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Circuit Mechanisms of Itch in the Brain

  • Di Mu
    Affiliations
    Department of Anesthesiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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  • Yan-Gang Sun
    Correspondence
    Correspondence: Yan-Gang Sun, Institute of Neuroscience (ION), State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
    Affiliations
    Institute of Neuroscience, State Key Laboratory of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology (CEBSIT), Chinese Academy of Sciences, Shanghai, China

    Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China
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Published:October 15, 2021DOI:https://doi.org/10.1016/j.jid.2021.09.022
      Itch is an unpleasant somatic sensation with the desire to scratch, and it consists of sensory, affective, and motivational components. Acute itch serves as a critical protective mechanism because an itch-evoked scratching response will help to remove harmful substances invading the skin. Recently, exciting progress has been made in deciphering the mechanisms of itch at both the peripheral nervous system and the CNS levels. Key neuronal subtypes and circuits have been revealed for ascending transmission and the descending modulation of itch. In this review, we mainly summarize the current understanding of the central circuit mechanisms of itch in the brain.

      Abbreviations:

      5-HT (5-hydroxytryptophan), ACC (anterior cingulate cortex), CeA (central amygdala), CGRP (calcitonin gene-related peptide), CPA (conditional place aversion), GABA (γ-aminobutyric acid), GRP (gastrin-releasing peptide), GRPR (gastrin-releasing peptide receptor), IC (insular cortex), NAc (nucleus accumbens), NE (norepinephrine), NPY (neuropeptide Y), PAG (periaqueductal gray), PBN (parabrachial nucleus), PFC (prefrontal cortex), Po (posterior thalamic nucleus), PoT (posterior triangular nucleus), RVM (rostral ventromedial medulla), S1 (primary somatosensory cortex), TAC1 (tachykinin 1), TACR1 (tac1 receptor), UCN3 (Urocortin 3), VB (ventrobasal nucleus), VPM (ventral posteromedial nucleus), VTA (ventral tegmental area)

      Introduction

      Itch (also known as pruritus) is defined as an unpleasant somatic sensation that evokes a desire to scratch (
      • Ikoma A.
      • Steinhoff M.
      • Ständer S.
      • Yosipovitch G.
      • Schmelz M.
      The neurobiology of itch.
      ). The strong emotional and motivational components of itch play important roles in driving scratching behaviors. The scratching behaviors will not only relieve itchiness but also induce pleasure (
      • Mochizuki H.
      • Tanaka S.
      • Morita T.
      • Wasaka T.
      • Sadato N.
      • Kakigi R.
      The cerebral representation of scratching-induced pleasantness.
      ), which leads to the vicious itch‒scratching cycle. The itch‒scratching cycle could cause severe skin damage in patients with chronic itch. These unique characteristics make itch a complex physiological function whose neural mechanism is largely unresolved.
      Recent studies have revealed the molecular markers and circuits of itch processing in the spinal cord. Neurons expressing gastrin-releasing peptide receptor (GRPR) are predominantly excitatory neurons, representing a key component of the spinal chemical itch circuit (
      • Sun Y.G.
      • Chen Z.F.
      A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord.
      ;
      • Sun Y.G.
      • Zhao Z.Q.
      • Meng X.L.
      • Yin J.
      • Liu X.Y.
      • Chen Z.F.
      Cellular basis of itch sensation.
      ). Natriuretic peptide receptor A‒expressing neurons in the dorsal spinal cord coexpressed with gastrin-releasing peptide (GRP) are located upstream of GRPR+ neurons along the spinal pathway for the chemical itch (
      • Mishra S.K.
      • Hoon M.A.
      The cells and circuitry for itch responses in mice.
      ). Spinal inhibitory interneurons, such as galanin-positive neurons and neuronal nitric oxide synthase‒positive neurons, form predominant inhibitory synapses with GRPR+ neurons and play an important role in gating chemical itch (
      • Kardon A.P.
      • Polgár E.
      • Hachisuka J.
      • Snyder L.M.
      • Cameron D.
      • Savage S.
      • et al.
      Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord.
      ;
      • Liu M.Z.
      • Chen X.J.
      • Liang T.Y.
      • Li Q.
      • Wang M.
      • Zhang X.Y.
      • et al.
      Synaptic control of spinal GRPR+ neurons by local and long-range inhibitory inputs.
      ;
      • Ross S.E.
      • Mardinly A.R.
      • McCord A.E.
      • Zurawski J.
      • Cohen S.
      • Jung C.
      • et al.
      Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice.
      ). A specific population of interneurons expressing transcription factor BHLHB5 inhibits itch by releasing opioid peptide dynorphin, and the kappa opioid receptor agonists might have therapeutic potential for treating pruritus (
      • Kardon A.P.
      • Polgár E.
      • Hachisuka J.
      • Snyder L.M.
      • Cameron D.
      • Savage S.
      • et al.
      Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord.
      ;
      • Ross S.E.
      • Mardinly A.R.
      • McCord A.E.
      • Zurawski J.
      • Cohen S.
      • Jung C.
      • et al.
      Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice.
      ). In addition to the chemical itch evoked by pruritogens, itch sensation can also be evoked by light tactile stimuli, known as the mechanical itch. Recent studies found that the mechanical itch is independent of spinal GRPR+ neurons but requires spinal excitatory interneurons expressing Urocortin 3 (UCN3) (
      • Pan H.
      • Fatima M.
      • Li A.
      • Lee H.
      • Cai W.
      • Horwitz L.
      • et al.
      Identification of a spinal circuit for mechanical and persistent spontaneous itch.
      ). The neuropeptide Y (NPY)+ neurons form functional inhibitory synaptic connections with UCN3+ neurons and gate the mechanical itch circuit in the spinal level (
      • Acton D.
      • Ren X.
      • Di Costanzo S.
      • Dalet A.
      • Bourane S.
      • Bertocchi I.
      • et al.
      Spinal neuropeptide Y1 receptor-expressing neurons form an essential excitatory pathway for mechanical itch.
      ;
      • Bourane S.
      • Duan B.
      • Koch S.C.
      • Dalet A.
      • Britz O.
      • Garcia-Campmany L.
      • et al.
      Gate control of mechanical itch by a subpopulation of spinal cord interneurons.
      ;
      • Pan H.
      • Fatima M.
      • Li A.
      • Lee H.
      • Cai W.
      • Horwitz L.
      • et al.
      Identification of a spinal circuit for mechanical and persistent spontaneous itch.
      ).
      Human brain imaging has been employed to study the cerebral mechanisms of itch since the 1990s (
      • Hsieh J.C.
      • Hägermark O.
      • Ståhle-Bäckdahl M.
      • Ericson K.
      • Eriksson L.
      • Stone-Elander S.
      • et al.
      Urge to scratch represented in the human cerebral cortex during itch.
      ) and revealed that many brain areas are involved in itch processing, including the primary somatosensory cortex (S1), prefrontal cortex (PFC), insular cortex (IC), and thalamus (
      • Mochizuki H.
      • Kakigi R.
      Central mechanisms of itch.
      ;
      • Mochizuki H.
      • Hernandez L.E.
      • Yosipovitch G.
      What does brain imaging tell us about itch?.
      ). Besides human brain imaging studies, the transmission of itch signals has also been examined by in vivo electrophysiological studies in animals. These studies have revealed that the spinothalamic and trigeminothalamic tract neurons are activated by peripheral pruritic stimuli in cats (
      • Andrew D.
      • Craig A.D.
      Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch.
      ), rodents (
      • Lipshetz B.
      • Giesler Jr., G.J.
      Effects of scratching and other counterstimuli on responses of trigeminothalamic tract neurons to itch-inducing stimuli in rats.
      ;
      • Moser H.R.
      • Giesler Jr., G.J.
      Characterization of pruriceptive trigeminothalamic tract neurons in rats.
      ), and nonhuman primates (
      • Davidson S.
      • Zhang X.
      • Khasabov S.G.
      • Simone D.A.
      • Giesler Jr., G.J.
      Relief of itch by scratching: state-dependent inhibition of primate spinothalamic tract neurons.
      ,
      • Davidson S.
      • Zhang X.
      • Yoon C.H.
      • Khasabov S.G.
      • Simone D.A.
      • Giesler Jr., G.J.
      The itch-producing agents histamine and cowhage activate separate populations of primate spinothalamic tract neurons.
      ;
      • Simone D.A.
      • Zhang X.
      • Li J.
      • Zhang J.M.
      • Honda C.N.
      • LaMotte R.H.
      • et al.
      Comparison of responses of primate spinothalamic tract neurons to pruritic and algogenic stimuli.
      ). Besides spinal projections to the thalamus, the trigeminoparabrachial tract is also involved in itch processing (
      • Akiyama T.
      • Curtis E.
      • Nguyen T.
      • Carstens M.I.
      • Carstens E.
      Anatomical evidence of pruriceptive trigeminothalamic and trigeminoparabrachial projection neurons in mice.
      ;
      • Jansen N.A.
      • Giesler Jr., G.J.
      Response characteristics of pruriceptive and nociceptive trigeminoparabrachial tract neurons in the rat.
      ). These studies suggest that several critical nuclei, including the thalamus and the parabrachial nucleus (PBN), are involved in itch processing. Recent studies have begun to dissect the functional roles of these nuclei and central circuits of itch using optogenetic, pharmacogenetic, and genetic approaches. The progress on both peripheral and central neural mechanisms has been well-summarized in several critical reviews (
      • Chen X.J.
      • Sun Y.G.
      Central circuit mechanisms of itch.
      ;
      • Dong X.
      • Dong X.
      Peripheral and central mechanisms of itch.
      ). In this review, we will focus on the recent progress on brain circuits in ascending transmission (Figure 1) and descending modulation (Figure 2) of itch.
      Figure thumbnail gr1
      Figure 1Neural circuits underlying different components of itch. VB thalamus, Po, and S1 (cyan) are involved in the processing of the sensory component of itch. PBN, CeA, and PAG (orange) are involved in the processing of the emotional component of itch. VTA and NAc (ocher) are involved in the processing of the motivational component of itch. CeA, central amygdala; CVLM, caudal ventrolateral medulla; ILN, intralaminar thalamic nuclei; NAc, nucleus accumbens; NAc LaSh, lateral shell of the nucleus accumbens; PAG, periaqueductal gray; PBN, parabrachial nucleus; Po, posterior thalamic nucleus; PoT, posterior triangular nucleus; PVT, paraventricular thalamic nucleus; S1, primary somatosensory cortex; TRN, thalamic reticular nucleus; VB, ventrobasal nucleus; VPL, ventral posterolateral nucleus; VPM, ventral posteromedial nucleus; VTA, ventral tegmental area.
      Figure thumbnail gr2
      Figure 2Neural circuit underlying descending modulation of itch. CeA, PAG, RVM, and locus coeruleus are involved in descending modulation of itch through the targeting of spinal GRPR+ neurons, 5-HT1A+ neurons, and Galanin+ neurons. AM thalamic nucleus, ACC, DMS are also involved in modulating Bhlhb5+ neurons in the spinal cord. 5-HT, 5-hydroxytryptophan; ACC, anterior cingulate cortex; AM, anteromedial thalamic nucleus; CeA, central amygdala; DMS, dorsal medial striatum; GABA, γ-aminobutyric acid; PAG, periaqueductal gray; RVM, rostral ventromedial medulla.

      Sensory component of itch

      Previous human brain imaging studies have examined the difference in brain activity in healthy volunteers in response to histamine or saline injection and showed significant activation of the primary S1 and premotor cortex but not the secondary somatosensory cortex (
      • Darsow U.
      • Drzezga A.
      • Frisch M.
      • Munz F.
      • Weilke F.
      • Bartenstein P.
      • et al.
      Processing of histamine-induced itch in the human cerebral cortex: a correlation analysis with dermal reactions.
      ;
      • Mochizuki H.
      • Tashiro M.
      • Kano M.
      • Sakurada Y.
      • Itoh M.
      • Yanai K.
      Imaging of central itch modulation in the human brain using positron emission tomography.
      ). Similar activation was also detected in human subjects watching video clips of scratching (
      • Holle H.
      • Warne K.
      • Seth A.K.
      • Critchley H.D.
      • Ward J.
      Neural basis of contagious itch and why some people are more prone to it.
      ). In patients with atopic dermatitis, higher activation was detected in the contralateral thalamus, bilateral cingulate cortex, and PFC than in healthy volunteers (
      • Ishiuji Y.
      • Coghill R.C.
      • Patel T.S.
      • Oshiro Y.
      • Kraft R.A.
      • Yosipovitch G.
      Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis.
      ;
      • Schneider G.
      • Ständer S.
      • Burgmer M.
      • Driesch G.
      • Heuft G.
      • Weckesser M.
      Significant differences in central imaging of histamine-induced itch between atopic dermatitis and healthy subjects.
      ). By contrast, studies in rodents showed elevated activities in many brain nuclei, including the thalamus, hypothalamus, and brainstem nuclei, but these studies did not detect the activation of S1 and the premotor cortex (
      • Jeong K.Y.
      • Kang J.H.
      Investigation of the pruritus-induced functional activity in the rat brain using manganese-enhanced MRI.
      ;
      • Jeong K.Y.
      • Kim H.M.
      • Kang J.H.
      Investigation of the functional difference between the pathological itching and neuropathic pain-induced rat brain using manganese-enhanced MRI.
      ).
      Recent animal studies have begun to examine the functional role of thalamic nuclei in itch processing. The ventrobasal thalamus (VB) is the primary relay nuclei in the thalamus, which can be divided into two subnuclei: the ventral posterolateral nucleus and the ventral posteromedial nucleus (VPM).
      • Lipshetz B.
      • Khasabov S.G.
      • Truong H.
      • Netoff T.I.
      • Simone D.A.
      • Giesler Jr., G.J.
      Responses of thalamic neurons to itch- and pain-producing stimuli in rats.
      found that >70% of the VPM neurons were responsive to one or several kinds of pruritogens. The posterior triangular nucleus (PoT), a high-order thalamic nucleus, has also been shown to be itch responsive. Extracellular recording results showed that the neurons in the PoT responded at higher frequencies than those in the VPM to both histamine-dependent and -independent pruritogens applied to the cheek, indicating that the PoT might be a particularly interesting region for itch transmission from the cheek (
      • Lipshetz B.
      • Khasabov S.G.
      • Truong H.
      • Netoff T.I.
      • Simone D.A.
      • Giesler Jr., G.J.
      Responses of thalamic neurons to itch- and pain-producing stimuli in rats.
      ). A recent study confirmed that the posterior thalamic nucleus (Po) mediates facial histaminergic itch using fiber photometry and pharmacogenetic manipulation (
      • Zhu Y.B.
      • Xu L.
      • Wang Y.
      • Zhang R.
      • Wang Y.C.
      • Li J.B.
      • et al.
      Posterior thalamic nucleus mediates facial histaminergic itch.
      ). Consistently, previous tracing and electrophysiological studies showed that the Po receives pruriceptive information from the spinothalamic and trigeminothalamic tracts (
      • Chiaia N.L.
      • Rhoades R.W.
      • Bennett-Clarke C.A.
      • Fish S.E.
      • Killackey H.P.
      Thalamic processing of vibrissal information in the rat. I. Afferent input to the medial ventral posterior and posterior nuclei.
      ;
      • Gauriau C.
      • Bernard J.F.
      A comparative reappraisal of projections from the superficial laminae of the dorsal horn in the rat: the forebrain.
      ;
      • Lipshetz B.
      • Giesler Jr., G.J.
      Effects of scratching and other counterstimuli on responses of trigeminothalamic tract neurons to itch-inducing stimuli in rats.
      ;
      • Moser H.R.
      • Giesler Jr., G.J.
      Characterization of pruriceptive trigeminothalamic tract neurons in rats.
      ;
      • Veinante P.
      • Jacquin M.F.
      • Deschênes M.
      Thalamic projections from the whisker-sensitive regions of the spinal trigeminal complex in the rat.
      ;
      • Zhang X.
      • Giesler Jr., G.J.
      Response characterstics of spinothalamic tract neurons that project to the posterior thalamus in rats.
      ). VB thalamus and Po are also involved in the processing of pain (
      • Saadé N.E.
      • Al Amin H.
      • Abdel Baki S.
      • Safieh-Garabedian B.
      • Atweh S.F.
      • Jabbur S.J.
      Transient attenuation of neuropathic manifestations in rats following lesion or reversible block of the lateral thalamic somatosensory nuclei.
      ;
      • Zhang C.
      • Chen R.X.
      • Zhang Y.
      • Wang J.
      • Liu F.Y.
      • Cai J.
      • et al.
      Reduced GABAergic transmission in the ventrobasal thalamus contributes to thermal hyperalgesia in chronic inflammatory pain [published correction appears in Sci Rep 2017;7:46778].
      ;
      • Zhu X.
      • Tang H.D.
      • Dong W.Y.
      • Kang F.
      • Liu A.
      • Mao Y.
      • et al.
      Distinct thalamocortical circuits underlie allodynia induced by tissue injury and by depression-like states.
      ). It is likely that thalamic neurons process different somatosensory submodalities with population coding, given that most spinothalamic tract neurons are responsive to multiple types of stimuli (
      • Simone D.A.
      • Zhang X.
      • Li J.
      • Zhang J.M.
      • Honda C.N.
      • LaMotte R.H.
      • et al.
      Comparison of responses of primate spinothalamic tract neurons to pruritic and algogenic stimuli.
      ). However, further studies are warranted to investigate the underlying mechanisms.
      As shown by human brain imaging studies (
      • Gross J.
      • Schnitzler A.
      • Timmermann L.
      • Ploner M.
      Gamma oscillations in human primary somatosensory cortex reflect pain perception.
      ;
      • Kim W.
      • Kim S.K.
      • Nabekura J.
      Functional and structural plasticity in the primary somatosensory cortex associated with chronic pain.
      ;
      • Vierck C.J.
      • Whitsel B.L.
      • Favorov O.V.
      • Brown A.W.
      • Tommerdahl M.
      Role of primary somatosensory cortex in the coding of pain.
      ), the S1 is a critical cortical region for the sensory component of itch processing. A recent in vivo electrophysiological study examined the responses of S1 neurons to the application of mechanical stimuli and intradermal injections of pruritic and algesic chemicals in anesthetized rats (
      • Khasabov S.G.
      • Truong H.
      • Rogness V.M.
      • Alloway K.D.
      • Simone D.A.
      • Giesler Jr., G.J.
      Responses of neurons in the primary somatosensory cortex to itch- and pain-producing stimuli in rats.
      ). They found that most of the recorded neurons were activated by one or more stimuli and that no neurons were excited exclusively by pruritogens, arguing against a specificity theory for the sensation of itch. Thus, how S1 neurons encode and process different sensory modalities remains elusive.

      Emotional component of itch

      Itch sensation is associated with a strong negative emotional component, and scratching behavior induces pleasure and itch relief. In addition, chronic itch is associated with increased stress, anxiety, and other mood disorders. These disorders further exacerbate itch, leading to a vicious cycle that worsens the disease prognosis and reduces QOL (
      • Golpanian R.S.
      • Kim H.S.
      • Yosipovitch G.
      Effects of stress on itch.
      ;
      • Marron S.E.
      • Tomas-Aragones L.
      • Boira S.
      • Campos-Rodenas R.
      Quality of life, emotional wellbeing and family repercussions in dermatological patients experiencing chronic itching: a pilot study.
      ;
      • Oh S.H.
      • Bae B.G.
      • Park C.O.
      • Noh J.Y.
      • Park I.H.
      • Wu W.H.
      • et al.
      Association of stress with symptoms of atopic dermatitis.
      ;
      • Sanders K.M.
      • Akiyama T.
      The vicious cycle of itch and anxiety.
      ;
      • Simpson E.L.
      • Gadkari A.
      • Worm M.
      • Soong W.
      • Blauvelt A.
      • Eckert L.
      • et al.
      Dupilumab therapy provides clinically meaningful improvement in patient-reported outcomes (PROs): a phase IIb, randomized, placebo-controlled, clinical trial in adult patients with moderate to severe atopic dermatitis (AD).
      ). Human brain imaging studies have found that patients with chronic itch exhibited higher activation in several brain areas that are involved in emotion, including the IC and PFC (especially the cingulate cortex), in response to pruritic stimuli, indicating altered neural activity in chronic conditions (
      • Ishiuji Y.
      • Coghill R.C.
      • Patel T.S.
      • Oshiro Y.
      • Kraft R.A.
      • Yosipovitch G.
      Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis.
      ;
      • Napadow V.
      • Li A.
      • Loggia M.L.
      • Kim J.
      • Schalock P.C.
      • Lerner E.
      • et al.
      The brain circuitry mediating antipruritic effects of acupuncture.
      ;
      • Schneider G.
      • Ständer S.
      • Burgmer M.
      • Driesch G.
      • Heuft G.
      • Weckesser M.
      Significant differences in central imaging of histamine-induced itch between atopic dermatitis and healthy subjects.
      ). Animal studies also confirmed that both the IC and cingulate cortex are involved in negative emotions associated with aversive somatosensation (
      • Gehrlach D.A.
      • Dolensek N.
      • Klein A.S.
      • Roy Chowdhury R.
      • Matthys A.
      • Junghänel M.
      • et al.
      Aversive state processing in the posterior insular cortex.
      ;
      • Juarez-Salinas D.L.
      • Braz J.M.
      • Etlin A.
      • Gee S.
      • Sohal V.
      • Basbaum A.I.
      GABAergic cell transplants in the anterior cingulate cortex reduce neuropathic pain aversiveness.
      ;
      • Meda K.S.
      • Patel T.
      • Braz J.M.
      • Malik R.
      • Turner M.L.
      • Seifikar H.
      • et al.
      Microcircuit mechanisms through which mediodorsal thalamic input to anterior cingulate cortex exacerbates pain-related aversion.
      ;
      • Wu Y.
      • Chen C.
      • Chen M.
      • Qian K.
      • Lv X.
      • Wang H.
      • et al.
      The anterior insular cortex unilaterally controls feeding in response to aversive visceral stimuli in mice.
      ;
      • Zang K.K.
      • Xiao X.
      • Chen L.Q.
      • Yang Y.
      • Cao Q.L.
      • Tang Y.L.
      • et al.
      Distinct function of estrogen receptors in the rodent anterior cingulate cortex in pain-related aversion.
      ;
      • Zhou H.
      • Zhang Q.
      • Martinez E.
      • Dale J.
      • Hu S.
      • Zhang E.
      • et al.
      Ketamine reduces aversion in rodent pain models by suppressing hyperactivity of the anterior cingulate cortex.
      ).
      Animal studies have begun to reveal the mechanisms underlying negative and positive emotional components of itch (
      • Mu D.
      • Sun Y.G.
      Itch induces conditioned place aversion in mice.
      ;
      • Sanders K.M.
      • Sakai K.
      • Henry T.D.
      • Hashimoto T.
      • Akiyama T.
      A subpopulation of amygdala neurons mediates the affective component of itch.
      ;
      • Su X.Y.
      • Chen M.
      • Yuan Y.
      • Li Y.
      • Guo S.S.
      • Luo H.Q.
      • et al.
      Central processing of itch in the midbrain reward center.
      ). It is thought that the spinoparabrachial tract and the PBN are involved in pain processing (
      • Basbaum A.I.
      • Bautista D.M.
      • Scherrer G.
      • Julius D.
      Cellular and molecular mechanisms of pain.
      ;
      • Dunckley P.
      • Wise R.G.
      • Fairhurst M.
      • Hobden P.
      • Aziz Q.
      • Chang L.
      • et al.
      A comparison of visceral and somatic pain processing in the human brainstem using functional magnetic resonance imaging.
      ;
      • Youssef A.M.
      • Macefield V.G.
      • Henderson L.A.
      Pain inhibits pain; human brainstem mechanisms.
      ). Several tracing and in vivo electrophysiological studies in rodents have shown that the PBN is also involved in itch processing (
      • Akiyama T.
      • Curtis E.
      • Nguyen T.
      • Carstens M.I.
      • Carstens E.
      Anatomical evidence of pruriceptive trigeminothalamic and trigeminoparabrachial projection neurons in mice.
      ;
      • Jansen N.A.
      • Giesler Jr., G.J.
      Response characteristics of pruriceptive and nociceptive trigeminoparabrachial tract neurons in the rat.
      ;
      • Li J.N.
      • Ren J.H.
      • Zhao L.J.
      • Wu X.M.
      • Li H.
      • Dong Y.L.
      • et al.
      Projecting neurons in spinal dorsal horn send collateral projections to dorsal midline/intralaminar thalamic complex and parabrachial nucleus.
      ). A study found that the PBN serves as a critical itch-processing nucleus (
      • Mu D.
      • Deng J.
      • Liu K.F.
      • Wu Z.Y.
      • Shi Y.F.
      • Guo W.M.
      • et al.
      A central neural circuit for itch sensation.
      ). Inhibition of the PBN neurons impairs itch-induced scratching behaviors, and silencing synaptic transmission in the PBN alleviates both acute itch and chronic itch. However, it is noteworthy that this study did not determine whether the manipulation of the PBN affects the sensory component or affective component. A more recent study showed that a subtype of PBN neurons expressing calcitonin gene-related peptide (CGRP) are activated by noxious and pruritic stimuli and that silencing of CGRP+ neurons attenuates fear responses and itch-induced scratching behaviors, indicating that the PBN might be involved in various affective‒behavioral states, including both itch and pain (
      • Campos C.A.
      • Bowen A.J.
      • Roman C.W.
      • Palmiter R.D.
      Encoding of danger by parabrachial CGRP neurons.
      ).
      The PBN sends projections to various brain areas, with the central amygdala (CeA) being the most critical downstream target, which is also thought to be the primary center for anxiety and fear (
      • Chiang M.C.
      • Nguyen E.K.
      • Canto-Bustos M.
      • Papale A.E.
      • Oswald A.M.
      • Ross S.E.
      Divergent neural pathways emanating from the lateral parabrachial nucleus mediate distinct components of the pain response.
      ). Previous human brain imaging studies have shown that the amygdala was activated by itch stimuli and deactivated by scratching, indicating that the CeA might contribute to processing itch-induced unpleasure (
      • Papoiu A.D.
      • Nattkemper L.A.
      • Sanders K.M.
      • Kraft R.A.
      • Chan Y.H.
      • Coghill R.C.
      • et al.
      Brain’s reward circuits mediate itch relief. A functional MRI study of active scratching [published correction appears in PLoS One 2014;9].
      ,
      • Papoiu A.D.
      • Coghill R.C.
      • Kraft R.A.
      • Wang H.
      • Yosipovitch G.
      A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch.
      ;
      • Vierow V.
      • Forster C.
      • Vogelgsang R.
      • Dörfler A.
      • Handwerker H.O.
      Cerebral networks linked to itch-related sensations induced by histamine and capsaicin.
      ). A rodent study has shown that pruritic stimuli activate the lateral external subdivision of PBN that projects to CeA (
      • Sanders K.M.
      • Sakai K.
      • Henry T.D.
      • Hashimoto T.
      • Akiyama T.
      A subpopulation of amygdala neurons mediates the affective component of itch.
      ). Furthermore, selective activation of itch-responsive CeA neurons could enhance both scratching and anxiety-like behaviors but not in some aversive and appetitive behaviors previously ascribed to CeA neurons, indicating that itch-activated CeA neurons are critical for mediating sensory and affective components of itch (
      • Samineni V.K.
      • Grajales-Reyes J.G.
      • Grajales-Reyes G.E.
      • Tycksen E.
      • Copits B.A.
      • Pedersen C.
      • et al.
      Cellular, circuit and transcriptional framework for modulation of itch in the central amygdala.
      ;
      • Sanders K.M.
      • Sakai K.
      • Henry T.D.
      • Hashimoto T.
      • Akiyama T.
      A subpopulation of amygdala neurons mediates the affective component of itch.
      ).
      Previous studies have shown that the periaqueductal gray (PAG) is involved in emotion regulation (
      • Etkin A.
      • Büchel C.
      • Gross J.J.
      The neural bases of emotion regulation.
      ;
      • Motta S.C.
      • Carobrez A.P.
      • Canteras N.S.
      The periaqueductal gray and primal emotional processing critical to influence complex defensive responses, fear learning and reward seeking.
      ). A recent study revealed that the PAG is critical for modulating the affective component of itch. Pharmacogenetic activation of PAG γ-aminobutyric acid (GABA)ergic neurons impairs itch-induced scratching behaviors and itch-associated conditional place aversion (CPA), suggesting the PAG GABAergic neurons also play a prominent role in modulating sensory and affective components of itch (
      • Samineni V.K.
      • Grajales-Reyes J.G.
      • Sundaram S.S.
      • Yoo J.J.
      • Gereau 4th, R.W.
      Cell type-specific modulation of sensory and affective components of itch in the periaqueductal gray.
      ). Furthermore, the ventral tegmental area (VTA) GABAergic neurons are critical in encoding the unpleasant or aversive aspect of itch sensation (
      • Su X.Y.
      • Chen M.
      • Yuan Y.
      • Li Y.
      • Guo S.S.
      • Luo H.Q.
      • et al.
      Central processing of itch in the midbrain reward center.
      ). VTA GABAergic neurons positively regulate scratching behaviors during acute itch and contribute to itch-associated CPA.
      The mechanism underlying scratching-evoked pleasure in itch is a fascinating question. The VTA is a well-known reward-related center in the brain. Brain imaging studies found that the VTA is involved in the processing of scratching and in encoding the reward perceived in the scratching of itch (
      • Mochizuki H.
      • Tanaka S.
      • Morita T.
      • Wasaka T.
      • Sadato N.
      • Kakigi R.
      The cerebral representation of scratching-induced pleasantness.
      ;
      • Papoiu A.D.
      • Nattkemper L.A.
      • Sanders K.M.
      • Kraft R.A.
      • Chan Y.H.
      • Coghill R.C.
      • et al.
      Brain’s reward circuits mediate itch relief. A functional MRI study of active scratching [published correction appears in PLoS One 2014;9].
      ).
      • Mochizuki H.
      • Tanaka S.
      • Morita T.
      • Wasaka T.
      • Sadato N.
      • Kakigi R.
      The cerebral representation of scratching-induced pleasantness.
      showed that the VTA was significantly activated during scratching in the pleasant condition (on-target scratching) compared with that in the control condition (off-target scratching). Besides,
      • Papoiu A.D.
      • Nattkemper L.A.
      • Sanders K.M.
      • Kraft R.A.
      • Chan Y.H.
      • Coghill R.C.
      • et al.
      Brain’s reward circuits mediate itch relief. A functional MRI study of active scratching [published correction appears in PLoS One 2014;9].
      showed that the VTA is activated during the active scratching by subjects themselves but not during the passive scratching by an investigator. These studies indicate that the VTA could contribute to the pleasure and the addictive features of scratching. In addition,
      • Su X.Y.
      • Chen M.
      • Yuan Y.
      • Li Y.
      • Guo S.S.
      • Luo H.Q.
      • et al.
      Central processing of itch in the midbrain reward center.
      found that dopaminergic neuron activation lags behind GABAergic neurons and is dependent on the scratching of the itchy site. Inhibition of VTA dopaminergic neurons reduced scratching behaviors and attenuated scratching-associated conditional place preference (
      • Su X.Y.
      • Chen M.
      • Yuan Y.
      • Li Y.
      • Guo S.S.
      • Luo H.Q.
      • et al.
      Central processing of itch in the midbrain reward center.
      ). These studies suggest that VTA dopaminergic neurons are critical in scratching-evoked pleasure.

      Motivational component of itch

      The motivational component of itch plays a key role in driving scratching behavior. The earlier brain imaging study has unraveled a coactivation of the anterior cingulate cortex (ACC), motor cortex, and premotor cortex that depicts a motor intention of the urge to scratch (
      • Hsieh J.C.
      • Hägermark O.
      • Ståhle-Bäckdahl M.
      • Ericson K.
      • Eriksson L.
      • Stone-Elander S.
      • et al.
      Urge to scratch represented in the human cerebral cortex during itch.
      ). This is consistent with the finding that scratching in the pleasant condition (on-target scratching) deactivated the cingulate cortex and the primary motor cortex (
      • Mochizuki H.
      • Tanaka S.
      • Morita T.
      • Wasaka T.
      • Sadato N.
      • Kakigi R.
      The cerebral representation of scratching-induced pleasantness.
      ), supporting the idea that these brain regions could be involved in motivation for scratching behavior. The negative emotional component of itch could also drive the scratching behavior. The VTA GABAergic neurons, which are involved in the emotional component of itch, might also be involved in generating motivation for scratching (
      • Su X.Y.
      • Chen M.
      • Yuan Y.
      • Li Y.
      • Guo S.S.
      • Luo H.Q.
      • et al.
      Central processing of itch in the midbrain reward center.
      ).
      It is well known that VTA dopaminergic neurons play an important role in motivation, and dopamine receptors have been shown to be involved in itch-evoked scratching behavior (
      • Akimoto Y.
      • Furuse M.
      SCH23390, a dopamine D1 receptor antagonist, suppressed scratching behavior induced by compound 48/80 in mice.
      ;
      • Bromberg-Martin E.S.
      • Matsumoto M.
      • Hikosaka O.
      Dopamine in motivational control: rewarding, aversive, and alerting.
      ).
      • Yuan L.
      • Liang T.Y.
      • Deng J.
      • Sun Y.G.
      Dynamics and functional role of dopaminergic neurons in the ventral tegmental area during itch processing.
      strictly defined the different characteristics of scratching behaviors recorded by the magnetic induction system. Scratching induces a cluster of voltage peaks (each peak during scratching is defined as a scratching event). Some scratching events are closer to each other, and a cluster of adjacent scratching events is defined as a scratching bout. A cluster of adjacent scratching bouts is defined as a scratching train (
      • Yuan L.
      • Liang T.Y.
      • Deng J.
      • Sun Y.G.
      Dynamics and functional role of dopaminergic neurons in the ventral tegmental area during itch processing.
      ). By precisely manipulating the VTA dopaminergic neurons,
      • Yuan L.
      • Liang T.Y.
      • Deng J.
      • Sun Y.G.
      Dynamics and functional role of dopaminergic neurons in the ventral tegmental area during itch processing.
      found that brief photoinhibition of VTA dopaminergic neurons significantly shortened the duration of the scratching train, suggesting that the activation of dopaminergic neurons near the onset of scratching behavior likely codes the motivation driving subsequent scratching. This result is in line with the ability of dopaminergic neurons to process aversive signals (
      • Bromberg-Martin E.S.
      • Matsumoto M.
      • Hikosaka O.
      Dopamine in motivational control: rewarding, aversive, and alerting.
      ). This is also supported by the human imaging study showing that the VTA was activated during itching without scratching (
      • Mochizuki H.
      • Tanaka S.
      • Morita T.
      • Wasaka T.
      • Sadato N.
      • Kakigi R.
      The cerebral representation of scratching-induced pleasantness.
      ).
      The VTA dopaminergic neurons are reported to mediate the reward to scratch-induced relief of itch and code motivation driving subsequent scratching in different studies (
      • Su X.Y.
      • Chen M.
      • Yuan Y.
      • Li Y.
      • Guo S.S.
      • Luo H.Q.
      • et al.
      Central processing of itch in the midbrain reward center.
      ;
      • Yuan L.
      • Liang T.Y.
      • Deng J.
      • Sun Y.G.
      Dynamics and functional role of dopaminergic neurons in the ventral tegmental area during itch processing.
      ). The complex functions of dopaminergic neurons might be mediated by different subpopulations of dopaminergic neurons or different dopaminergic receptors in the downstream brain regions of the VTA, especially the nucleus accumbens (NAc). Previous studies have found that dopamine 1 receptor and dopamine 2 receptor in the NAc have different functions in learning and behavioral plasticity.

      Descending modulation of itch

      The neuromodulatory system plays important roles in gating sensory processing (
      • Dasgupta R.
      • Seibt F.
      • Beierlein M.
      Synaptic release of acetylcholine rapidly suppresses cortical activity by recruiting muscarinic receptors in layer 4.
      ;
      • Gil S.M.
      • Metherate R.
      Enhanced sensory-cognitive processing by activation of nicotinic acetylcholine receptors.
      ;
      • Jacob S.N.
      • Nienborg H.
      Monoaminergic neuromodulation of sensory processing.
      ). Among them, norepinephrine (NE, or noradrenaline) and serotonin have been shown to be involved in descending control of itch signal processing. NE-positive neurons are located in several brainstem nuclei, including the locus coeruleus, which is a small brain area located deep in the brainstem and provides broad noradrenergic projections through the CNS (
      • Chandler D.J.
      • Jensen P.
      • McCall J.G.
      • Pickering A.E.
      • Schwarz L.A.
      • Totah N.K.
      Redefining noradrenergic neuromodulation of behavior: impacts of a modular locus coeruleus architecture.
      ;
      • Poe G.R.
      • Foote S.
      • Eschenko O.
      • Johansen J.P.
      • Bouret S.
      • Aston-Jones G.
      • et al.
      Locus coeruleus: a new look at the blue spot.
      ). Previous studies have shown that NE is involved in regulating spinal itch signal processing through both α1 and α2 adrenoceptors (
      • Gotoh Y.
      • Andoh T.
      • Kuraishi Y.
      Noradrenergic regulation of itch transmission in the spinal cord mediated by α-adrenoceptors.
      ,
      • Gotoh Y.
      • Omori Y.
      • Andoh T.
      • Kuraishi Y.
      Tonic inhibition of allergic itch signaling by the descending noradrenergic system in mice.
      ). Recent studies have revealed that α1 adrenoceptors are preferentially expressed in spinal inhibitory interneurons and that α1A adrenoceptors are expressed in spinal dynorphin-positive interneurons (
      • Häring M.
      • Zeisel A.
      • Hochgerner H.
      • Rinwa P.
      • Jakobsson J.E.T.
      • Lönnerberg P.
      • et al.
      Neuronal atlas of the dorsal horn defines its architecture and links sensory input to transcriptional cell types.
      ;
      • Serafin E.K.
      • Chamessian A.
      • Li J.
      • Zhang X.
      • McGann A.
      • Brewer C.L.
      • et al.
      Transcriptional profile of spinal dynorphin-lineage interneurons in the developing mouse.
      ).
      • Koga K.
      • Shiraishi Y.
      • Yamagata R.
      • Tozaki-Saitoh H.
      • Shiratori-Hayashi M.
      • Tsuda M.
      Intrinsic braking role of descending locus coeruleus noradrenergic neurons in acute and chronic itch in mice.
      showed that the descending locus coeruleus noradrenergic pathways control acute and chronic itch by facilitating inhibitory synaptic inputs onto spinal GRPR+ neurons. Furthermore, the projection from locus coeruleus to the ACC is also involved in the modulation of itch (
      • Koga K.
      • Yamada A.
      • Song Q.
      • Li X.H.
      • Chen Q.Y.
      • Liu R.H.
      • et al.
      Ascending noradrenergic excitation from the locus coeruleus to the anterior cingulate cortex [published correction appears in Mol Brain 2020;13:152].
      ), suggesting that the locus coeruleus has complex modulatory effects on itch according to diverse efferents and adrenergic receptors. Serotonin (5-hydroxytryptophan [5-HT]) is another neuromodulator that plays a vital role in descending control of the spinal itch signal processing. Depleting the spinal 5-HT+ fibers attenuates pruritogen-induced scratching behavior (
      • Zhao Z.Q.
      • Liu X.Y.
      • Jeffry J.
      • Karunarathne W.K.
      • Li J.L.
      • Munanairi A.
      • et al.
      Descending control of itch transmission by the serotonergic system via 5-HT1A-facilitated GRP-GRPR signaling.
      ), suggesting a facilitating role of 5-HT in itch. This effect is mediated by the 5-HT1A receptor, which facilitates GRP‒GRPR signaling by directly interacting with GRPR. Many other types of receptors for 5-HT are also expressed in the spinal cord (
      • Majczyński H.
      • Cabaj A.M.
      • Jordan L.M.
      • Sławińska U.
      Contribution of 5-HT2 receptors to the control of the spinal locomotor system in intact rats.
      ;
      • Xie D.J.
      • Uta D.
      • Feng P.Y.
      • Wakita M.
      • Shin M.C.
      • Furue H.
      • et al.
      Identification of 5-HT receptor subtypes enhancing inhibitory transmission in the rat spinal dorsal horn in vitro.
      ), and their functional roles in descending control of itch remain to be determined.
      The PAG is a critical hub that modulates nociceptive signals in the descending pathway (
      • Basbaum A.I.
      • Fields H.L.
      Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry.
      ;
      • Huang J.
      • Gadotti V.M.
      • Chen L.
      • Souza I.A.
      • Huang S.
      • Wang D.
      • et al.
      A neuronal circuit for activating descending modulation of neuropathic pain.
      ;
      • Kuner R.
      • Kuner T.
      Cellular circuits in the brain and their modulation in acute and chronic pain.
      ;
      • Ossipov M.H.
      • Dussor G.O.
      • Porreca F.
      Central modulation of pain.
      ). A human brain imaging study showed that the PAG was activated during simultaneous stimulation of itch and cold pain but not during itch alone (
      • Mochizuki H.
      • Tashiro M.
      • Kano M.
      • Sakurada Y.
      • Itoh M.
      • Yanai K.
      Imaging of central itch modulation in the human brain using positron emission tomography.
      ), and the PAG was found to be significantly deactivated by scratching during itch in humans (
      • Papoiu A.D.
      • Nattkemper L.A.
      • Sanders K.M.
      • Kraft R.A.
      • Chan Y.H.
      • Coghill R.C.
      • et al.
      Brain’s reward circuits mediate itch relief. A functional MRI study of active scratching [published correction appears in PLoS One 2014;9].
      ). Rodent imaging studies also detected increased activity of the PAG during itch (
      • Jeong K.Y.
      • Kang J.H.
      Investigation of the pruritus-induced functional activity in the rat brain using manganese-enhanced MRI.
      ;
      • Jeong K.Y.
      • Kim H.M.
      • Kang J.H.
      Investigation of the functional difference between the pathological itching and neuropathic pain-induced rat brain using manganese-enhanced MRI.
      ). These studies suggested that PAG might be involved in itch modulation. PAG could integrate the itch-related information from both the ascending and descending pathways because PAG receives itch-related information from both the CeA and the PBN (
      • Li J.N.
      • Ren J.H.
      • He C.B.
      • Zhao W.J.
      • Li H.
      • Dong Y.L.
      • et al.
      Projections from the lateral parabrachial nucleus to the lateral and ventral lateral periaqueductal gray subregions mediate the itching sensation.
      ;
      • Samineni V.K.
      • Grajales-Reyes J.G.
      • Grajales-Reyes G.E.
      • Tycksen E.
      • Copits B.A.
      • Pedersen C.
      • et al.
      Cellular, circuit and transcriptional framework for modulation of itch in the central amygdala.
      ). Recent studies have revealed diverse roles of different subtypes of neurons in PAG in itch (
      • Gao Z.R.
      • Chen W.Z.
      • Liu M.Z.
      • Chen X.J.
      • Wan L.
      • Zhang X.Y.
      • et al.
      Tac1-expressing neurons in the periaqueductal gray facilitate the itch-scratching cycle via descending regulation.
      ;
      • Samineni V.K.
      • Grajales-Reyes J.G.
      • Sundaram S.S.
      • Yoo J.J.
      • Gereau 4th, R.W.
      Cell type-specific modulation of sensory and affective components of itch in the periaqueductal gray.
      ,
      • Samineni V.K.
      • Grajales-Reyes J.G.
      • Copits B.A.
      • O’Brien D.E.
      • Trigg S.L.
      • Gomez A.M.
      • et al.
      Divergent modulation of nociception by glutamatergic and GABAergic neuronal subpopulations in the periaqueductal gray.
      ).
      • Gao Z.R.
      • Chen W.Z.
      • Liu M.Z.
      • Chen X.J.
      • Wan L.
      • Zhang X.Y.
      • et al.
      Tac1-expressing neurons in the periaqueductal gray facilitate the itch-scratching cycle via descending regulation.
      found that a subpopulation of PAG glutamatergic neurons expressing tachykinin 1 (PAGTac1) facilitates the itch‒scratching cycle through the descending mechanism (
      • Gao Z.R.
      • Chen W.Z.
      • Liu M.Z.
      • Chen X.J.
      • Wan L.
      • Zhang X.Y.
      • et al.
      Tac1-expressing neurons in the periaqueductal gray facilitate the itch-scratching cycle via descending regulation.
      ). They showed that ablation or inhibition of these neurons reduced itch-induced scratching behaviors, and activation of these neurons induced spontaneous scratching behaviors. They also found that ablation of TAC1+ neurons did not cause significant changes in mouse behavioral responses to thermal or mechanical stimuli or to a formalin-evoked nociceptive insult, indicating that PAG TAC1+ neurons are differentially involved in the modulation of itch and pain processing. Moreover, TAC1+ neurons form glutamatergic synapses with the rostral ventromedial medulla (RVM) neurons, and the PAGTac1 activation‒induced scratching behavior is reduced by ablation of spinal GRPR+ neurons, suggesting that the PAGTac1‒RVM circuit modulates GRPR+ neurons in the descending modulation of itch. Given that RVM neurons form strong inhibitory synapses with GRPR+ neurons (
      • Liu M.Z.
      • Chen X.J.
      • Liang T.Y.
      • Li Q.
      • Wang M.
      • Zhang X.Y.
      • et al.
      Synaptic control of spinal GRPR+ neurons by local and long-range inhibitory inputs.
      ), it is possible that the PAGTac1 neurons facilitate spinal itch processing through a disynaptic disinhibition circuit. However, a recent study showed that the TAC1 receptor (TACR1)-positive neurons in RVM are GABAergic and have an inhibitory effect on itch (Follansbee et al., 2021
      Follansbee AT, Domocos D, Nguyen E, Nguyen A, Bountouvas A, Velasquez L. Descending inhibition of itch by neurokinin 1 receptor (Tacr1) - expressing ON cells in the rostral ventromedial medulla. bioRxiv 2021.
      ). Thus, the specific subpopulation of PAGTac1 downstream in RVM is still elusive.
      The ACC, a higher-order cortical region, is also involved in the modulation of itch. Several brain imaging studies suggested that the cingulate cortex is activated by both itching and pain (
      • Herde L.
      • Forster C.
      • Strupf M.
      • Handwerker H.O.
      Itch induced by a novel method leads to limbic deactivations a functional MRI study.
      ;
      • Mochizuki H.
      • Sadato N.
      • Saito D.N.
      • Toyoda H.
      • Tashiro M.
      • Okamura N.
      • et al.
      Neural correlates of perceptual difference between itching and pain : a human fMRI study [published correction appears in Neuroimage 2008;39:911–2].
      ,
      • Mochizuki H.
      • Tashiro M.
      • Kano M.
      • Sakurada Y.
      • Itoh M.
      • Yanai K.
      Imaging of central itch modulation in the human brain using positron emission tomography.
      ). They also found that subregions of the cingulate cortex might be more involved in itch than in pain (
      • Herde L.
      • Forster C.
      • Strupf M.
      • Handwerker H.O.
      Itch induced by a novel method leads to limbic deactivations a functional MRI study.
      ;
      • Mochizuki H.
      • Sadato N.
      • Saito D.N.
      • Toyoda H.
      • Tashiro M.
      • Okamura N.
      • et al.
      Neural correlates of perceptual difference between itching and pain : a human fMRI study [published correction appears in Neuroimage 2008;39:911–2].
      ). Besides, rodent studies found that chronic itch could potentiate synaptic transmission in the ACC (
      • Zhang T.T.
      • Shen F.Y.
      • Ma L.Q.
      • Wen W.
      • Wang B.
      • Peng Y.Z.
      • et al.
      Potentiation of synaptic transmission in rat anterior cingulate cortex by chronic itch.
      ). Recent studies have shown that the anteromedial thalamic nucleus‒ACC‒dorsal medial striatum circuit modulates histaminergic itch likely through a spinal BHLHB5+ interneuron-dependent mechanism (
      • Deng Y.Z.
      • Lu Y.C.
      • Wu W.W.
      • Cheng L.
      • Zan G.Y.
      • Chai J.R.
      • et al.
      Anteromedial thalamic nucleus to anterior cingulate cortex inputs modulate histaminergic itch sensation.
      ;
      • Lu Y.C.
      • Wang Y.J.
      • Lu B.
      • Chen M.
      • Zheng P.
      • Liu J.G.
      ACC to dorsal medial striatum inputs modulate histaminergic itch sensation.
      ).

      Conclusion and future directions

      In summary, dramatic progress has been made in deciphering the central circuit mechanisms of itch. Several critical brain regions and neural circuits have been revealed for the processing or modulation of itch. The mechanism of contagious itch has been partially elucidated (
      • Holle H.
      • Warne K.
      • Seth A.K.
      • Critchley H.D.
      • Ward J.
      Neural basis of contagious itch and why some people are more prone to it.
      ;
      • Yu Y.Q.
      • Barry D.M.
      • Hao Y.
      • Liu X.T.
      • Chen Z.F.
      Molecular and neural basis of contagious itch behavior in mice.
      ). Despite all these exciting findings, several key issues of itch signal coding and processing remain to be addressed.
      First, how is itch encoded and perceived? The coding mechanism of the itch is still controversial (
      • Braz J.
      • Solorzano C.
      • Wang X.
      • Basbaum A.I.
      Transmitting pain and itch messages: a contemporary view of the spinal cord circuits that generate gate control.
      ;
      • Koch S.C.
      • Acton D.
      • Goulding M.
      Spinal circuits for touch, pain, and itch.
      ;
      • Ma Q.
      Labeled lines meet and talk: population coding of somatic sensations.
      ;
      • Prescott S.A.
      • Ma Q.
      • De Koninck Y.
      Normal and abnormal coding of somatosensory stimuli causing pain.
      ). A series of extracellular recording studies have been performed to examine the responses of spinothalamic, trigeminothalamic, thalamic, and cortical neurons to pruritic stimuli (
      • Davidson S.
      • Zhang X.
      • Khasabov S.G.
      • Moser H.R.
      • Honda C.N.
      • Simone D.A.
      • et al.
      Pruriceptive spinothalamic tract neurons: physiological properties and projection targets in the primate.
      ;
      • Khasabov S.G.
      • Truong H.
      • Rogness V.M.
      • Alloway K.D.
      • Simone D.A.
      • Giesler Jr., G.J.
      Responses of neurons in the primary somatosensory cortex to itch- and pain-producing stimuli in rats.
      ;
      • Lipshetz B.
      • Khasabov S.G.
      • Truong H.
      • Netoff T.I.
      • Simone D.A.
      • Giesler Jr., G.J.
      Responses of thalamic neurons to itch- and pain-producing stimuli in rats.
      ;
      • Moser H.R.
      • Giesler Jr., G.J.
      Characterization of pruriceptive trigeminothalamic tract neurons in rats.
      ). These studies found that the majority of recorded neurons were excited by both pruritic and nociceptive stimuli. Thus, the coding principle of itch and how itch is perceived remain elusive. It will be critical to perform large-scale in vivo extracellular recording or cellular calcium imaging to examine the activity of thalamic or cortical neurons during itch processing in awake animals. The PBN, CeA, PAG, and other nuclei are also closely involved in pain sensation, and it is likely that different neuronal populations are involved. For example, the PAG TAC1+ neurons regulate itch rather than pain. However, how these nuclei are discriminately processing itch and other modalities need further research. Further transcriptomic analyses and genetic manipulation should decipher the cellular mechanism underlying itch and pain modulation.
      Second, the circuit mechanisms underlying the itch-associated emotion and motivation need further examination. Several brain areas and subtypes of neurons have been implicated in itch-associated emotion and motivation. How these neurons or brain areas receive itch-associated emotion and motivational components is still unknown. It is also important to further study the functional role of itch-associated‒negative and ‒positive emotions in itch‒scratching cycle.
      Finally, the central mechanisms underlying chronic itch are largely unknown. Recent studies in chronic pain have recognized that synaptic plasticity could function as a critical mechanism underlying pathological pain (
      • Kuner R.
      Central mechanisms of pathological pain.
      ;
      • Kuner R.
      • Flor H.
      Structural plasticity and reorganisation in chronic pain [published correction appears in Nat Rev Neurosci 2017;18:158] [published correction appears in Nat Rev Neurosci 2017;18:113].
      ;
      • Luo C.
      • Kuner T.
      • Kuner R.
      Synaptic plasticity in pathological pain.
      ). The chronic itch, including the psychogenic itch, is likely resulted from the central sensitization and loss of descending control (
      • Misery L.
      Pruriplastic itch-a novel pathogenic concept in chronic pruritus.
      ;
      • Misery L.
      • Dutray S.
      • Chastaing M.
      • Schollhammer M.
      • Consoli S.G.
      • Consoli S.M.
      Psychogenic itch.
      ). It will be necessary to further study the neural plasticity during chronic itch and show the involvement of synaptic plasticity in the development of chronic itch.

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      We thank Hui Li for the comments on the manuscript. This work is supported by the National Natural Science Foundation of China (numbers 31771158 and 31900717), the Shanghai Municipal Science and Technology Major Project (grant number 2018SHZDZX05), the Shanghai Sailing Program (19YF1438700), and the Youth talent support program from China Association for Science and Technology (2019QNRC001).

      Author Contributions

      Writing - Original Draft Preparation: DM; Writing - Review and Editing: YGS

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