioning of histamine by bradykinin alters responses of rat nociceptor and human itch sensationNeuroscience Letters, Vol. 152, No. 1-2Is substance P a primary afferent neurotransmitter for nociceptive input? I. Analysis of pain-related behaviors resulting from intrathecal administration of substance P and 6 excitatory compoundsBrain Research, Vol. 455, No. 2Itch Evoked by Electrical Stimulation of the SkinJournal of Investigative Dermatology, Vol. 79, No. 6Dermatologic concepts and management of pruritus aniThe American Journal of Surgery, Vol. 90, No. 5 More from this issue > Volume 21Issue 2April 1941Pages 357-381 https://doi.org/10.1152/physrev.1941.21.2.357History Published online 1 April 1941 Published in print 1 April 1941 Metrics