Neuroscience Forefront ReviewNeural processing of itch
Introduction
Itch and pain are defined as “an unpleasant cutaneous sensation which provokes the desire to scratch” (Rothman, 1941) and “unpleasant sensory and emotional experience associated with actual or potential tissue damage” (McCracken et al., 2004), respectively. Itch and pain are similar in that they signal the organism of potentially dangerous stimuli, and are associated with protective motor responses. Itch and pain might share a common pathway, based on the following observations. (1) Both sensory qualities are transmitted via spinothalamic tract (STT). (2) Itch is absent in patients congenitally insensitive to pain. (3) Light touch surrounding a region of itch or pain elicits a sensation of itch (alloknesis) or pain (allodynia), respectively. (4) Many spinal neurons respond to both pruritic and algesic stimuli. (5) Brain-imaging studies have revealed considerable overlap in areas that are active during itch or pain, such as prefrontal areas, supplementary motor areas (SMA), premotor cortex, anterior insular cortex, anterior midcingulate cortex, primary (S1) and secondary (S2) somatosensory cortices, thalamus, basal ganglia, and cerebellum (Pfab et al., 2012). However, itch and pain differ on a number of points. Firstly, itch-inducing stimuli typically elicit scratching to remove an irritant from the skin surface or to dig out parasites invading the skin, whereas algogenic stimuli typically elicit withdrawal of the stimulated body area away from the stimulus, and/or other integrated escape or aggressive motor responses. Secondly, pain is attenuated by μ-opioids which can elicit or exacerbate itch (Ständer and Schmelz, 2006). Conversely, μ-opioid antagonists suppress itch (Heyer et al., 1997) while sometimes inducing hyperalgesia (Levine et al., 1978, Gracely et al., 1983). Thirdly, painful counterstimuli (scratch, cold, and heat) inhibit itch. These differences have been used to differentiate between itch and pain in animal models (Shimada and LaMotte, 2008, Akiyama et al., 2010a, LaMotte et al., 2011) (see Animal models of itch). Fourthly, while pain occurs on the body surface as well as in deep tissues (e.g., muscle, joints, or inner organs), itch only occurs at the surface of the body including skin, cornea, and other mucosal surfaces.
Itch (pruritus) is distinguished as acute or chronic, with the latter defined as pruritus lasting more than 6 weeks (Ständer et al., 2007). Chronic pruritus is associated with inflammatory skin diseases as well as systemic diseases and has been classified by several groups. An early classification scheme was based on the origin of itch (Twycross et al., 2003). Later, in 2007, the International Forum for the Study of Itch (IFSI) proposed a clinically-oriented classification scheme (Ständer et al., 2007) consisting of 6 categories: (1) dermatological (atopic dermatitis, psoriasis, etc.), (2) systemic (kidney dialysis, liver cholestasis, etc.), (3) neurological (postherpetic neuralgia, etc.), (4) psychogenic (e.g., delusional parasitosis), (5) Mixed (overlapping and coexistence of several diseases) and (6) others (undetermined origin). Epidemiological data for each classification of chronic pruritus have been reported by various groups. Among patients with atopic dermatitis, 83–87% reported daily itch (Yosipovitch et al., 2002, Chrostowska-Plak et al., 2009). The incidence of patients with psoriasis reporting itch was 64–85% (Yosipovitch et al., 2000, Sampogna et al., 2004, Prignano et al., 2009). Between 22% and 90% of hemodialysis patients suffered from uremic itch (Feramisco et al., 2010). In a large epidemiological study of 18,801 hemodialysis patients, moderate to extreme itch was experienced by 42% (Pisoni et al., 2006). The prevalence of itch in primary biliary cirrhosis was variable, ranging from 25% to 70% (Rishe et al., 2008). Of patients with hepatitis C, 24% reported having itch (Bonacini, 2000). The prevalence of pruritus at 2 years following burn injury was 73% (Carrougher et al., 2013) while another study reported that 87% of burn survivors experience itch on a daily basis (Laura et al., 2012). The prevalence of shingles-associated itch is 17–58% (Oaklander et al., 2003). Among psychiatric inpatients, 36–42% reported idiopathic itch (Kretzmer et al., 2008, Mazeh et al., 2008). Overall, the incidence of chronic itch is high under a variety of different conditions. A population-based cohort study revealed that one out of four people experience chronic itch during their lifetime (Matterne et al., 2013). While the economic costs of chronic pain have been estimated as $560–635 billion per year in the US (Institute of Medicine of the National Academies, 2011), the exact economic costs of chronic itch have not been estimated. NIAMS reported that direct costs of chronic itch (atopic dermatitis) may exceed $3 billion per year (NIAMS, 2009). Considering the high incidence of chronic itch under many different conditions, the economic costs of chronic itch are likely to be much higher. Treatment is challenging, with no current universally accepted therapy for itch (Patel and Yosipovitch, 2010). Although some topical and systemic antipruritic drugs are available, the optimal therapy is not easy to classify due to a lack of knowledge about the mechanisms underlying the various sub-types of itch (Steinhoff et al., 2011).
Pain pathways have been investigated extensively. The spinal cord plays a central role, receiving ascending sensory input from peripheral afferents as well as descending input from supraspinal modulatory curcuits that include the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) (Basbaum et al., 2009, Heinricher et al., 2009, Dubin and Patapoutian, 2010). In contrast to pain, there have been until recently few studies of the spinal processing and modulation of itch, despite the fact that chronic itch is difficult to treat and can significantly reduce the quality of life as much as chronic pain. Recent studies indicate that itch appears to be transmitted by subsets of spinal nociceptive neurons (see below). Thus, a better understanding of basic mechanisms of itch will not only lead to novel mechanisms-based strategies to treat itch, but will also move forward our understanding of pain signaling.
Section snippets
Pruritogens
A list of pruritogens is shown in Table 1.
Animal models of itch
The close association between itch and scratching has led to the use of scratching behavior as a readout of itch in most animal models. However, itch may also be associated with other behaviors such as biting or licking the itchy area. These models are discussed, below.
Primary sensory afferents
Itch is mediated by unmyelinated C-fiber afferents as well as thinly myelinated Aδ-fiber afferents. In microneurographic recordings in humans, mechano-insensitive C-fibers preferentially respond to histamine but not cowhage (Schmelz et al., 1997, Namer et al., 2008). In contrast, mechano-sensitive, polymodal C-fibers readily respond to cowhage with lesser or no responses to histamine in humans and primates (Johanek et al., 2008, Namer et al., 2008). Thus, cowhage and histamine appear to
Gastrin-releasing peptide (GRP), SP and glutamate
The neurotransmitters involved in spinal or trigeminal transmission of itch have recently come under investigation, with particular emphasis on GRP, SP, and glutamate. Neurotoxic ablation of neurokinin-1 (NK-1) receptor-expressing neurons in the superficial dorsal horn of rats attenuated 5-HT-evoked scratching (Carstens et al., 2010), and selective NK-1 antagonists reduced scratching elicited by chloroquine, but not histamine, in mice, implying a role for SP in non-histaminergic itch (Akiyama
Pruritogen-responsive spinal neurons
The dorsal horn is the major site processing information from primary sensory afferents. Superficial dorsal horn neurons (laminae І–ІІ) receive direct input from most nociceptive Aδ- and C-fibers, while deep dorsal horn neurons (laminae ІІІ–V) receive direct input from Aβ-fibers (Todd, 2002). Recent molecular studies have further categorized the central projections of nociceptive C-fibers and low-threshold mechanoreceptors (LTMRs) in the spinal cord (Basbaum et al., 2009, Li et al., 2011).
Trigeminal processing of itch
Using calcium imaging of trigeminal ganglion (TG) cells, 15.4% and 5.8% responded to histamine and SLIGRL-NH2, respectively (Akiyama et al., 2010c). Of these, more than 70% additionally responded to capsaicin or AITC. We also recorded from 58 neurons in Vc with afferent input from the cheek (Akiyama et al., 2010c). Out of 32 pruritogen-responsive Vc neurons, 4 were MI and responded to either capsaicin or AITC. In this study, a subpopulation of nociceptive neurons was isolated using an algogen
Inhibitory interneurons
Inhibitory interneurons in laminae І–ІІІ consist of four distinct neurochemical populations containing neuropeptide Y (NPY), galanin, parvalbumin and neuronal nitric oxide synthase (nNOS) (Tiong et al., 2011). The transcription factor Bhlhb5 is transiently expressed in the dorsal horn of the developing spinal cord to regulate a unique population of inhibitory interneurons that inhibit itch (Ross et al., 2010). Approximately 65% of inhibitory interneurons are innervated by Aδ-fibers and/or
Opioid modulation of itch
As noted earlier, morphine inhibits pain but can induce or enhance itch, whereas μ-opiate antagonists suppress itch but not pain. One possible explanation for morphine-induced itch is that opioid peptide-expressing inhibitory interneurons in the spinal cord might synapse onto the Bhlhb5 interneurons; activity in the opioid interneurons (or exogenous application of μ-agonists) would inhibit the Bhlhb5 interneurons to disinhbit itch-signaling neurons (Handwerker, 2010). An alternative explanation
Descending modulation of itch
Scratch-evoked inhibition of spinal itch-signaling neurons involves both segmental and supraspinal circuits. Cold-block or complete transection of the upper cervical spinal cord reduced scratch-evoked inhibition of spontaneous activity in dorsal horn neurons with input from dry skin by 30% and 50%, respectively. This implies that scratch-evoked inhibition is mediated partially via the activation of supraspinal neurons that, in turn, engage descending pathways to result in the spinal release of
Sensitization of itch-signaling pathways
Peripheral and central sensitization play important roles in the establishment of chronic pain, and the same processes may contribute to various types of chronic itch. Chronic pain is often associated with ongoing spontaneous pain, hyperalgesia, and allodynia (touch-evoked pain). These conditions can also be experimentally reproduced in human skin by intradermal injection of capsaicin. In primates, capsaicin enhanced the responses of monkey STT neurons to touch and noxious heat, as well as
Theories of itch
It has been debated for over a century whether itch and pain are mediated via distinct pathways, a concept known as specificity theory or labeled-line coding, or if itch is a low-level form of pain on the same sensory continuum, a concept known as the intensity (or frequency) theory (von Frey, 1922). Intensity theory holds that a common population of sensory neurons responds to both pruritic and noxious stimuli, with itch being signaled by a low firing rate and pain by a higher firing rate in
Acknowledgements
The work was supported by supported by Grants from the National Institutes of Health DE013685, AR057194 and AR063228.
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