Background:While mild itching may seem harmless,it can worsen over time,necessitating early treatment.Epicutaneous sensitization has recently gained attention.Oral exposure may promote immune tolerance,but ingestion a...Background:While mild itching may seem harmless,it can worsen over time,necessitating early treatment.Epicutaneous sensitization has recently gained attention.Oral exposure may promote immune tolerance,but ingestion after epicutaneous sensitization can trigger severe allergic responses.Therefore,this study focused on the initial stages of allergic symptoms before they become severe and investigated the mechanisms underlying food ingestion-induced mild itching following epicutaneous sensitization.Methods:Female mice were epicutaneously sensitized with ovalbumin(OVA).Scratching behavior was recorded,and serum and tissue samples were collected.Levels of OVA-specific immunoglobulin(Ig)E/IgG1,histamine,and mast cell protease-1(MCPT-1)were measured by ELISA.Histological analysis of skin tissues and immune cell infiltration was performed via staining.Results:OVA challenge following epicutaneous sensitization induced mild itching in the OVA group.Scratching behavior peaked between 1 and 2 h and persisted for 8 h before returning to baseline.This itching was accompanied by dynamic fluctuations in OVA-specific IgE and IgG1,histamine,and MCPT-1 levels.Histological analysis revealed increased epidermal thickness and granulocytic infiltration,particularly of mast cells and eosinophils,within 2 h of OVA challenge.Mast cell and eosinophil migration into the skin tissues was significant,with eosinophil migration into the dermis persisted despite normalization of histamine levels and mast cell degranulation.These results suggest that mast cells and eosinophils play significant roles even in mild itching.Conclusion:This study provides insights into the early immune responses involved in food allergies,contributing to a better understanding of how mild symptoms can progress to more severe reactions.展开更多
Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular se...Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily （TRPV1, TRPV3, and TRPV4）, and finally members of the melastatin group （TRPM2, TRPM3, and TRPMS）. Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory com- pounds targeting specific pain/itch-TRPs so that physio- logical protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1- modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accom- plished via simple dosing strategies, and also by incorpo- rating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.展开更多
Toll-like receptors （TLRs） are germline-encoded pattern-recognition receptors that initiate innate immune re- sponses by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associ...Toll-like receptors （TLRs） are germline-encoded pattern-recognition receptors that initiate innate immune re- sponses by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associated molecular patterns （PAMPs）. After tissue injury or cellular stress, TLRs also detect endogenous ligands known as danger-associated molecular patterns （DAMPs）. TLRs are expressed in both non-neuronal and neuronal cell types in the central nervous system （CNS） and contribute to both infectious and non-infectious disorders in the CNS. Following tissue insult and nerve injury, TLRs （such as TLR2, TLR3, and TLR4） induce the activation of microglia and astrocytes and the production of the proinflammatory cytokines in the spinal cord, leading to the development and maintenance of inflammatory pain and neu- ropathic pain. In particular, primary sensory neurons, such as nociceptors, express TLRs （e.g., TLR4 and TLR7） to sense exogenous PAMPs and endogenous DAMPs released after tissue injury and cellular stress. These neuronal TLRs are new players in the processing of pain and itch by increasing the excitability of primary sensory neurons. Given the prevalence of chronic pain and itch and the suffering of affected people, insights into TLR signaling in the nervous system will open a new avenue for the management of clinical pain and itch.展开更多
Objective To investigate the role of oxidative stress in itch-indicative scratching behavior in mice, and further- more, to define the cellular and molecular mechanisms underlying oxidative stress-mediated itch. Metho...Objective To investigate the role of oxidative stress in itch-indicative scratching behavior in mice, and further- more, to define the cellular and molecular mechanisms underlying oxidative stress-mediated itch. Methods Scratching behavior was induced by intradermal injection of the oxidants hydrogen peroxide （H202） or tert-butylhydroperoxide （tBHP） into the nape of the neck in mice. The mice were observed for 30 rain. Results Intradermal H202 （0.03%-1%） or tBHP （1-30 pmol） elicited robust scratching behavior, displaying an inverted U-shaped dose-response curve. Naloxone, an opioid receptor antagonist, but not morphine, largely suppressed the oxidant-induced scratching. Chlorpheniramine, a histamine H1 receptor antagonist, blocked histamine- but not oxidant-induced scratching, indicating the involvement of a histamine-independent mechanism in oxidant-evoked itch. Further, resiniferatoxin treatment abolished oxidant-induced scratching, suggesting an essential role of C-fibers. Notably, blockade of transient receptor potential subtype ankyrin 1 （TRPA1） with the selective TRPA1 antagonist HC-030031, or genetic deletion of Trpal but not Trpvl （subfamily V, mem- ber 1） resulted in a profound reduction in H202-evoked scratching. Finally, systemic administration of the antioxidant N- acetyl-L-cysteine or trolox （a water-soluble vitamin E analog） attenuated scratching induced by the oxidants. Conclusion Oxidative stress by different oxidants induces profound scratching behavior, which is largely histamine- and TRPV1- independent but TRPAl-dependent. Antioxidants and TRPA1 antagonists may be used to treat human itch conditions as- sociated with oxidative stress.展开更多
Chronic pain and itch are a pathological operation of the somatosensory system at the levels of primary sensory neurons, spinal cord and brain. Pain and itch are clearly distinct sensations, and recent studies have re...Chronic pain and itch are a pathological operation of the somatosensory system at the levels of primary sensory neurons, spinal cord and brain. Pain and itch are clearly distinct sensations, and recent studies have revealed the separate neuronal pathways that are involved in each sensation. However, the mechanisms by which these sensations turn into a pathological chronic state are poorly understood. A proposed mechanism underlying chronic pain and itch involves abnormal excitability in dorsal horn neurons in the spinal cord. Furthermore, an increasing body of evidence from models of chronic pain and itch has indicated that synaptic hyperexcitability in the spinal dorsal horn might not be a consequence simply of changes in neurons, but rather of multiple alterations in glial cells. Thus, understanding the key roles of glial cells may provide us with exciting insights into the mechanisms of chronicity of pain and itch, and lead to new targets for treating chronic pain and itch.展开更多
Pain and itch are unpleasant sensations that often accompany infections caused by viral, bacterial, parasitic, and fungal pathogens. Recent studies show that sensory neurons are able to directly detect pathogens to me...Pain and itch are unpleasant sensations that often accompany infections caused by viral, bacterial, parasitic, and fungal pathogens. Recent studies show that sensory neurons are able to directly detect pathogens to mediate pain and itch. Nociceptor and pruriceptor neurons respond to pathogen-associated molecular patterns, including Toll-like receptor ligands, N-formyl peptides, and bacterial toxins. Other pathogens are able to silence neuronal activity to produce analgesia during infection. Pain and itch could lead to neuronal modulation of the immune system or behavioral avoidance of future patho- gen exposure. Conversely, pathogens could modulate neuronal signaling to potentiate their pathogenesis and facilitate their spread to other hosts. Defining how pathogens modulate pain and itch has critical implications for sensory neurobiology and our understanding of host- microbe interactions.展开更多
In 1905, Henry Head first suggested that trans- mission of pain-related protopathic information can be negatively modulated by inputs from afferents sensing innocuous touch and temperature. In 1965, Melzak and Wall pr...In 1905, Henry Head first suggested that trans- mission of pain-related protopathic information can be negatively modulated by inputs from afferents sensing innocuous touch and temperature. In 1965, Melzak and Wall proposed a more concrete gate control theory of pain that highlights the interaction between unmyelinated C fibers and myelinated A fibers in pain transmission. Here we review the current understanding of the spinal micro- circuits transmitting and gating mechanical pain or itch. We also discuss how disruption of the gate control could cause pain or itch evoked by innocuous mechanical stimuli, a hallmark symptom for many chronic pain or itch patients.展开更多
Recent studies have shown that the chemokine receptor CXCR3 and its ligand CXCL10 in the dorsal root ganglion mediate itch in experimental allergic contact dermatitis （ACD）. CXCR3 in the spinal cord also con- tribut...Recent studies have shown that the chemokine receptor CXCR3 and its ligand CXCL10 in the dorsal root ganglion mediate itch in experimental allergic contact dermatitis （ACD）. CXCR3 in the spinal cord also con- tributes to the maintenance of neuropathic pain. However, whether spinal CXCR3 is involved in acute or chronic itch remains unclear. Here, we report that Cxcr3-/- mice showed normal scratching in acute itch models but reduced scratching in chronic itch models of dry skin and ACD. In contrast, both formalin-induced acute pain and complete Freund＇s adjuvant-induced chronic inflammatory pain were reduced in Cxcr3-/- mice. In addition, the expression of CXCR3 and CXCL10 was increased in the spinal cord in the dry skin model induced by acetone and diethyl ether followed by water （AEW）. Intrathecal injection of a CXCR3 antagonist alleviated AEW-induced itch. Further- more, touch-elicited itch （alloknesis） after compound 48/80 or AEW treatment was suppressed in Cxcr3-/- mice. Finally, AEW-induced astrocyte activation was inhibited in Cxcr3-/- mice. Taken together, these data suggest that spinal CXCR3 mediates chronic itch and alloknesis, and targeting CXCR3 may provide effective treatment for chronic pruritus.展开更多
Increasing evidence suggests that cytokines and chemokines play crucial roles in chronic itch. In the present study, we evaluated the roles of tumor necrosis factor-alpha （TNF-c0 and its receptors TNF receptor subtyp...Increasing evidence suggests that cytokines and chemokines play crucial roles in chronic itch. In the present study, we evaluated the roles of tumor necrosis factor-alpha （TNF-c0 and its receptors TNF receptor subtype-I （TNFR1） and TNFR2 in acute and chronic itch in mice. Compared to wild-type （WT） mice, TNFRl-knockout （TNFR1-KO） and TNFR1/R2 double-KO （DKO）, but not TNFR2-KO mice, exhibited reduced acute itch induced by compound 48/80 and chloroquine （CQ）. Application of the TNF-synthesis inhibitor thalidomide and the TNF-at antagonist etanercept dose-dependently suppressed acute itch. Intradermal injection of TNF-α was not sufficient to evoke scratching, but potentiated itch induced by compound 48/80, but not CQ. In addition, compound 48/80 induced TNF-α mRNA expression in the skin, while CQ induced its expression in the dorsal root ganglia （DRG） and spinal cord. Furthermore, chronic itch induced by dry skin was reduced by administration of thalidomide and etaner- cept and in TNFR1/R2 DKO mice. Dry skin induced TNF- expression in the skin, DRG, and spinal cord and TNFR1 expression only in the spinal cord. Thus, our findings suggest that TNF-c^-fNFR1 signaling is required for the full expression of acute and chronic itch via peripheral and central mechanisms, and targeting TNFR1 may be benefi- cial for chronic itch treatment.展开更多
基金supported by JSPS KAKENHI Grant Number(22K11779).
文摘Background:While mild itching may seem harmless,it can worsen over time,necessitating early treatment.Epicutaneous sensitization has recently gained attention.Oral exposure may promote immune tolerance,but ingestion after epicutaneous sensitization can trigger severe allergic responses.Therefore,this study focused on the initial stages of allergic symptoms before they become severe and investigated the mechanisms underlying food ingestion-induced mild itching following epicutaneous sensitization.Methods:Female mice were epicutaneously sensitized with ovalbumin(OVA).Scratching behavior was recorded,and serum and tissue samples were collected.Levels of OVA-specific immunoglobulin(Ig)E/IgG1,histamine,and mast cell protease-1(MCPT-1)were measured by ELISA.Histological analysis of skin tissues and immune cell infiltration was performed via staining.Results:OVA challenge following epicutaneous sensitization induced mild itching in the OVA group.Scratching behavior peaked between 1 and 2 h and persisted for 8 h before returning to baseline.This itching was accompanied by dynamic fluctuations in OVA-specific IgE and IgG1,histamine,and MCPT-1 levels.Histological analysis revealed increased epidermal thickness and granulocytic infiltration,particularly of mast cells and eosinophils,within 2 h of OVA challenge.Mast cell and eosinophil migration into the skin tissues was significant,with eosinophil migration into the dermis persisted despite normalization of histamine levels and mast cell degranulation.These results suggest that mast cells and eosinophils play significant roles even in mild itching.Conclusion:This study provides insights into the early immune responses involved in food allergies,contributing to a better understanding of how mild symptoms can progress to more severe reactions.
基金supported by the National Institutes of Health,USA(DE018549,UL1TR001117,P30AR066527,and AR48182 to WL,AR48182-S1 to WL as co-investigatorF33DE024668 and K12DE022793 to YC)+1 种基金the US Department of Defense(W81XWH-13-1-0299 to WL)the Harrington Discovery Institute,Cleveland OH(to WL)
文摘Nociception is an important physiological process that detects harmful signals and results in pain perception. In this review, we discuss important experimental evidence involving some TRP ion channels as molecular sensors of chemical, thermal, and mechanical noxious stimuli to evoke the pain and itch sensations. Among them are the TRPA1 channel, members of the vanilloid subfamily （TRPV1, TRPV3, and TRPV4）, and finally members of the melastatin group （TRPM2, TRPM3, and TRPMS）. Given that pain and itch are pro-survival, evolutionarily-honed protective mechanisms, care has to be exercised when developing inhibitory/modulatory com- pounds targeting specific pain/itch-TRPs so that physio- logical protective mechanisms are not disabled to a degree that stimulus-mediated injury can occur. Such events have impeded the development of safe and effective TRPV1- modulating compounds and have diverted substantial resources. A beneficial outcome can be readily accom- plished via simple dosing strategies, and also by incorpo- rating medicinal chemistry design features during compound design and synthesis. Beyond clinical use, where compounds that target more than one channel might have a place and possibly have advantageous features, highly specific and high-potency compounds will be helpful in mechanistic discovery at the structure-function level.
基金supported by the US National Institutes of Health (R01-DE17794, R01-NS54362 and R01-NS67686)
文摘Toll-like receptors （TLRs） are germline-encoded pattern-recognition receptors that initiate innate immune re- sponses by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associated molecular patterns （PAMPs）. After tissue injury or cellular stress, TLRs also detect endogenous ligands known as danger-associated molecular patterns （DAMPs）. TLRs are expressed in both non-neuronal and neuronal cell types in the central nervous system （CNS） and contribute to both infectious and non-infectious disorders in the CNS. Following tissue insult and nerve injury, TLRs （such as TLR2, TLR3, and TLR4） induce the activation of microglia and astrocytes and the production of the proinflammatory cytokines in the spinal cord, leading to the development and maintenance of inflammatory pain and neu- ropathic pain. In particular, primary sensory neurons, such as nociceptors, express TLRs （e.g., TLR4 and TLR7） to sense exogenous PAMPs and endogenous DAMPs released after tissue injury and cellular stress. These neuronal TLRs are new players in the processing of pain and itch by increasing the excitability of primary sensory neurons. Given the prevalence of chronic pain and itch and the suffering of affected people, insights into TLR signaling in the nervous system will open a new avenue for the management of clinical pain and itch.
基金supported by grants from the US National Institutes of Health (R01-DE17794,R01-NS54362 and R01-NS67686)
文摘Objective To investigate the role of oxidative stress in itch-indicative scratching behavior in mice, and further- more, to define the cellular and molecular mechanisms underlying oxidative stress-mediated itch. Methods Scratching behavior was induced by intradermal injection of the oxidants hydrogen peroxide （H202） or tert-butylhydroperoxide （tBHP） into the nape of the neck in mice. The mice were observed for 30 rain. Results Intradermal H202 （0.03%-1%） or tBHP （1-30 pmol） elicited robust scratching behavior, displaying an inverted U-shaped dose-response curve. Naloxone, an opioid receptor antagonist, but not morphine, largely suppressed the oxidant-induced scratching. Chlorpheniramine, a histamine H1 receptor antagonist, blocked histamine- but not oxidant-induced scratching, indicating the involvement of a histamine-independent mechanism in oxidant-evoked itch. Further, resiniferatoxin treatment abolished oxidant-induced scratching, suggesting an essential role of C-fibers. Notably, blockade of transient receptor potential subtype ankyrin 1 （TRPA1） with the selective TRPA1 antagonist HC-030031, or genetic deletion of Trpal but not Trpvl （subfamily V, mem- ber 1） resulted in a profound reduction in H202-evoked scratching. Finally, systemic administration of the antioxidant N- acetyl-L-cysteine or trolox （a water-soluble vitamin E analog） attenuated scratching induced by the oxidants. Conclusion Oxidative stress by different oxidants induces profound scratching behavior, which is largely histamine- and TRPV1- independent but TRPAl-dependent. Antioxidants and TRPA1 antagonists may be used to treat human itch conditions as- sociated with oxidative stress.
基金supported by JSPS KAKENHI Grant Numbers 15H02522the Core Research for Evolutional Science and Technology(CREST)program+3 种基金the Practical Research Project for Allergic Diseases and Immunology(Research on Allergic Diseases and Immunology)from Japan Agency for Medical Research and Developmentthe Toray Science FoundationTakeda Science FoundationThe Nakatomi Foundation
文摘Chronic pain and itch are a pathological operation of the somatosensory system at the levels of primary sensory neurons, spinal cord and brain. Pain and itch are clearly distinct sensations, and recent studies have revealed the separate neuronal pathways that are involved in each sensation. However, the mechanisms by which these sensations turn into a pathological chronic state are poorly understood. A proposed mechanism underlying chronic pain and itch involves abnormal excitability in dorsal horn neurons in the spinal cord. Furthermore, an increasing body of evidence from models of chronic pain and itch has indicated that synaptic hyperexcitability in the spinal dorsal horn might not be a consequence simply of changes in neurons, but rather of multiple alterations in glial cells. Thus, understanding the key roles of glial cells may provide us with exciting insights into the mechanisms of chronicity of pain and itch, and lead to new targets for treating chronic pain and itch.
基金supported by funding from the National Institutes of Health(NCCIH DP2AT009499 and MAID K22AI114810),USA
文摘Pain and itch are unpleasant sensations that often accompany infections caused by viral, bacterial, parasitic, and fungal pathogens. Recent studies show that sensory neurons are able to directly detect pathogens to mediate pain and itch. Nociceptor and pruriceptor neurons respond to pathogen-associated molecular patterns, including Toll-like receptor ligands, N-formyl peptides, and bacterial toxins. Other pathogens are able to silence neuronal activity to produce analgesia during infection. Pain and itch could lead to neuronal modulation of the immune system or behavioral avoidance of future patho- gen exposure. Conversely, pathogens could modulate neuronal signaling to potentiate their pathogenesis and facilitate their spread to other hosts. Defining how pathogens modulate pain and itch has critical implications for sensory neurobiology and our understanding of host- microbe interactions.
基金supported by NIH Grants(R01 NS086372 and R01 DE018025)
文摘In 1905, Henry Head first suggested that trans- mission of pain-related protopathic information can be negatively modulated by inputs from afferents sensing innocuous touch and temperature. In 1965, Melzak and Wall proposed a more concrete gate control theory of pain that highlights the interaction between unmyelinated C fibers and myelinated A fibers in pain transmission. Here we review the current understanding of the spinal micro- circuits transmitting and gating mechanical pain or itch. We also discuss how disruption of the gate control could cause pain or itch evoked by innocuous mechanical stimuli, a hallmark symptom for many chronic pain or itch patients.
基金supported by Grants from the National Natural Science Foundation of China(31371121,81300954,and 31671091)the Priority Academic Program Development of Jiangsu Higher Education Institutions,China
文摘Recent studies have shown that the chemokine receptor CXCR3 and its ligand CXCL10 in the dorsal root ganglion mediate itch in experimental allergic contact dermatitis （ACD）. CXCR3 in the spinal cord also con- tributes to the maintenance of neuropathic pain. However, whether spinal CXCR3 is involved in acute or chronic itch remains unclear. Here, we report that Cxcr3-/- mice showed normal scratching in acute itch models but reduced scratching in chronic itch models of dry skin and ACD. In contrast, both formalin-induced acute pain and complete Freund＇s adjuvant-induced chronic inflammatory pain were reduced in Cxcr3-/- mice. In addition, the expression of CXCR3 and CXCL10 was increased in the spinal cord in the dry skin model induced by acetone and diethyl ether followed by water （AEW）. Intrathecal injection of a CXCR3 antagonist alleviated AEW-induced itch. Further- more, touch-elicited itch （alloknesis） after compound 48/80 or AEW treatment was suppressed in Cxcr3-/- mice. Finally, AEW-induced astrocyte activation was inhibited in Cxcr3-/- mice. Taken together, these data suggest that spinal CXCR3 mediates chronic itch and alloknesis, and targeting CXCR3 may provide effective treatment for chronic pruritus.
基金supported by grants from the National Natural Science Foundation of China(31371179 and 81300968)the Natural Science Foundation of Jiangsu Province,China(BK20140372)+2 种基金the Scientific Funding from Jiangsu Province,China(2015-JY-029)the Second Affiliated Hospital of Soochow University Preponderant Clinic Discipline Group Project Funding(XKQ2015007)a Project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions,Jiangsu Province,China
文摘Increasing evidence suggests that cytokines and chemokines play crucial roles in chronic itch. In the present study, we evaluated the roles of tumor necrosis factor-alpha （TNF-c0 and its receptors TNF receptor subtype-I （TNFR1） and TNFR2 in acute and chronic itch in mice. Compared to wild-type （WT） mice, TNFRl-knockout （TNFR1-KO） and TNFR1/R2 double-KO （DKO）, but not TNFR2-KO mice, exhibited reduced acute itch induced by compound 48/80 and chloroquine （CQ）. Application of the TNF-synthesis inhibitor thalidomide and the TNF-at antagonist etanercept dose-dependently suppressed acute itch. Intradermal injection of TNF-α was not sufficient to evoke scratching, but potentiated itch induced by compound 48/80, but not CQ. In addition, compound 48/80 induced TNF-α mRNA expression in the skin, while CQ induced its expression in the dorsal root ganglia （DRG） and spinal cord. Furthermore, chronic itch induced by dry skin was reduced by administration of thalidomide and etaner- cept and in TNFR1/R2 DKO mice. Dry skin induced TNF- expression in the skin, DRG, and spinal cord and TNFR1 expression only in the spinal cord. Thus, our findings suggest that TNF-c^-fNFR1 signaling is required for the full expression of acute and chronic itch via peripheral and central mechanisms, and targeting TNFR1 may be benefi- cial for chronic itch treatment.
