Elsevier

Neuroscience

Volume 250, 10 October 2013, Pages 697-714
Neuroscience

Neuroscience Forefront Review
Neural processing of itch

https://doi.org/10.1016/j.neuroscience.2013.07.035Get rights and content

Highlights

  • There are histamine-dependent and -independent types of itch.

  • Molecular detectors of pruritogens include Mrgprs, PARs, and many others.

  • Spinal transmitters include gastrin releasing peptide and natriuretic polypeptide B.

  • Pruritogen-sensitive sensory neurons usually also respond to pain-producing stimuli.

  • Pruritogen-responsive sensory neurons connect to an itch-specific central pathway.

Abstract

While considerable effort has been made to investigate the neural mechanisms of pain, much less effort has been devoted to itch, at least until recently. However, itch is now gaining increasing recognition as a widespread and costly medical and socioeconomic issue. This is accompanied by increasing interest in the underlying neural mechanisms of itch, which has become a vibrant and rapidly-advancing field of research. The goal of the present forefront review is to describe the recent progress that has been made in our understanding of itch mechanisms.

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.

References (216)

  • A. Basbaum et al.

    Cellular and molecular mechanisms of pain

    Cell

    (2009)
  • K. Benjamin et al.

    The development of an objective method for measuring scratch in children with atopic dermatitis suitable for clinical use

    J Am Acad Dermatol

    (2004)
  • M. Bonacini

    Pruritus in patients with chronic human immunodeficiency virus, hepatitis B and C virus infections

    Digestive and liver disease: official journal of the Italian society of gastroenterology and the Italian association for the study of the liver

    (2000)
  • H.M. Brash et al.

    A repetitive movement detector used for automatic monitoring and quantification of scratching in mice

    J Neurosci Methods

    (2005)
  • E. Chudler et al.

    Responses of cat C1 spinal cord dorsal and ventral horn neurons to noxious and non-noxious stimulation of the head and face

    Brain Res

    (1991)
  • R. Cridland et al.

    Bombesin, neuromedin C and neuromedin B given intrathecally facilitate the tail flick reflex in the rat

    Brain Res

    (1992)
  • J.M. Cuellar et al.

    Deletion of the preprotachykinin A gene in mice does not reduce scratching behavior elicited by intradermal serotonin

    Neurosci Lett

    (2003)
  • X. Dong et al.

    A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons

    Cell

    (2001)
  • G.R. Elliott et al.

    An automated method for registering and quantifying scratching activity in mice: use for drug evaluation

    J Pharmacol Toxicol Methods

    (2000)
  • J. Feramisco et al.

    Innovative management of pruritus

    Dermatol Clin

    (2010)
  • L. Gomes et al.

    Endothelin-1 induces itch and pain in the mouse cheek model

    Life Sci

    (2012)
  • Y. Gotoh et al.

    Tonic inhibition of allergic itch signaling by the descending noradrenergic system in mice

    J Pharmacol Sci

    (2011)
  • B.G. Green et al.

    The sensory response to capsaicin during repeated topical exposures: differential effects on sensations of itching and pungency

    Pain

    (1993)
  • O. Hagermark et al.

    Flare and itch induced by substance P in human skin

    J Invest Dermatol

    (1978)
  • S.-K. Han et al.

    Phospholipase Cbeta 3 mediates the scratching response activated by the histamine H1 receptor on C-fiber nociceptive neurons

    Neuron

    (2006)
  • H.O. Handwerker

    Microneurography of pruritus

    Neurosci Lett

    (2010)
  • M.M. Heinricher et al.

    Descending control of nociception: specificity, recruitment and plasticity

    Brain Res Rev

    (2009)
  • G. Heyer et al.

    Opiate and H1 antagonist effects on histamine induced pruritus and alloknesis

    Pain

    (1997)
  • M. Hosogi et al.

    Bradykinin is a potent pruritogen in atopic dermatitis: a switch from pain to itch

    Pain

    (2006)
  • N. Inagaki et al.

    Involvement of unique mechanisms in the induction of scratching behavior in BALB/c mice by compound 48/80

    Eur J Pharmacol

    (2002)
  • N. Inagaki et al.

    Participation of histamine H1 and H2 receptors in passive cutaneous anaphylaxis-induced scratching behavior in ICR mice

    Eur J Pharmacol

    (1999)
  • E. Joseph et al.

    PLC-beta 3 signals upstream of PKC epsilon in acute and chronic inflammatory hyperalgesia

    Pain

    (2007)
  • S. Kagami et al.

    Serum gastrin-releasing peptide levels correlate with pruritus in patients with atopic dermatitis

    J Invest Dermatol

    (2013)
  • H. Kim et al.

    Characterizations of sphingosylphosphorylcholine-induced scratching responses in ICR mice using naltrexon, capsaicin, ketotifen and Y-27632

    Eur J Pharmacol

    (2008)
  • A.Y. Kim et al.

    Pirt, a phosphoinositide-binding protein, functions as a regulatory subunit of TRPV1

    Cell

    (2008)
  • G.E. Kretzmer et al.

    Idiopathic pruritus in psychiatric inpatients: an explorative study

    Gen Hosp Psychiatry

    (2008)
  • Y. Kuraishi et al.

    Scratching behavior induced by pruritogenic but not algesiogenic agents in mice

    Eur J Pharmacol

    (1995)
  • M.C. Lagerstrom et al.

    VGLUT2-dependent sensory neurons in the TRPV1 population regulate pain and itch

    Neuron

    (2010)
  • B. Abila et al.

    Effects of two antihistamines on chloroquine and histamine induced weal and flare in healthy African volunteers

    Afr J Med Med Sci

    (1994)
  • T. Akiyama et al.

    Excitation of mouse superficial dorsal horn neurons by histamine and/or PAR-2 agonist: potential role in itch

    J Neurophysiol

    (2009)
  • T. Akiyama et al.

    Differential itch- and pain-related behavioral responses and μ-opoid modulation in mice

    Acta Derm Venereol

    (2010)
  • T. Akiyama et al.

    Facial injections of pruritogens and algogens excite partly overlapping populations of primary and second-order trigeminal neurons in mice

    J Neurophysiol

    (2010)
  • T. Akiyama et al.

    Enhanced responses of lumbar superficial dorsal horn neurons to intradermal PAR-2 agonist but not histamine in a mouse hindpaw dry skin itch model

    J Neurophysiol

    (2011)
  • T. Akiyama et al.

    Transmitters and pathways mediating inhibition of spinal itch-signaling neurons by scratching and other counterstimuli

    PLoS ONE

    (2011)
  • T. Akiyama et al.

    Activation of superficial dorsal horn neurons in the mouse by a PAR-2 agonist and 5-HT: potential role in itch

    J Neurosci

    (2009)
  • T. Akiyama et al.

    Site-dependent and state-dependent inhibition of pruritogen-responsive spinal neurons by scratching

    Eur J Neurosci

    (2012)
  • T. Akiyama et al.

    Roles for substance P and gastrin releasing peptide as neurotransmitters released by primary afferent pruriceptors

    J Neurophysiol

    (2012)
  • F. Alemi et al.

    The TGR5 receptor mediates bile acid-induced itch and analgesia

    J Clin Investig

    (2013)
  • D. Andersson et al.

    Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress

    J Neurosci

    (2008)
  • T. Andoh et al.

    Involvement of leukotriene B4 in spontaneous itch-related behaviour in NC mice with atopic dermatitis-like skin lesions

    Exp Dermatol

    (2011)
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