Neuropathic Itch Research Articles

Pregabalin for Neuropathic Pain and Itch in Recessive Dystrophic Epidermolysis Bullosa

Patients with recessive dystrophic epidermolysis bullosa (RDEB) experience neuropathic pain and itch. There is a lack of evidence on any treatment for these symptoms in patients with RDEB. To test the efficacy of pregabalin in the treatment of neuropathic pain and itch in patients with RDEB. A randomized, double-blinded, crossover trial of oral pregabalin (50-300 mg/d) vs placebo was conducted at 2 sites, Toronto (Canada) and Santiago (Chile) from January 1, 2019, to December 31, 2020. Patients eligible to participate were diagnosed with RDEB, aged 8 to 40 years, not pregnant or lactating (if female), and had evidence of probable neuropathic pain and itching defined as distal thermal sensory loss (confirmed by thermal roller), score of 4 or greater on the Douleur Neuropathique 4 questionnaire (DN4), and score greater than 4 on the 10-point visual analog scale [VAS]). Patients with a clinically important or poorly controlled medical or psychiatric condition or pregabalin intolerance or allergy were excluded. Of 41 patients screened, 3 were not eligible and 28 declined enrollment. Data analyses were performed in 2021 through 2023. Participants received both pregabalin and matched placebo (titrated to a maximum-tolerated dose of 300 mg/day) in a randomized sequence so that comparisons could be made within participants and between groups. Difference in the mean pain and itch scores between pregabalin and placebo treatment (measured using VAS) before and after intervention. In all, 10 participants were randomized to 2 groups, 6 patients (mean [SD] age, 26.7 [8.1] years; 3 females [50%]) in group 1, and 4 patients (mean [SD] age, 26.5 [7.8] years, 2 females [50%]) in group 2. Group 1 received a sequence of pregabalin-placebo while group 2 received placebo-pregabalin. Pregabalin significantly reduced mean (SD) pain scores by 1.9 (1.5) points when controlling for sequence and treatment period vs baseline, while placebo had 0.1 (2.0) points of reduction. The effect of pregabalin was a mild but significant reduction in itch compared to baseline (mean [SD] points, 0.9 [2.2]), whereas the placebo produced no reduction (0.1 [2.5]). The mean pregabalin dose was generally well tolerated. The results of this randomized crossover trial indicate that pregabalin significantly reduced pain and itch scores from baseline compared to placebo in patients with RDEB. This feasibility study provided preliminary data on the efficacy of pregabalin in managing pain and itch in RDEB and gathered essential data to inform the design of a larger cohort trial. ClinicalTrials.gov Identifier: NCT03928093.

From Compression to Itch: Exploring the Link Between Nerve Compression and Neuropathic Pruritus.

Neuropathic itch is a type of chronic pruritus resulting from neural dysfunction along the afferent pathway. It is often accompanied by abnormal sensations such as paresthesia, hyperesthesia, or hypoesthesia. This condition, which may involve motor or autonomic neural damage, significantly impacts patients' quality of life, causing severe itch and associated comorbidities such as depression, disrupted sleep, and social strain. Neuropathic itch accounts for 8% of chronic pruritus cases, though this may be underestimated. This comprehensive review focuses on nerve impingement as the primary pathophysiological mechanism for various forms of neuropathic itch including brachioradial pruritus (BRP), notalgia paresthetica (NP), and anogenital itch. BRP, often seen in middle-aged white women, manifests as pruritus in the dorsolateral forearms typically exacerbated by ultraviolet (UV) exposure and related to cervical spine pathology. NP, prevalent in middle-aged women, presents as pruritus in the upper back due to thoracic spine nerve compression. Anogenital pruritus, affecting 1-5% of adults, is often linked to lumbosacral spine issues after ruling out dermatologic conditions such as lichen sclerosus or lichen simplex chronicus. The pathophysiology of neuropathic itch involves both peripheral and central mechanisms, with nerve damage being a key factor. Diagnosis requires a thorough history, physical examination, and potentially imaging studies. Topical agents such as menthol, capsaicin, and lidocaine are used for mild cases, while systemic medications such as gabapentin, pregabalin, and antidepressants are prescribed for moderate to severe cases; however, no USFood and Drug Administration (FDA)-approved therapies currently exist specifically for neuropathic itch. Understanding the underlying neural dysfunction and appropriate therapeutic strategies is crucial for managing neuropathic itch effectively.

Patient perspective on symptoms of Notalgia paresthetica: subpopulation results from the Neuropathic Itch Patient Survey (NIRVE)

Background: Notalgia paresthetica (NP) is a form of neuropathic itch characterized by recurrent itch in the mid back. Much about NP remains unclear, especially the patient experience. Objectives: The Neuropathic Itch Patient Survey (NIRVE) was a global, online survey conducted to better characterize the symptom burden of neuropathic itch from the patient perspective. Patients and methods: This report focuses on the symptom burden of the subpopulation of NIRVE participants with a self-reported diagnosis of NP (N = 91). Respondents reported visiting a median of 2 healthcare providers (HCPs) for their symptoms before receiving an accurate diagnosis of NP. Results: The most common cutaneous symptoms ever experienced were itch/pruritus, sensitive skin, painful or raw skin, numbness, and tingling. The symptoms reported by the most respondents as currently being experienced included itch/pruritus, numbness, painful or raw skin, tingling, and burning or hot sensation. Of patients currently experiencing symptoms, numbness and itch/pruritus were ranked as the most intense, followed by tingling, burning or hot sensation, and then painful or raw skin. Most patients consult multiple healthcare providers (HCPs) before receiving a diagnosis for their condition. Conclusion: Itch is overwhelmingly the most prevalent symptom of the condition, although half of patients also report experiencing sensitive skin, painful or raw skin, numbness, or tingling.

Neuroinflammation evoked mechanisms for neuropathic itch in the spared nerve injury mouse model of neuropathic pain

A large portion of neuropathic pain suffering patients may also concurrently experience neuropathic itch, with a negative impact on the quality of life. The limited understanding of neuropathic itch and the low efficacy of current anti-itch therapies dictate the urgent need of a better comprehension of molecular mechanisms involved and development of relevant animal models. This study was aimed to characterize the itching phenotype in a model of trauma-induced peripheral neuropathy, the spared nerve injury (SNI), and the molecular events underlying the overlap with the nociceptive behavior. SNI mice developed hyperknesis and spontaneous itch 7–14 days after surgery that was prevented by gabapentin treatment. Itch was associated with pain hypersensitivity, loss of intraepidermal nerve fiber (IENF) density and increased epidermal thickness. In coincidence with the peak of scratching behavior, SNI mice showed a spinal overexpression of IBA1 and GFAP, microglia and astrocyte markers respectively. An increase of the itch neuropeptide B-type natriuretic peptide (BNP) in NeuN+ cells, of its downstream effector interleukin 17 (IL17) along with increased pERK1/2 levels occurred in the spinal cord dorsal horn and DRG. A raise in BNP and IL17 was also detected at skin level. Stimulation of HaCat cells with conditioned medium from BV2-stimulated SH-SY5Y cells produced a dramatic reduction of HaCat cell viability. This study showed that SNI mice might represent a model for neuropathic itch and pain. Collectively, our finding suggest that neuropathic itch might initiate at spinal level, then affecting skin epidermis events, through a glia-mediated neuroinflammation-evoked BNP/IL17 mechanism.

Neuropathy in pruritus medicine : Recommended diagnostics and therapy

Chronic itch is afrequent and debilitating condition that greatly affects the quality of life of those affected. In asubset of patients, damage to the peripheral or central nervous system constitutes the cause of the itch. Small-fiber neuropathy, nerve compression syndromes, post-herpetic neuralgia, scars and burns are possible conditions affecting the peripheral nervous system potentially causing itch, whereas space-occupying lesions affecting the spinal cord and stroke are examples of conditions that may induce central itch. Neuropathic itch starts on normal appearing skin, is often accompanied by pain sensations and other dysesthesias, and usually relieved by local cold application. Its distribution depends on the affected site of the somatosensory system. Acomprehensive medical history is paramount to reach the diagnosis, while complementary diagnostics with skin biopsies for the investigation of cutaneous neuromorphological alterations or medical imaging to rule out nerve impingement may be advised in selected cases. Topical agents such as capsaicin or local anesthetics as well as systemic drugs such as gabapentinoids, antidepressants and opioid receptor modulators are used in the treatment of neuropathic itch. This review article provides an overview of the clinical features, underlying causes, diagnostic workup and therapeutic approach in neuropathic itch.

약물 치료에 반응하지 않는 대상포진후 가려움 환자에서의 삼차신경절주사와 싸이모신알파1 치료 효과 증례

Postherpetic itch (PHI), a common condition in neuropathic itch is not as well studied as postherpetic neuralgia. Intractable PHI is thought to be hyperexcitability of itch-transmission nervous system caused by neural injury from herpes zoster. In some cases, PHI is very severe to compromise patient’s quality of life and refractory to conventional treatments. Here, it is reported that a case of severe chronic PHI was reduced with trigeminal ganglion blocks and thymosin alpha 1 injections. A 74-year-old man complained of severe itching with hypoesthesia in his left eyebrow and scalp for 5 years after the initial onset of herpes zoster at the same site, despite treatment with two types of antihistamines, gabapentin, and amitriptyline. He developed ulcers on his forehead and scalp because of his scratching. Trigeminal ganglion blocks and thymosin alpha 1 injections reduced itching, with the ulcers disappearing within 1 month. In this case, it is suggested that trigeminal ganglion blocks and thymosin alpha 1 injection may be a useful treatment option for PHI.

The COL6A5-p.Glu2272* mutation induces chronic itch in mice.

Pruritus is a common irritating sensation that provokes the desire to scratch. Environmental and genetic factors contribute to the onset of pruritus. Moreover, itch can become a major burden when it becomes chronic. Interestingly, the rare Collagen VI alpha 5 (COL6A5) gene variant p.Glu2272* has been identified in two families and an independent patient with chronic neuropathic itch. These patients showed reduced COL6A5 expression in skin and normal skin morphology. However, little progress has been made until now toward understanding the relationships between this mutation and chronic itch. Therefore, we developed the first mouse model that recapitulates COL6A5-p.Glu2272* mutation using the CRISPR-Cas technology and characterized this new mouse model. The mutant mRNA, measured by RT-ddPCR, was expressed at normal levels in dorsal root ganglia and was decreased in skin. The functional exploration showed effects of the mutation with some sex dysmorphology. Mutant mice had increased skin permeability. Elevated spontaneous scratching and grooming was detected in male and female mutants, with increased anxiety-like behavior in female mutants. These results suggest that the COL6A5-p.Glu2272* mutation found in patients contributes to chronic itch and induces in mice additional behavioral changes. The COL6A5-p.Glu2272* mouse model could elucidate the pathophysiological mechanisms underlying COL6A5 role in itch and help identify potential new therapeutic targets.

Scratching increases epidermal neuronal branching and alters psychophysical testing responses in atopic dermatitis and brachioradial pruritus.

Chronic scratching imposes a major stress on the skin and can lead to itch intensity worsening, and consequently, patients may enter an itch-scratch cycle. This repetitive mechanical stress can result in lichenification, worsening of epidermal barrier function, and enhanced cutaneous inflammation. Furthermore, a reduction of intraepidermal nerve fibers was previously described in lichenification. The aim of this study was to investigate the influence of chronic scratching on the epidermal neuroanatomy and on sensory changes, in particular the prevalence of hyperknesis and alloknesis in patients after mechanical, chemical, and electrical stimuli. Analyses were performed on pruritic lichenified (chronically scratched), pruritic non-lichenified (not chronically scratched), and non-pruritic non-lesional (unaffected) skin areas of patients with inflammatory pruritus, i.e., atopic dermatitis (n = 35), and neuropathic pruritus, i.e., brachioradial pruritus (n = 34) vs. healthy matched controls (n = 64). Our fine-grained spatial skin characterization enabled specifically studying the differential effects of chronic scratching in inflammatory and neuropathic itch. Analysis of intraepidermal nerve fiber density showed rarefaction of fibers in all three skin areas of patients compared with healthy controls in both diagnoses. Even more, the two pruritic areas had significantly less nerve fibers than the unaffected skin, whereas electrically induced itch was massively increased. Epidermal branching of the remaining nerve fibers in lichenified/chronically scratched skin was increased, particularly in patients with brachioradial pruritus, which may contribute to the pronounced local neuronal sensitivity. Hyperknesis and alloknesis were found to increase independently of lichenification. Our results indicate that chronic scratching may not affect intraepidermal nerve fiber density but leads to a stronger branching pattern of intraepidermal nerve fibers, which may contribute to local hypersensitivity. The increased sensitivity in the pruritic areas suggests mechanisms of peripheral sensitization, whereas the increased sensation of electrically and chemically induced itch in unaffected skin indicates central sensitization for itch.

A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas

A Call for Discovery and Therapeutic Development for Cutaneous Neurofibromas

Resolution of a Focal Pruritic Rash Following Neurosurgical Decompression in an Adolescent With Chiari I and Syringomyelia

BackgroundChiari I malformation (Chiari I) is defined by the downward displacement of one or both cerebellar tonsils below the foramen magnum of the skull with crowding altering cerebrospinal fluid flow. It can be associated with the development of a fluid-filled cavity within the spinal cord, syringomyelia. Neurological deficits or symptoms can occur at the level of anatomic involvement of syringomyelia. Case PresentationA young man presented to dermatology clinic for evaluation of a pruritic rash. Recognizing a unique left “cape-like” distribution of neuropathic itch leading to prurigo nodularis, he was referred for further evaluation by neurology in the local emergency department. After additional history and neurological exam, a magnetic resonance imaging confirmed Chiari I with an associated syringobulbia and a syrinx extending to T10/11 of the spinal cord. Anteriorly the syrinx extended into the left parenchyma of his spinal cord involving the dorsal horn, a lesion explaining his neuropathic itch. The sensation of itch and rash resolved after posterior fossa craniectomy and C1 laminectomy with duraplasty. ConclusionNeuropathic itch, in addition to pain, can be a symptom of Chiari I with syringomyelia. Focal pruritus without an obvious cutaneous trigger should prompt providers to consider a central neurological pathology. While many patients with Chiari I are asymptomatic, the presence of neurological deficits and syringomyelia, are indications for neurosurgical evaluation.

Aetiology, pathogenesis and management of neuropathic itch: A narrative review with recent updates.

Neuropathic itch is a relatively common yet under-reported cause of systemic pruritus. It is a debilitating condition often associated with pain, which impairs the patient's quality of life. Although much literature exists about renal and hepatic pruritus, there is a dearth of information and awareness about neuropathic itch. The pathogenesis of neuropathic itch is complex and can result from an insult at any point along the itch pathway, ranging from the peripheral receptors and nerves until the brain. There are several causes of neuropathic itch, many of which do not produce any skin lesions and are thus, often missed. A detailed history and clinical examination are necessary for the diagnosis, while laboratory and radiologic investigations may be needed in select cases. Several therapeutic strategies currently exist involving both non-pharmacological and pharmacological measures, the latter including topical, systemic, and invasive options. Further research is ongoing to clarify its pathogenesis and to design newer targeted therapies with minimal adverse effects. This narrative review highlights the current understanding of this condition, focusing on its causes, pathogenesis, diagnosis, and management, along with newer investigational drugs.

Mechanisms and treatments of neuropathic itch in a mouse model of lymphoma.

Our understanding of neuropathic itch is limited due to a lack of relevant animal models. Patients with cutaneous T cell lymphoma (CTCL) experience severe itching. Here, we characterize a mouse model of chronic itch with remarkable lymphoma growth, immune cell accumulation, and persistent pruritus. Intradermal CTCL inoculation produced time-dependent changes in nerve innervations in lymphoma-bearing skin. In the early phase (20 days), CTCL caused hyperinnervations in the epidermis. However, chronic itch was associated with loss of epidermal nerve fibers in the late phases (40 and 60 days). CTCL was also characterized by marked nerve innervations in mouse lymphoma. Blockade of C-fibers reduced pruritus at early and late phases, whereas blockade of A-fibers only suppressed late-phase itch. Intrathecal (i.t.) gabapentin injection reduced late-phase, but not early-phase, pruritus. IL-31 was upregulated in mouse lymphoma, whereas its receptor Il31ra was persistently upregulated in Trpv1-expressing sensory neurons in mice with CTCL. Intratumoral anti-IL-31 treatment effectively suppressed CTCL-induced scratching and alloknesis (mechanical itch). Finally, i.t. administration of a TLR4 antagonist attenuated pruritus in early and late phases and in both sexes. Collectively, we have established a mouse model of neuropathic and cancer itch with relevance to human disease. Our findings also suggest distinct mechanisms underlying acute, chronic, and neuropathic itch.

Paroxysmal Neuropathic Pruritus in Patients With Chiari Malformation Type I: A Rare Phenotype

Chiari malformation type I (CM-I) is a group of deformities in the posterior fossa and hindbrain, including the pons, cerebellum, and medulla oblongata. Paroxysmal pruritus in CM-I has been reported only once before in the literature. This study was a cross-sectional study over 12 months at a tertiary care pediatric hospital involving children aged one to 18 years with CM-I presenting with paroxysmal itching. Three patients with CM-I presented with severe episodes of paroxysmal itching. Patient 3 was started on carbamazepine therapy for seizures, and incidentally, his itching subsided. The pruritus of neuropathic etiology has been reported to be associated with syringomyelia, spongiform encephalopathies, autoimmune disorders like multiple sclerosis, patients with end-stage renal failure on dialysis, and neoplasms. Antihistamines and antiallergics are ineffective in treating these patients, reiterating a central mechanism for pruritus. At present, no drugs have been approved for the treatment of neuropathic pruritus specifically. The commonly used treatments for neuropathic itch are antiseizure medications, tricyclic antidepressants, gabapentinoids, ketamine, and oral kappa opioids, including butorphanol and difelikefalin. Better structured prospective studies are needed to analyze the prevalence and scales to assess disability caused due to neuropathic itch in CM and may enhance understanding in this area.

Increased touch-evoked itch (punctate hyperknesis) in postherpetic itch: Implications of reduced intraepidermal nerve fibers representing small fiber neuropathy.

Chronic itch conditions are often accompanied by neural itch sensitization, known as hyperknesis (excessive itch induced by stimuli that would normally induce only mild itching or pain) and alloknesis (considerable itch evoked by light tactile stimuli). Herpes zoster (shingles) can cause neuropathic itch (postherpetic itch), although it is unknown whether hyperknesis accompanies postherpetic itch. The authors report five patients with postherpetic itch who showed increased touch-evoked itch (punctate hyperknesis) in the affected skin areas compared with the contralateral site. Collected skin biopsy specimens from two patients showed histopathologically detected reduced intraepidermal nerve fibers in the affected skin areas, reflective of small C/Aδ fiber neuropathy. In one case, improvement in itching and comparable levels of touch-evoked itch on the affected and contralateral sites were noted after 6months without any medication, accompanied by restored intraepidermal nerve fibers proven through rebiopsy of the affected site. Reduced intraepidermal nerve fibers could be one of the precipitating factors for postherpetic itch and its associated punctate hyperknesis.

Role of burn severity and posttraumatic stress symptoms in the co-occurrence of itch and neuropathic pain after burns: A longitudinal study.

Itch and pain are common after burns. Neuropathic mechanisms may underlie both modalities but remain not well-understood. This study aims to prospectively document neuropathic pain symptoms and to identify potential itch symptom profiles that differ regarding duration and co-occurrence with neuropathic pain which may inform underlying pathophysiological mechanisms and respond to different treatments. Adult burn survivors (n = 192) self-reported itch and neuropathic pain at 2 weeks post-discharge, 3, 6, 12, and 18 months post-burn. Based on the presence of itch and pain symptoms over time, participants were allocated to one itch profile: transient itch/pain, chronic itch, or chronic itch & pain. Profiles were compared on itch intensity over time using General Linear Modeling. Age, gender, burn severity, posttraumatic stress (PTS) symptoms and baseline itch intensity were examined as potential predictors of the profiles in a Multi-nominal regression analysis. Neuropathic pain occurred in 54% after discharge which decreased to 24% 18 months later. Itch intensity was highest in the chronic itch & pain profile. Compared to the transient itch profile, the chronic itch & pain profile was associated with higher burn severity and more PTS symptoms. Compared to the chronic itch profile, the chronic itch & pain profile was associated with more PTS symptoms. Findings suggest that biological and psycho-dermatological processes underlie both chronic neuropathic pain and itch processes in burn scars. Further research should elucidate the mechanisms underlying the different itch profiles, with specific focus on skin innervation and psychological factors.

Vulvar Pruritus in Postmenopausal Diabetic Women With Candidiasis Secondary to Sodium-Glucose Cotransporter Receptor-2 Inhibitors.

Vulvar pruritus with external rash in postmenopausal women on sodium-glucose cotransporter receptor-2 inhibitors may indicate vulvovaginal candidiasis, which requires early yeast culture for prompt diagnosis and management. Objective/Purpose We present a case series of recurrent vulvovaginal candidiasis (RVVC) secondary to sodium-glucose cotransporter receptor-2 (SGLT2) inhibitor-induced glucosuria in postmenopausal women that resulted in extensive vulvar skin involvement. Materials and Methods We describe 5 cases of RVVC presenting primarily with vulvar pruritus and external rash, in type 2 diabetic, postmenopausal women on SGLT2 inhibitor therapy. This work was exempt from institutional review board approval in compliance with the university guidelines for determining human subject research. All patients consented to the use of pictures for educational and research purposes. Results All patients developed RVVC, with vulvar cultures positive for Candida albicans and resolution of symptoms after treatment with oral fluconazole. All patients presented primarily with severe vulvar pruritus that developed after beginning treatment with SGLT2 inhibitors (range: 4 wk–16 mo). Given the intermittent nature of symptoms, variable degree of activity at presentation, lack of vaginal discharge, atypical population, and extensive skin involvement, RVVC was not considered initially. Three patients were misdiagnosed with lichen sclerosus and treated with topical steroids, which may have allowed for disease progression. Two patients were prescribed topical estrogen creams for presumed vaginal atrophy. One patient was misdiagnosed with improper vulvar hygiene and neuropathic itch. Because of these diagnostic missteps, 4 patients endured symptomatically for extended periods (range: 2–6 years) without adequate treatment. Four patients have discontinued their SGLT2 inhibitor, all with resolution of vulvar symptoms. Conclusions Postmenopausal, diabetic women taking SGLT2 inhibitors presenting with vulvar pruritus and rash require early evaluation for RVVC to prevent misdiagnoses and need for diabetic medication alterations.

Neuropathic pain and itch: mechanisms in allergic conjunctivitis.

Allergic conjunctivitis is highly prevalent and affects up to one third of the general population. The current understanding of the pathophysiology and therapeutic strategies center around the type 2 inflammatory pathway. However, there is an increasing body of evidence that suggests neurogenic mechanisms also play a role in allergic inflammation, with a substantial proportion of allergic conjunctivitis patients experiencing both ocular itch and pain. Unmyelinated C fibres on the ocular surface transmit histaminergic itch and can be directly activated by mast cell mediators. The conjunctival mucosa also contains TRPV1+ (histamine-dependent) and TRPA1+ (histamine-independent) neurons that enhance ocular pain and itch in allergic conjunctivitis. Allergen-complexed IgE also binds directly to FcεRI expressed on peripheral neurons. Environmental aeroallergens can also directly stimulate neuronal nociceptors to release inflammatory substances. Allergic inflammation thus stimulates nerve terminals to release vasoactive and inflammatory neuropeptides, leading to a cyclical neuronal dysregulation that augments mast cell activity. These repetitive cycles lead to both peripheral and central sensitization and neuronal plasticity, resulting in decreased itch/pain thresholds and a heightened itch/pain response. Neurogenic mechanisms including peripheral and central sensitization may drive chronic ocular itch and pain secondary to allergic inflammation. Research into these pathways may help to identify therapeutic targets in allergic conjunctivitis patients with refractory symptoms.

Neuroinflammation Involved in Diabetes-Related Pain and Itch.

Diabetes mellitus (DM) is a global epidemic with increasing incidence, which results in diverse complications, seriously affects the patient quality of life, and brings huge economic burdens to society. Diabetic neuropathy is the most common chronic complication of DM, resulting in neuropathic pain and chronic itch. The precise mechanisms of diabetic neuropathy have not been fully clarified, hindering the exploration of novel therapies for diabetic neuropathy and its terrible symptoms such as diabetic pain and itch. Accumulating evidence suggests that neuroinflammation plays a critical role in the pathophysiologic process of neuropathic pain and chronic itch. Indeed, researchers have currently made significant progress in knowing the role of glial cells and the pro-inflammatory mediators produced from glial cells in the modulation of chronic pain and itch signal processing. Here, we provide an overview of the current understanding of neuroinflammation in contributing to the sensitization of the peripheral nervous system (PNS) and central nervous system (CNS). In addition, we also summarize the inflammation mechanisms that contribute to the pathogenesis of diabetic itch, including activation of glial cells, oxidative stress, and pro-inflammatory factors. Targeting excessive neuroinflammation may provide potential and effective therapies for the treatment of chronic neuropathic pain and itch in DM.

Histamine Is Responsible for the Neuropathic Itch Induced by the Pseudorabies Virus Variant in a Mouse Model.

Pseudorabies virus (PRV) is the causative agent of pseudorabies (PR). It can infect a wide range of mammals. PRV infection can cause severe acute neuropathy (the so-called “mad itch”) in nonnatural hosts. PRV can infect the peripheral nervous system (PNS), where it can establish a quiescent, latent infection. The dorsal root ganglion (DRG) contains the cell bodies of the spinal sensory neurons, which can transmit peripheral sensory signals, including itch and somatic pain. Little attention has been paid to the underlying mechanism of the itch caused by PRV in nonnatural hosts. In this study, a mouse model of the itch caused by PRV was elaborated. BALB/c mice were infected intramuscularly with 105 TCID50 of PRV TJ. The frequency of the bite bouts and the durations of itch were recorded and quantified. The results showed that the PRV-infected mice developed spontaneous itch at 32 h postinfection (hpi). The frequency of the bite bouts and the durations of itch were increased over time. The mRNA expression levels of the receptors and the potential cation channels that are relevant to the itch-signal transmission in the DRG neurons were quantified. The mRNA expression levels of tachykinin 1 (TAC1), interleukin 2 (IL-2), IL-31, tryptases, tryptophan hydroxylase 1 (TPH1), and histidine decarboxylase (HDC) were also measured by high-throughput RNA sequencing and real-time reverse transcription PCR. The results showed that the mean mRNA level of the HDC in the DRG neurons isolated from the PRV-infected mice was approximately 25-fold higher than that of the controls at 56 hpi. An immunohistochemistry (IHC) was strongly positive for HDC in the DRG neurons of the PRV-infected mice, which led to the high expression of histamine at the injected sites. The itch of the infected mice was inhibited by chlorphenamine hydrogen maleate (an antagonist for the histamine H1 receptor) in a dose-dependent manner. The mRNA and protein levels of the HDC in the DRG neurons were proportional to the severity of the itch induced by different PRV strains. Taken together, the histamine synthesized by the HDC in the DRG neurons was responsible for the PRV-induced itch in the mice.

Probing the Cellular Basis of Spinal Kappa Opioid Receptor Inhibition of Itch

The kappa opioid receptor (KOR, encoded by Oprk1) is an extremely attractive target for the treatment of chronic itch. The KOR agonist nalfurafine is used to treat chronic itch associated with kidney and liver disease in Japan, with additional KOR agonists in development for atopic dermatitis and neuropathic itch. Despite the clinical promise of KOR agonists, the cellular basis of KOR inhibition of itch remains unknown. Previous work from our lab demonstrated that KOR inhibition of itch occurs – at least in part – at the level of the spinal cord, raising the question: how does KOR signaling inhibit itch spinal circuits? We are addressing this fundamental gap in knowledge through a combination of molecular, genetic, behavioral, and physiological approaches in mice. First, we used fluorescent in situ hybridization to determine which spinal neuron populations express Oprk1. We show that Oprk1 is expressed within a heterogenous population of spinal neurons, but primarily those that express the neuropeptide substance P or the neurokinin-1 receptor, which drive itch behavior. Moreover, retrograde viral labeling revealed that Oprk1 is expressed in spinoparabrachial neurons that relay itch input from the spinal cord to the brain. Next, we tested whether Oprk1 spinal neurons contribute to itch behaviors. We selectively expressed excitatory chemogenetic tools in Oprk1-Cre spinal neurons and found that chemogenetic activation of these neurons potentiated itch behaviors. Finally, we used ex vivo two-photon calcium imaging of the spinal cord to visualize the neuron networks activated by spinal itch neuropeptides and investigated how KOR agonists inhibit these networks. Notably, these data are the first in-depth look into the cellular basis of spinal KOR inhibition of itch and provide fundamental mechanistic insights into KOR agonists that are clinically effective in alleviating chronic itch. Supported by NIH grants F32NS110155 (TDS) and R01NS0967905 (SER).