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Glial Cells Are Involved in Itch Processing

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Glial Cells Are Involved in Itch Processing Acta Derm Venereol 2016; 96: 723–727 REVIEW ARTICLE Glial Cells are Involved in Itch Processing Hjalte H. ANDERSEN, Lars ARENDT-NIELSEN and Parisa GAZERANI SMI®, Department of Health Science and Technology, School of Medicine, Aalborg University, Denmark Recent discoveries in itch neurophysiology include itch- worsening the skin lesions and leading to more or pro- selective neuronal pathways, the clinically relevant non- longed pruritus (5, 6). This phenomenon, known as the histaminergic pathway, and elucidation of the notable itch–scratch–itch vicious cycle, is physiologically com- similarities and differences between itch and pain. Po- plex and is likely to involve: local inflammatory medi- tential involvement of glial cells in itch processing and ators and structural changes, reward components, and the possibility of glial modulation of chronic itch have the autonomic nervous system (5, 7). In most conditions recently been identified, similarly to the established glial associated with chronic itch, very limited or ambiguous modulation of pain processing. This review outlines the evidence is found for the effectiveness of pharmaceutical similarities and differences between itch and pain, and interventions, and the evidence is often characterized by how different types of central and peripheral glial cells off-label small-scale trials or case series. Histamine is may be differentially involved in the development of ch- now widely accepted not to have a key role in evoking ronic itch akin to their more investigated role in chronic itch in most of the clinical conditions characterized by pain. Improvements are needed in the management of chronic pruritus (for an overview of itch neurobiology chronic itch, and future basic and interventional studies and mechanisms, see recent reviews in the field [8, 9]). on glial activity modulation would both enhance our This is in agreement with the fact that these conditions understanding of mechanisms underlying the chroni- are often largely or entirely resistant to treatment with fication of itch and provide novel opportunities for the topical as well as systemic antihistamines (3, 10). Hence, prevention or treatment of this debilitating and common the current treatment regimens for reliev ing itch, beyond condition. Key words: itch; glia; glial cells; astrocytes; targeting the underlying disorder, are suboptimal (3). micro glia; neurophysiology; satellite glial cells; Schwann Preclinical studies have recently shown that glial cells cells; pain; surrogate models of itch. may also play an important role in the development of pathological chronic itch (11–13). This review aims to Accepted Feb 10, 2016; Epub ahead of print Feb 11, 2016 recapitulate on these novel findings and highlights the Acta Derm Venereol 2016; 96: 723–727. similarities and differences between pain and itch in relation to neuron-glial interactions. Finally, this paper Parisa Gazerani, SMI®, Department of Health Science provides an overview of the currently elucidated mole- and Technology, School of Medicine, Aalborg University, cular mechanisms of glial involvement in itch, and future Fredrik Bajers Vej 7, Bld. A2-208, DK-9220 Aalborg E, interventional opportunities are discussed, in order to Denmark. E-mail: [email protected] stimulate further investigation within this novel area. Itch is a sensory modality defined as the “unpleasant ITCH AND PAIN somatosensation that evokes a desire to scratch” (1). In its acute form, itch carries a protective purpose by Itch and pain, although distinct, are highly entwined prompting a scratch response in the affected area. In cases sensory modalities with numerous similarities, but also of pathologically associated itch, e.g. in conditions such distinct differences. In chronic conditions, both itch and as psoriasis, prurigo nodularis, uraemic pruritus, drug- pain tend to generalize anatomically, decrease quality induced pruritus, or atopic dermatitis (AD), however, of life, and precipitate secondary reactive depression itch often turns into a chronic or frequently recurring (14). Notably, mild cutaneous pain is commonly found debilitation. Chronic itch affects millions of individu- to co-exist with chronic itch, for instance in patients als (2), imposes a significant burden on the quality of with AD and psoriasis, who nonetheless typically life of the afflicted patients, and interferes with vital report itch as their primary sensory complaint (15). functions such as sleep, attention, and sexual activity Itch and pain are also pathophysiologically grouped (3, 4). Similar to the events leading to chronification of in a similar way; often presenting as inflammatory or pain conditions, certain pathological predispositions, neuropathic (16). Moreover, itch causes the central such as inflammatory skin disorders, frequently lead to sensitization-associated signs termed “alloknesis” and the intensification and chronification of pruritus. This, in “hyperknesis”, similar to those produced by painful turn, leads to excessive, recurrent scratching, typically stimuli, “allodynia” and “hyperalgesia”, respectively © 2016 The Authors. doi: 10.2340/00015555-2366 Acta Derm Venereol 96 Journal Compilation © 2016 Acta Dermato-Venereologica. ISSN 0001-5555 724 H. H. Andersen et al. (14). Alloknesis describes the dysesthetic state, in and more recently a number of studies have emerged which otherwise non-pruritic stimuli, e.g. light touch, focusing on the role of peripheral glia, e.g. satellite glial provoke a sensation of itch (17, 18), and hyperknesis is cells (SGCs) in relation to pain. Recent accumulating an exaggerated itch response elicited after a normally evidence reviewed here proposes a possible interaction pruritic or prickling stimulus (16, 19). A study by van between glial cells and pruriceptive neurons that might Laarhoven et al. (20) compared somatosensory proces- play a role in the chronification of itch. sing of itch and pain using quantitative sensory testing (QST) and itch provocations between patients with rheumatoid arthritis and psoriasis. The patients with NEURON-GLIA INTERACTIONS IN PAIN – AND psoriasis had an increased itch response to histamine ITCH? iontophoresis (visual analogue scale (VAS)=3, 0–10 scale), but not electrical itch stimulation, while the A large amount of strong evidence supports a role of patients with rheumatoid arthritis displayed decreased glial cells in relation to both neuropathic and inflam- tolerance to painful stimuli (cold pressor test and me- matory pain (26–28). The neuron-glia interactions are chanical stimulation) indicative of pathway-specific shown to be crucial in modulating several induced pruriceptive and nociceptive sensitization, respectively pathological pain conditions particularly associated (20). At the same time, a few studies using QST indi- with sub-acute and chronic pain (29, 30). Neuronal cate that sensory aberrations, particularly associated excitability of nociceptive circuits can be extensively with thermal parameters and conditioned pain modu- augmented by neurotransmitters, but also by immune lation, are present in patients with itch, as have also mediators directly released from, or modulated by, been thoroughly established and utilized for a number glial cells, such as microglia, astrocytes and, to a of pain conditions. However, some studies are notably lesser extent, oligodendrocytes (28). The notion of in disagreement with the concept of central sensiti- neuro-inflammation as a maintainer of pain-induced zation as a significant feature in relation to chronic hyperexcitability and pain chronification has promp- itch (21–24). Finally, several treatment opportunities ted similar research related to the role of glial cells in represent commonalities; as with chronic pain, itch oc- prolongation or chronification of itch (11, 12). New casionally responds to, for example, topical capsaicin, strategies considered promising in glial modulation of anticonvulsants, local anaesthetics, and homotopic some pathological pain states, which could be equally cold counter-stimulation (3, 14). Interestingly, and in applicable and important for itch modulation and treat- complete contrast to the aforementioned, a frequent ment. Table I highlights recent and important findings side-effect of μ-opioid analgesics is induction of on the contribution of glial cells in itch processing. severe itch, which is thought to be, at least in part, a Drawing on these parallels between itch and pain consequence of decreased activity in the dorsal horn opens up the possibility of understanding the underlying neurons of the nociceptive system, thereby causing mechanisms of chronification and potential modula- spinal disinhibition of itch-signalling (25). The para- tion of itch (26, 29). Considering the fact that itch and doxical itch response to opioids underlines the notion pain are mediated mostly by primary afferent C-fibres of separate neuronal pathways and central proces- with their cell bodies located in the dorsal root ganglia sing of itch and pain. In relation to pain processing, (DRG) or the trigeminal ganglia (TG), the interactions non-neuronal glial cells are widely accepted to play between neuronal tissue conveying itch and the non- a significant role in the initiation or maintenance of neuronal component (e.g. SGCs) at the level of the pain. Central glia, foremost astrocytes and microglia, sensory ganglia, are hypothesized to be similar to the have been extensively implicated in pain processing, established interactions between SGCs and nociceptive
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