Sensitization Mechanisms of Chronic Itch

Abstract

Introduction Pruritus is defined as an unpleasant sensation that evokes a desire to scratch. According to its duration, pruritus can be classified as acute or chronic, with the latter defined as pruritus lasting longer than 6 weeks.1 Chronic itch is a persistent, burdensome condition with a serious unmet clinical need. The pathophysiology of chronic itch differs considerably from that of acute itch. The causes of chronic itch are complex, including dermatologic diseases and various systematic diseases. Chronic itch can be a disease or syndrome resembling chronic pain, and is divided into spontaneous itch, hyperknesis (enhanced itch response to a normal itch stimulus), and alloknesis (itch elicited by an innocuous touch stimulus).2 The subtypes of chronic itch have been broadly delineated as dermatologic (eg, atopic dermatitis [AD] and psoriasis), systemic (eg, chronic kidney disease and cholestasis), neuropathic (eg, post-herpetic itch), and psychogenic (eg, obsessive-compulsive disorder and drug use).3 The mechanisms underlying chronic itch are multifaceted and involve keratinocytes, cutaneous nerve fibers, pruritogenic molecules, and the peripheral and central nervous systems. Activating mediators of itch include histamine, 5-hydroxytryptamine, nerve growth factor (NGF), and substance P (SP). Peripheral and central sensitization plays an important role in the establishment of chronic pain and itch,4 is mediated not only by peripheral inflammatory mediators but also by the effect of amplifying information directly processed by the central nervous system. Peripheral sensitization Peripheral sensitization induces plasticity changes in pruriceptive nerves via diverse itch signal transmission pathways. Pruritogens are mostly synthesized and released by keratinocytes, and then they transmit an itch signal to a transient receptor potential (TRP) integrator by binding to its specific receptor, producing itch. The compound effect of inflammatory mediators is complicated by their interactions, such as the mutual reinforcement of prostaglandin E2 and histamine.5 However, the acute effects of combinations of mediators cannot explain the occurrence of persistent sensitization on account of adaptation and rapid desensitization of primary afferent nerve fibers.6 Therefore, development of a clinical hypersensitivity status requires long-term structural changes. And NGF plays an important role in the process. Sustained exposure to inflammatory mediators or trauma can cause skin sensory nerve endings to become sensitized, in which increased expression of NGF in the skin is important. The levels of NGF in serum and skin have been shown to be increased in AD patients. In addition, NGF can cause skin nerve sensitization and sprouting.7 NGF is upregulated in injured and inflammatory tissues. It specifically binds to tropomyosin receptor kinase A (TrkA), after which a signal is sent to the dorsal root ganglion (DRG) via retrograde axons. This signal induces increased expression of neuropeptides associated with nerve growth and sensitivity, such as SP and calcitonin gene-related peptide, thus activating and enhancing pruritus signals.8 In cutaneous inflammatory diseases, such as prurigo nodularis, cutaneous T-cell lymphoma, and psoriasis, the expression of NGF is elevated in the dermal papillae, and NGF receptors are present in the membrane of cells in the basal and spinal layers of the epidermis.7,9-10 Although many randomized controlled trials (RCTs) have shown positive results of treatment with tanezumab (a monoclonal antibody targeting NGF) for neoplasms, osteoarthritis, and cystitis, few studies have focused on the anti-pruritic efficacy of tanezumab. A phase II RCT involving patients with psoriasis showed significant improvement in the itch intensity by administration of pegcantratinib, a TrkA inhibitor (previously CT327).10 Another significant pruritogen, tryptase, is revealed by previous studies, which shown that the concentration of tryptase, which is considered an endogenous agonist of neuronal proteinase-activated receptor-2 (PAR2), is increased in patients with AD and that intradermal administration of endogenous PAR-2 agonists elicits enhanced itch.11 Studies involving murine models of AD and chronic dermatitis also showed that the activity of tryptase and the expression level of PAR2 in skin were increased.12-13 These results suggest that tryptase and PAR2 are involved in the development of chronic pruritus. Pruritogens and inflammatory mediators sensitize temperature-sensitive TRP channels by binding to pruriceptors, such as the noxious receptor channels TRP ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1).14 TRPV1 and TRPA1 share structural similarity, but they also have important differences on function. Histamine-independent itch signal transmission is associated with TRPA1, while TRPV1 plays an important role in both histamine-dependent and -independent itch.15 NGF leads to itch via binding to the TrkA receptors on skin nerve terminals and then activating TRPV1.8 Histamine activates TRPV1 by binding to histamine receptor 1.16 Mas-related G protein-coupled receptors A3 and C11 couple TRPA1 via G beta-gamma complex (Gβγ) and a phospholipase C-dependent signaling pathway, respectively, to transmit pruritus.17 Lysophosphatidic acid-induced itchy behavior is related to activated TRPA1 and TRPV1 channels by intracellular lysophosphatidic acid.18 The activation thresholds of sensitized TRPV1 and TRPA1 are reduced, and noxious sensation can be produced by innocuous stimuli in the internal and external environment19-20; this is closely related to spontaneous itch and alloknesis. Therefore, the sensitization of temperature-sensitive TRP channel integrators is the main peripheral molecular mechanism of chronic pruritus. A recent study showed that chronic pruritus is dependent on the transmission of nerve signals by janus kinase 1 and that its inhibitors exert an anti-pruritic effect by suppressing the activity of TRPV1.21 RCTs have shown that both topical treatment and systemic treatment of the janus kinase inhibitor tofacitinib lead to improvement in the itch intensity of inflammatory dermatoses, such as AD and plaque psoriasis.22-23 Cytokines and chemokines also play crucial roles in chronic itch. In mouse models, dry skin induced tumor necrosis factor-alpha (TNF-α) expression in the skin, and chronic itch induced by dry skin was reduced by administration of the TNF-α antagonist etanercept; this treatment also reduced chronic itch in mice with TNF receptor subtype 1/2-knockout.24 Another cytokine, thymic stromal lymphopoietin (TSLP), is a major driver of AD by transmitting signals between epithelial and immune cells. A recent study showed that itch can be promoted directly by TSLP, which is released from keratinocytes and acts on a TRPA1-positive sensory neurons.25 Because studies on the role of TSLP are very new, therapeutic research targeting TSLP is only emerging. Tezepelumab is a monoclonal antibody that targets circulating TSLP and has shown benefits in treating asthma.26 Two phase II RCTs of tezepelumab in patients with AD are ongoing (NCT03809663, EudraCT2018-001997-52). The immune system also plays a key role in mediating chronic itch associated with sensory neuron terminals and epithelial cells. In one study, interleukin (IL)-31 evoked intense itch and its concentration was significantly increased in murine skin with atopic-like dermatitis.27 A recent study revealed that the IL-31 receptor (IL-31R) is a critical neuro-immune link between T helper type 2 cells and sensory nerves and is expressed by a small subpopulation of IL-31RA+/TRPV1+/TRPA1+ neurons. This suggests that IL-31 may act on peripheral nerves, directly causing pruritus. TRPV1 and IL-31R are co-expressed on DRG neurons. Thus, TRPV1 and TRPA1 may participate in IL-31-induced itch.8 The monoclonal antibody nemolizumab, which targets the IL-31RA subunit, was recently developed. A phase II RCT including 191 patients with AD confirmed the long-term anti-pruritic effects and favorable safety profile of nemolizumab.28 In another phase II RCT, nemolizumab was administered to patients with prurigo nodularis and showed promising results as an anti-pruritic therapy (EudraCT2017-001715-36). Central sensitization Unlike in pain pathways, the molecular mechanisms of central sensitization in itch pathways have not been studied in depth. Central sensitization refers to abnormally increased excitability of pruritogen-responsive neurons or synaptic transmission in the spinal cord and supraspinal regions, including increased neuron spontaneous discharge activity, an enlarged receptive domain, a decreased threshold to external stimuli, and an enhanced response to suprathreshold stimuli. Together, these mechanisms amplify the transmission of itch signals. Sensitization of pruriceptors Increasing evidence suggests that neurotransmitters, secreted by activated spinal horn neurons, transmit itch signals29 such as gastrin-releasing peptide (GRP), brain natriuretic peptide (BNP), SP, and glutamate. Whether GRP acts as a peripheral or central neurotransmitter remains controversial. Some studies have suggested that GRP acts as a peripheral itch neurotransmitter that signals to second-order neurons, which express GRP receptors (GRPR) in the spinal cord, resulting in the transmission of itch signals. However, several other studies have shown little or no GRP staining in primary afferents but robust GRP expression in dorsal horn neurons.30 Despite the contradictory evidence of GRP expression, the GRP-GRPR system clearly has a key function in itch transmission. Previous studies have indicated that GRPR-knockout mice or GRP-saporin-treated mice showed a substantial reduction in scratching and suggested that GRPR-expressing neurons mediate both histamine-independent and -dependent itch.31 A recent study showed that the GRPR-positive spinal cord neural population is composed of interneurons that express the vesicular glutamate transporter-2 and transmit chemical and spontaneous itch stimuli via these excitatory interneurons.32 The BNP-natriuretic peptide receptor A (NPRA) system also regulates the transmission of itch signals, together with the GRP-GRPR system. BNP is the modified product of the NPPB gene and activates NPRA-expressing interneurons. The lack of BNP or NPRA-expressing interneurons in mice eliminated itch behaviors evoked by a wide variety of pruritogens. Recent studies have implicated that the BNP signaling pathway may function in an ascending manner in the GRP signaling pathway to regulate itch.30 Several lines of evidence support a model wherein BNP released by primary afferent neurons results in the release of GRP by spinal cord interneurons; SP then binds to neurokinin-1 receptor (NK1R), leading to potentiation of itch.33 NK1R is an important part of this pathway and is found in both the peripheral and central nervous systems.34 One RCT showed that in patients with prurigo nodularis, treatment with the NK1R antagonist serlopitant resulted in greater pruritus reduction than placebo.35 However, another NK1R antagonist (aprepitant) had no additive effect in patients with AD.36 Many RCTs testing the anti-pruritic efficacy of serlopitant are currently underway or have pending results for patients with AD, prurigo nodularis, and psoriasis (NCT03540160, NCT03841331, EudraCT2017-004211-40, and EudraCT2017-004210-25). Endothelin-1 (ET-1) has been implicated in non-histaminergic itch as a pruritogen that is expressed by immune cells, endothelial cells, and neurons. Interestingly, a recent study revealed that neural endothelin-converting enzyme 1 (ECE-1), an intracellular neural peptidase, is a key regulator of ET-1-induced itch and intracellular cell signaling in DRG neurons. ECE-1, ET-1, and endothelin A receptor (ETAR) are expressed and co-localize in murine DRG neurons and human skin nerves. ECE-1 inhibition slowed down ETAR recycling but prolonged the activation of extracellular signal-regulated kinase 1/2 induced by ET-1. The ET-1/ETAR/ECE-1/extracellular signal-regulated kinase 1/2 axis may be upregulated in patients with chronic itch.37 Disruption of spinal itch inhibition Another mechanism of central sensitization is the dysfunction or deficiency of inhibitory interneurons. Pruriceptive signals are transmitted by specific neural circuits in the spinal cord; these circuits are distinct from nerve circuits that transmit pain signals, but both circuits intersect in the process of itch inhibition. Clinically, itch can be inhibited by scratching, pain, and hot or cold noxious stimuli. The underlying mechanism is related to activation of inhibitory neurons of the pain circuit, producing inhibitory neurotransmitters such as γ aminobutyric acid, aminoacetic acid, and dynorphin and thereby inhibiting or weakening itch signal transmission.38 Several subtypes of inhibitory interneurons are present in the dorsal spinal. Genetic ablation of the Bhlhb5 transcription factor abolishes pain transmission and spontaneous itch behaviors. Genetic deletion studies have also suggested that the lack of Bhlhb5 enhances itch responses.39 Recent research has confirmed the hypothesis that the neuropathic itch in Bhlhb5-deficient mice can be controlled by restoring inhibitory function through spinal cord transplantation. Bhlhb5-deficient mice that received transplants demonstrated a significant reduction of excessive scratching and skin damage.40 Kardon et al.41 found that Bhlhb5-deficient mice lacked the spinal interneurons that express dynorphin, which has strong selectivity for the kappa opioid receptor. These findings suggest that kappa opioids may be an alternative therapy for chronic itch. Similarly, a recent study also showed that mice in which neuropeptide Y::Cre-derived neurons were selectively ablated also displayed augmented mechanical itch without increased sensitivity to chemical pruritus or pain. Neuropeptide Y::Cre inhibitory neurons in the spinal cord can be specifically activated by low-threshold mechanical-sensitive afferent fibers and can inhibit mechanical chronic pruritus, which is histamine-independent and is transmitted independently from neurons that express GRPR.42 Dysfunction of descending itch modulation Transmission of pruritus signals in the spinal cord is thought to undergo descending modulation from the brain. The spinal itch circuit is tightly controlled by spinal inhibitory neurons. Therefore, if the descending modulation pathway is abnormal, the pruritus signal can be generated and amplified. Subtypes of spinal inhibitory neurons that are involved in gating the spinal itch circuit have recently been identified.43 Noradrenergic inhibition involves excitatory α1-adrenoceptors located on inhibitory interneurons and inhibitory α2-adrenoceptors located on central terminals of primary sensory neurons. The noradrenergic pathways may exert their inhibitory effect by activating inhibitory α2-adrenoceptors, descending from the locus coeruleus and adjacent regions. Depletion of norepinephrine in the spinal cord leads to robust itch behavior.44 Serotonergic pathways descending from the rostral ventromedial medulla may also contribute to the modulation of itch. Previous studies have shown that depletion of supraspinal serotonin reduces itch behavior.45 A recent study also proved that serotonin and noradrenaline are involved in the modulation of pruritus signal processing. Co-administration of selective serotonin reuptake inhibitors and noradrenaline reuptake inhibitors attenuated itch-evoked scratching behavior.46 Another descending itch modulation pathway is the periaqueductal gray pathway. Inhibitory interneurons in the spinal cord are activated by the periaqueductal gray pathway to release itch.47 A very recent study showed that tachykinin 1 (Tac1)-expressing glutamatergic neurons exhibit scratching behavior-related neural activity and are located in the lateral and ventrolateral periaqueductal gray (l/vlPAG). Suppressing the activity of l/vlPAG neurons reduces itch-evoked scratching behavior, while the activity of Tac1-expressing glutamatergic neurons in the l/vlPAG is impaired during itch-induced scratching behavior. During itch-evoked scratching, the activity of Tac1-expressing glutamatergic neurons located in the l/vlPAG is increased, whereas scratching behavior is decreased by ablating or inhibiting the activity of these neurons. The activation of Tac1-expressing neurons has also been shown to be associated with robust spontaneous scratching and grooming behaviors.48 Altered supraspinal processing of itch signal Because of technological advances in functional brain imaging and previous studies on pain-related brain functions, the numbers of studies focusing on pruritus-related brain functions have gradually increased. Many previous studies involving resting-state functional magnetic resonance imaging have investigated the interactions among multiple brain regions in itch. Studies of AD and chronic spontaneous urticaria have shown that itch is associated with multiple brain regions, including the insula, cingulate cortex, and basal ganglia.45,49 Research has shown revealed reduced functional connectivity in itch sensation between the insular and cingulate cortices and the basal ganglia and increased connectivity between the superior parietal lobule and dorsolateral prefrontal cortex.49 The intrinsic functional organization of the brain is also associated with surface behavior. The basal ganglia are involved in action motivation and initiation to withdraw from itch, and the supplementary motor area and basal ganglia are involved in scratching movement and the urge to scratch. The anterior cingulate cortex is associated with emotion.49-50 The major ascending pathway for transmission of itch signals is the spinothalamic tract, which can be divided into two pathways. One is the histaminergic pathway and the other is the non-histaminergic pathway. These pathways activate common brain regions including the first somatosensory area, second somatosensory area, insular cortex, thalamus, and motor-related regions. In contrast to histamine, cowhage induces more extensive activation of the insular cortex, claustrum, globus pallidus, caudate body, putamen, and thalamic nuclei on the contralateral side of the stimulus.49 A recent study revealed an important central circuit from the spinal cord to the brain for itch sensation and indicated that the parabrachial nucleus plays a key role in pruritus information processing. The study showed that the spinoparabrachial pathway was activated during the transmission of itch signals and that the optogenetic suppression of this pathway decreased pruritus-induced scratching behavior. Itch-specific spinal neurons that express GRPR are disynaptically connected to the projection neurons in the parabrachial nucleus. Furthermore, the study showed that inhibiting the activity of the parabrachial nucleus neurons or selectively blocking the synaptic transmission of excitatory neurons can significantly reduce acute itching and slow down the establishment of chronic pruritus.51 Conclusion A greater understanding of the underlying peripheral and central sensitization mechanisms of chronic itch has been gained in recent years, revealing a number of mediators, such as NGF, PAR-2, Lysophosphatidic acid, TNF-α, TSLP, IL-31 and central nervous system pathways, including the BNP-NPRA system, the pain-transmitting circuits, the noradrenergic pathways, the periaqueductal gray pathway, and the spinoparabrachial pathway for future antipruritic therapeutics to block the transmission of itch signal, enhance inhibitory function of spinal itch inhibition or restore descending itch modulation. Also, many studies using rs-fMRI have showed the interactions for itch among multiple brain regions, including the insula, cingulate cortex, and basal ganglia. Furthermore, various of clinical trials targeting in different mediators are in progress or have already been finished. We can expect these studies may guide the advent of new effective treatment strategies for chronic itch.