Understanding neural mechanisms of mechanical itch

Chronic itch, which is associated with many skin disorders and systemic diseases, is often difficult to treat and can greatly affect quality of life. Patients with chronic itch commonly have both peripheral and central sensitization of itch signaling pathways, which enables pruritogens to elicit an exaggerated itch response (known as chemical itch) and allows innocuous mechanical stimuli to evoke itch sensation (known as mechanical itch), resulting in persistent and ongoing itch. Fully understanding the mechanism of itch sensitization is critical for designing successful therapeutic strategies to treat chronic itch. In recent years, significant progress has been made in identifying the molecular, cellular, and circuit mechanisms underlying chemical itch.1Dong X. Dong X. Peripheral and central mechanisms of itch.Neuron. 2018; 98: 482-494Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar However, understanding the pathways and mechanisms of mechanical itch associated with both acute and chronic itch is still in its early stages. Mechanical itch is a type of itch caused by light tactile stimuli on the skin, such as pressure, stroking, or vibration.1Dong X. Dong X. Peripheral and central mechanisms of itch.Neuron. 2018; 98: 482-494Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar Studies have made significant progress in identifying the spinal circuits in mice that transmit and gate mechanical itch.2Bourane 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.Science. 2015; 350: 550-554Crossref PubMed Scopus (182) Google Scholar,3Pan H. Fatima M. Li A. Lee H. Cai W. Horwitz L. et al.Identification of a spinal circuit for mechanical and persistent spontaneous itch.Neuron. 2019; 103: 1135-1149.e6Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar A unique subpopulation of excitatory interneurons expressing neuropeptide urocortin 3 (Ucn3) in the inner lamina II and lamina III of the spinal cord has been identified as transmitting mechanical itch.3Pan H. Fatima M. Li A. Lee H. Cai W. Horwitz L. et al.Identification of a spinal circuit for mechanical and persistent spontaneous itch.Neuron. 2019; 103: 1135-1149.e6Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Selectively ablating or silencing Ucn3+ neurons in the dorsal spinal cord by using intersectional genetic strategies abolishes gentle poking-evoked acute mechanical itch without affecting pruritogen-induced chemical itch or other somatosensory modalities, such as pain, touch, and temperature sensations.3Pan H. Fatima M. Li A. Lee H. Cai W. Horwitz L. et al.Identification of a spinal circuit for mechanical and persistent spontaneous itch.Neuron. 2019; 103: 1135-1149.e6Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Ucn3+ excitatory interneurons in the dorsal spinal cord receive synaptic inputs from Aβ-low-threshold mechanoreceptors (Aβ-LTMRs), but the activation of Ucn3+ neurons is normally inhibited by neuropeptide Y–expressing (NPY+) inhibitory interneurons that receive inputs from distinct Aβ-LTMRs.3Pan H. Fatima M. Li A. Lee H. Cai W. Horwitz L. et al.Identification of a spinal circuit for mechanical and persistent spontaneous itch.Neuron. 2019; 103: 1135-1149.e6Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Activation of NPY+ inhibitory interneurons attenuates mechanical itch, whereas ablating these neurons results in spontaneous itch, which is abolished by ablating Ucn3+ interneurons.3Pan H. Fatima M. Li A. Lee H. Cai W. Horwitz L. et al.Identification of a spinal circuit for mechanical and persistent spontaneous itch.Neuron. 2019; 103: 1135-1149.e6Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Thus, NPY+ inhibitory interneurons suppress mechanical itch through Ucn3+ interneurons (Fig 1). This feedforward inhibitory circuit in the spinal cord might explain the prevention of hypersensitivity to mechanical itch stimuli in most areas of the skin. In the periphery, which population of primary sensory neurons is required for mechanical itch transmission? Spinal Ucn3+ neurons mainly receive monosynaptic inputs from Toll-like receptor 5–expressing (TLR5+) Aβ-LTMRs.3Pan H. Fatima M. Li A. Lee H. Cai W. Horwitz L. et al.Identification of a spinal circuit for mechanical and persistent spontaneous itch.Neuron. 2019; 103: 1135-1149.e6Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Interestingly, intradermal injection of TLR5 agonist triggers itch behaviors in mice, and pharmacologic silencing of TLR5+ neurons abolishes mechanical itch.3Pan H. Fatima M. Li A. Lee H. Cai W. Horwitz L. et al.Identification of a spinal circuit for mechanical and persistent spontaneous itch.Neuron. 2019; 103: 1135-1149.e6Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar These results suggest that TLR5+ Aβ-LTMRs may mediate mechanical itch in the skin (Fig 1). However, TLR5 is also expressed in immune cells within the skin, and pharmacologic manipulations might affect these TLR5+ immune cells rather than sensory neurons. Thus, whether TLR5+ Aβ-LTMRs are solely responsible for mechanical itch remains unclear. In addition to Aβ-LTMRs, a new pathway for transmitting mechanical itch via C-fibers has been discovered (Fig 1). Somatostatin and natriuretic peptide B coexpressing (Sst+/Nppb+) primary sensory neurons, which constitute a type of C-fiber chemical itch transmission neurons in the dorsal root ganglia (DRG), express mechanosensitive Piezo1 channels and are responsible for poking-evoked acute mechanical itch in mice.4Hill R.Z. Loud M.C. Dubin A.E. Peet B. Patapoutian A. PIEZO1 transduces mechanical itch in mice.Nature. 2022; 607: 104-110Crossref PubMed Scopus (21) Google Scholar Unlike Aβ-LTMR–mediated mechanical itch,3Pan H. Fatima M. Li A. Lee H. Cai W. Horwitz L. et al.Identification of a spinal circuit for mechanical and persistent spontaneous itch.Neuron. 2019; 103: 1135-1149.e6Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar high-threshold mechanical stimuli activate Piezo1 channels in Sst+/Nppb1+ sensory neurons and trigger C-fiber–dependent itch responses in mice.4Hill R.Z. Loud M.C. Dubin A.E. Peet B. Patapoutian A. PIEZO1 transduces mechanical itch in mice.Nature. 2022; 607: 104-110Crossref PubMed Scopus (21) Google Scholar Deletion of Piezo1 in Sst+/Nppb+ itch transmission neurons significantly attenuates acute mechanical itch. In contrast, mice with a gain-of-function PIEZO1 allele display enhanced mechanical itch behaviors, suggesting a role for Piezo1 channels in mechanical itch transmission.4Hill R.Z. Loud M.C. Dubin A.E. Peet B. Patapoutian A. PIEZO1 transduces mechanical itch in mice.Nature. 2022; 607: 104-110Crossref PubMed Scopus (21) Google Scholar Notably, a small subset of Sst+/Nppb+ sensory neurons also express mechanosensitive Piezo2 channels,4Hill R.Z. Loud M.C. Dubin A.E. Peet B. Patapoutian A. PIEZO1 transduces mechanical itch in mice.Nature. 2022; 607: 104-110Crossref PubMed Scopus (21) Google Scholar implying that Piezo2 channels in Sst+/Nppb+ neurons might partially contribute to mechanical itch transmission. Interestingly, Mas-related G protein–coupled receptor D-expressing (MrgprD+) C-fiber polymodal nociceptors, which are required to transmit chemical itch and mechanical pain, also express mechanosensitive Piezo1 and Piezo2 channels, raising the possibility of their involvement in mechanical itch transmission.4Hill R.Z. Loud M.C. Dubin A.E. Peet B. Patapoutian A. PIEZO1 transduces mechanical itch in mice.Nature. 2022; 607: 104-110Crossref PubMed Scopus (21) Google Scholar Nevertheless, further research is necessary to confirm this hypothesis. Taken together, current findings suggest that various mechanical inputs in the peripheral nervous system may trigger mechanical itch via distinct pathways. This highlights the complexity of the neural pathways and mechanisms underlying acute mechanical itch sensation. Chronic mechanical itch, or mechanical alloknesis (mechanical itch sensitization, which is analogous to allodynia for pain), which is characterized by an abnormal sensitivity to mechanical stimuli, is a form of chronic itch that is associated with various skin disorders such as atopic dermatitis, psoriasis, and dry skin. The mechanisms involve release of endogenous pruritogens from immune cells, overactivation of sensory neurons in the skin, and changes in the activity of the central nervous system.1Dong X. Dong X. Peripheral and central mechanisms of itch.Neuron. 2018; 98: 482-494Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar,5Wang F. Kim B.S. Itch: a paradigm of neuroimmune crosstalk.Immunity. 2020; 52: 753-766Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Recent studies have revealed the contributions of Aβ-LTMRs in mechanical alloknesis. One study has shown that silencing TLR5+ Aβ-LTMRs attenuates mechanical alloknesis in a mouse model of atopic dermatitis,3Pan H. Fatima M. Li A. Lee H. Cai W. Horwitz L. et al.Identification of a spinal circuit for mechanical and persistent spontaneous itch.Neuron. 2019; 103: 1135-1149.e6Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar suggesting that activation of Aβ-LTMR itch transmission neurons contributes to chronic mechanical itch (Fig 2). Another study has addressed the idea that loss of cutaneous Merkel cells, which are specialized mechanosensitive cells in the skin, results in mechanical alloknesis associated with aging and dry skin. Mice lacking Merkel cells or their associated Piezo2 channels display mechanical alloknesis, whereas chemogenetic activation of Merkel cells prevents mechanical alloknesis in dry skin.6Feng J. Luo J. Yang P. Du J. Kim B.S. Hu H. Piezo2 channel-Merkel cell signaling modulates the conversion of touch to itch.Science. 2018; 360: 530-533Crossref PubMed Scopus (109) Google Scholar The mechanism involves cutaneous Merkel cells sensing external mechanical stimuli via associated Piezo2 channels and activating innervating Aβ slowly adapting-LTMRs. The Merkel cell–Aβ slowly adapting-LTMR complex might activate downstream inhibitory interneurons in the spinal cord to suppress mechanical itch (Fig 2). Thus, the lack of Merkel cells in dry skin and aging individuals may lead to disinhibition of the mechanical itch pathway in the spinal cord, resulting in the development of mechanical alloknesis (Fig 2). Emerging evidence suggests that aside from Aβ-LTMRs, C-fiber itch transmission neurons also play essential roles in mechanical alloknesis. Conditional knockout of Piezo1 or blockade of Piezo1 channels in Sst+/Nppb+ C-polymodal itch transmission neurons attenuates mechanical alloknesis in a mouse model of atopic dermatitis,4Hill R.Z. Loud M.C. Dubin A.E. Peet B. Patapoutian A. PIEZO1 transduces mechanical itch in mice.Nature. 2022; 607: 104-110Crossref PubMed Scopus (21) Google Scholar whereas ubiquitous gain-of-function mutation of PIEZO1 develops mechanical alloknesis in mice.4Hill R.Z. Loud M.C. Dubin A.E. Peet B. Patapoutian A. PIEZO1 transduces mechanical itch in mice.Nature. 2022; 607: 104-110Crossref PubMed Scopus (21) Google Scholar These findings suggest that overactivation of Piezo1 in Sst+/Nppb+ C-polymodal itch transmission neurons may contribute to mechanical alloknesis (Fig 2). Interestingly, chemical itch mediator histamine sensitizes Piezo1 channel activity, whereas deletion of Piezo1 in DRG neurons attenuates histamine and IL-31–mediated chemical itch behaviors,4Hill R.Z. Loud M.C. Dubin A.E. Peet B. Patapoutian A. PIEZO1 transduces mechanical itch in mice.Nature. 2022; 607: 104-110Crossref PubMed Scopus (21) Google Scholar reflecting the potential interaction between chemical itch and mechanical itch pathways in chronic itch. Furthermore, the interaction between touch sensors and pruriceptors in the skin also plays a role in mechanical alloknesis. In dry itchy skin, MrgprA3+ chemical itch transmission neurons rewire toward Merkel cells in the skin, and mechanical stimulation of the skin activates Piezo2 channels on Merkel cells, causing MrgprA3+ neurons to fire.7Feng J. Zhao Y. Xie Z. Zang K. Sviben S. Hu X. et al.Miswiring of Merkel cell and pruriceptive C fiber drives the itch-scratch cycle.Sci Transl Med. 2022; 14eabn4819Crossref Scopus (6) Google Scholar This miswiring mechanism may contribute to the itch-scratch cycle in chronic itch conditions (Fig 2). It is important to note that the peripheral mechanisms underlying chronic mechanical itch are complex. Decreased epidermal-innervating C/Aδ fiber density, as well as increased mechanical itch, is observed in postherpetic patients,8Hashimoto T. Okuzawa M. Yamamoto M. Okuno S. Satoh T. Increased touch-evoked itch (punctate hyperknesis) in postherpetic itch: implications of reduced intraepidermal nerve fibers representing small fiber neuropathy.J Dermatol. 2023; 50: 393-396Crossref PubMed Scopus (3) Google Scholar challenging the contribution of C-fibers in chronic mechanical itch. Furthermore, studies have demonstrated that mechanosensitive Piezo1 channels detect mechanical cues in immune cells such as macrophages and T cells (Fig 2), and activation of Piezo1 in these cells is required to initiate immune responses.9Zhang X. Kim T.H. Thauland T.J. Li H. Majedi F.S. Ly C. et al.Unraveling the mechanobiology of immune cells.Curr Opin Biotechnol. 2020; 66: 236-245Crossref PubMed Scopus (40) Google Scholar Thus, further research is needed to fully understand the contribution of different types of cells in the skin to the development of chronic mechanical itch. Central sensitization, which is characterized by increased excitability of itch transmission neurons and enhanced synaptic transmission in the spinal cord and brain, plays a crucial role in chronic itch development. Recent studies have shown that spinal Ucn3+ mechanical itch transmission neurons are necessary to transmit mechanical alloknesis in various mouse models of chronic itch.3Pan H. Fatima M. Li A. Lee H. Cai W. Horwitz L. et al.Identification of a spinal circuit for mechanical and persistent spontaneous itch.Neuron. 2019; 103: 1135-1149.e6Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Additionally, in chronic itch models, the intrinsic excitability of Ucn3+ neurons is significantly elevated; this increase is mostly due to overexpression of the voltage-gated sodium channel Nav1.6.10Lee H. Graham R.D. Melikyan D. Smith B. Mirzakhalili E. Lempka S.F. et al.Molecular determinants of mechanical itch sensitization in chronic itch.Front Mol Neurosci. 2022; 15937890Crossref Scopus (4) Google Scholar In contrast, spinal NPY+ mechanical itch gating neurons have significantly lower levels of Nav1.6 expression under chronic itch conditions, which silences NPY+ neurons and opens the gate for mechanical itch transmission in the spinal cord.10Lee H. Graham R.D. Melikyan D. Smith B. Mirzakhalili E. Lempka S.F. et al.Molecular determinants of mechanical itch sensitization in chronic itch.Front Mol Neurosci. 2022; 15937890Crossref Scopus (4) Google Scholar Further computational simulation showed that reduced Nav1.6 conductance in NPY+ models play a major role in opening the itch gate under chronic itch conditions.10Lee H. Graham R.D. Melikyan D. Smith B. Mirzakhalili E. Lempka S.F. et al.Molecular determinants of mechanical itch sensitization in chronic itch.Front Mol Neurosci. 2022; 15937890Crossref Scopus (4) Google Scholar These findings suggest that mechanical alloknesis is caused by disinhibition in the mechanical itch circuit and that Nav1.6 channels may be a potential therapeutic target for treating chronic itch (Fig 2). How the spinal circuits for C-fiber mechanical itch transmission work is currently unclear. However, it is known that in chemical itch transmission, spinal excitatory interneurons expressing gastrin-releasing peptide receptor (GRPR) are activated by the activation of Sst+/Nppb+ pruritic sensory neurons via monosynaptic and/or polysynaptic transmission.1Dong X. Dong X. Peripheral and central mechanisms of itch.Neuron. 2018; 98: 482-494Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar Therefore, it is possible that GRPR+ neurons in the spinal cord may also play a role in chronic mechanical itch transmission (Fig 2). Remarkable progress is being made in revealing the contributions of different types of nerve fibers and cells in the skin, DRG, and spinal cord to the development of acute and chronic mechanical itch. To further our understanding, future research should focus on developing more precise and selective strategies to identify and manipulate the neural circuits involved in mechanical itch transmission from skin to brain, which will help us better understand the contribution of different neuron populations in chronic itch. Additionally, investigating the molecular mechanisms of mechanical alloknesis, including ion channels and neuropeptides, will allow for targeted treatment strategies for treating chronic itch. Potential therapeutic strategies may include targeting Piezo1/2 channels in Sst+/Nppb+ sensory neurons or Nav1.6 channels in Ucn3+ and NPY+ neurons in the spinal cord. Furthermore, to fully comprehend the molecular and cellular mechanisms underlying chronic itch, it is crucial to explore the interactions between chemical itch and mechanical itch, as well as the interactions between the nervous system and other systems involved in chronic itch, such as the immune system.5Wang F. Kim B.S. Itch: a paradigm of neuroimmune crosstalk.Immunity. 2020; 52: 753-766Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Finally, although the functions of Piezo1/2 ion channels in mechanical itch transmission have been identified in mice, there is currently no evidence showing that PIEZO1/2 variants affect itch sensitivity in humans. Moreover, the sensory neurons in humans and rodents are different. Thus, linking animal research with clinical research in future studies will be necessary. Supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (to B.D. [grants 5R01NS109170, 5R01NS118769]). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. We apologize to those investigators whose primary articles could not be cited owing to space limitations.