TNF-α/TNFR1 Signaling is Required for the Full Expression of Acute and Chronic Itch in Mice via Peripheral and Central Mechanisms
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摘要
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-a) and its receptors TNF receptor subtype-1(TNFR1) and TNFR2 in acute and chronic itch in mice.Compared to wild-type(WT) mice, TNFR1-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-αantagonist 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 etanercept and in TNFR1/R2 DKO mice. Dry skin induced TNF-α expression in the skin, DRG, and spinal cord and TNFR1 expression only in the spinal cord. Thus, our findings suggest that TNF-α/TNFR1 signaling is required for the full expression of acute and chronic itch via peripheral and central mechanisms, and targeting TNFR1 may be beneficial for chronic itch treatment.
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-a) and its receptors TNF receptor subtype-1(TNFR1) and TNFR2 in acute and chronic itch in mice.Compared to wild-type(WT) mice, TNFR1-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-αantagonist 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 etanercept and in TNFR1/R2 DKO mice. Dry skin induced TNF-α expression in the skin, DRG, and spinal cord and TNFR1 expression only in the spinal cord. Thus, our findings suggest that TNF-α/TNFR1 signaling is required for the full expression of acute and chronic itch via peripheral and central mechanisms, and targeting TNFR1 may be beneficial for chronic itch treatment.
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-a) and its receptors TNF receptor subtype-1(TNFR1) and TNFR2 in acute and chronic itch in mice.Compared to wild-type(WT) mice, TNFR1-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-αantagonist 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 etanercept and in TNFR1/R2 DKO mice. Dry skin induced TNF-α expression in the skin, DRG, and spinal cord and TNFR1 expression only in the spinal cord. Thus, our findings suggest that TNF-α/TNFR1 signaling is required for the full expression of acute and chronic itch via peripheral and central mechanisms, and targeting TNFR1 may be beneficial for chronic itch treatment.
引文
1.Green D,Dong X.The cell biology of acute itch.J Cell Biol2016,213:155-161.
2.LaMotte RH,Dong X,Ringkamp M.Sensory neurons and circuits mediating itch.Nat Rev Neurosci 2014,15:19-31.
3.Yosipovitch G,Bernhard JD.Clinical practice.Chronic pruritus.N Engl J Med 2013,368:1625-1634.
4.Bieber T.Atopic dermatitis.N Engl J Med 2008,358:1483-1494.
5.Wilson SR,The L,Batia LM,Beattie K,Katibah GE,McClain SP,et al.The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch.Cell 2013,155:285-295.
6.Kremer AE,Oude Elferink RP,Beuers U.Pathophysiology and current management of pruritus in liver disease.Gastroenterol Clin Biol 2011,35:89-97.
7.Kremer AE,Martens JJ,Kulik W,Rueff F,Kuiper EM,van Buuren HR,et al.Lysophosphatidic acid is a potential mediator of cholestatic pruritus.Gastroenterology 2010,139:1008-1018.
8.Yamaoka H,Sasaki H,Yamasaki H,Ogawa K,Ohta T,Furuta H,et al.Truncal pruritus of unknown origin may be a symptom of diabetic polyneuropathy.Diabetes Care 2010,33:150-155.
9.Mettang T,Kremer AE.Uremic pruritus.Kidney Int 2015,87:685-691.
10.Berger TG,Steinhoff M.Pruritus and renal failure.Semin Cutan Med Surg 2011,30:99-100.
11.Dhand A,Aminoff MJ.The neurology of itch.Brain 2014,137:313-322.
12.Stander S,Schmelz M.Chronic itch and pain-similarities and differences.Eur J Pain 2006,10:473-478.
13.Liu T,Ji RR.New insights into the mechanisms of itch:are pain and itch controlled by distinct mechanisms?Pflugers Arch 2013,465:1671-1685.
14.Luo J,Feng J,Liu S,Walters ET,Hu H.Molecular and cellular mechanisms that initiate pain and itch.Cell Mol Life Sci 2015,72:3201-3223.
15.Ji RR,Xu ZZ,Gao YJ.Emerging targets in neuroinflammationdriven chronic pain.Nat Rev Drug Discov 2014,13:533-548.
16.Zhang ZJ,Cao DL,Zhang X,Ji RR,Gao YJ.Chemokine contribution to neuropathic pain:respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons.Pain 2013,154:2185-2197.
17.Gao YJ,Ji RR.Chemokines,neuronal-glial interactions,and central processing of neuropathic pain.Pharmacol Ther 2010,126:56-68.
18.Ji RR,Berta T,Nedergaard M.Glia and pain:is chronic pain a gliopathy?Pain 2013,154 Suppl 1:S10-S28.
19.Ji RR,Chamessian A,Zhang YQ.Pain regulation by non-neuronal cells and inflammation.Science 2016,354:572-577.
20.Storan ER,O'Gorman SM,McDonald ID,Steinhoff M.Role of cytokines and chemokines in itch.Handb Exp Pharmacol 2015,226:163-176.
21.Cevikbas F,Wang X,Akiyama T,Kempkes C,Savinko T,Antal A,et al.A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch:Involvement of TRPV1 and TRPA1.J Allergy Clin Immunol 2014,133:448-460.
22.Dillon SR,Sprecher C,Hammond A,Bilsborough J,RosenfeldFranklin M,Presnell SR,et al.Interleukin 31,a cytokine produced by activated T cells,induces dermatitis in mice.Nat Immunol 2004,5:752-760.
23.Qu L,Fu K,Yang J,Shimada SG,LaMotte RH.CXCR3 chemokine receptor signaling mediates itch in experimental allergic contact dermatitis.Pain 2015,156:1737-46.
24.Oh MH,Oh SY,Lu J,Lou H,Myers AC,Zhu Z,et al.TRPA1-dependent pruritus in IL-13-induced chronic atopic dermatitis.J Immunol 2013,191:5371-5382.
25.McDermott MF.TNF and TNFR biology in health and disease.Cell Mol Biol(Noisy-le-grand)2001,47:619-635.
26.Leung L,Cahill CM.TNF-alpha and neuropathic pain-a review.J Neuroinflammation 2010,7:27.
27.Hehlgans T,Mannel DN.The TNF-TNF receptor system.Biol Chem 2002,383:1581-1585.
28.Zhang L,Berta T,Xu ZZ,Liu T,Park JY,Ji RR.TNF-alpha contributes to spinal cord synaptic plasticity and inflammatory pain:distinct role of TNF receptor subtypes 1 and 2.Pain 2011,152:419-427.
29.Junger H,Sorkin LS.Nociceptive and inflammatory effects of subcutaneous TNFalpha.Pain 2000,85:145-151.
30.Vogel C,Stallforth S,Sommer C.Altered pain behavior and regeneration after nerve injury in TNF receptor deficient mice.J Peripher Nerv Syst 2006,11:294-303.
31.Geis C,Graulich M,Wissmann A,Hagenacker T,Thomale J,Sommer C,et al.Evoked pain behavior and spinal glia activation is dependent on tumor necrosis factor receptor 1 and 2 in a mouse model of bone cancer pain.Neuroscience 2010,169:463-474.
32.Constantin CE,Mair N,Sailer CA,Andratsch M,Xu ZZ,Blumer MJ,et al.Endogenous tumor necrosis factor alpha(TNFalpha)requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model.J Neurosci 2008,28:5072-5081.
33.Rozas P,Lazcano P,Pina R,Cho A,Terse A,Pertusa M,et al.Targeted overexpression of tumor necrosis factor-alpha increases cyclin-dependent kinase 5 activity and TRPV1-dependent Ca~(2+)influx in trigeminal neurons.Pain 2016,157:1346-1362.
34.Russell FA,Fernandes ES,Courade JP,Keeble JE,Brain SD.Tumour necrosis factor alpha mediates transient receptor potential vanilloid 1-dependent bilateral thermal hyperalgesia with distinct peripheral roles of interleukin-lbeta,protein kinase C and cyclooxygenase-2 signalling.Pain 2009,142:264-274.
35.Jin X,Gereau RWt.Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-alpha.J Neurosci 2006,26:246-255.
36.Gudes S,Barkai O,Caspi Y,Katz B,Lev S,Binshtok AM.The role of slow and persistent TTX-resistant sodium currents in acute tumor necrosis factor-alpha-mediated increase in nociceptors excitability.J Neurophysiol 2015,113:601-619.
37.Schafers M,Svensson CI,Sommer C,Sorkin LS.Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons.J Neurosci 2003,23:2517-2521.
38.Wilson SR,Gerhold KA,Bifolck-Fisher A,Liu Q,Patel KN,Dong X,et al.TRPA1 is required for histamine-independent,Mas-related G protein-coupled receptor-mediated itch.Nat Neurosci 2011,14:595-602.
39.Liu T,Xu ZZ,Park CK,Berta T,Ji RR.Toll-like receptor 7mediates pruritus.Nat Neurosci 2010,13:1460-1462.
40.Liu T,Ji RR.Oxidative stress induces itch via activation of transient receptor potential subtype ankyrin 1 in mice.Neurosci Bull 2012,28:145-154.
41.Schlosburg JE,Boger DL,Cravatt BF,Lichtman AH.Endocannabinoid modulation of scratching response in an acute allergenic model:a new prospective neural therapeutic target for pruritus.J Pharmacol Exp Ther 2009,329:314-323.
42.Gao Y,Fang X,Sun H,Wang Y,Yao LJ,Li JP,et al.Toll-like receptor 4-mediated myeloid differentiation factor 88-dependent signaling pathway is activated by cerebral ischemia-reperfusion in hippocampal CA1 region in mice.Biol Pharm Bull 2009,32:1665-1671.
43.Liu T,Han Q,Chen G,Huang Y,Zhao LX,Berta T,et al.Tolllike receptor 4 contributes to chronic itch,alloknesis,and spinal astrocyte activation in male mice.Pain 2016,157:806-817.
44.Liu T,Gao YJ,Ji RR.Emerging role of Toll-like receptors in the control of pain and itch.Neurosci Bull 2012,28:131-144.
45.Baral P,Mills K,Pinho-Ribeiro FA,Chiu IM.Pain and itch:beneficial or harmful to antimicrobial defense?Cell Host Microbe 2016,19:755-759.
46.Shim WS,Oh U.Histamine-induced itch and its relationship with pain.Mol Pain 2008,4:29.
47.McNeil B,Dong X.Peripheral mechanisms of itch.Neurosci Bull2012,28:100-110.
48.Shimizu K,Andoh T,Yoshihisa Y,Shimizu T.Histamine released from epidermal keratinocytes plays a role in alpha-melanocyte-stimulating hormone-induced itching in mice.Am J Pathol 2015,185:3003-3010.
49.Liu Q,Tang Z,Surdenikova L,Kim S,Patel KN,Kim A,et al.Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.Cell 2009,139:1353-1365.
50.Sikand P,Dong X,LaMotte RH.BAM8-22 peptide produces itch and nociceptive sensations in humans independent of histamine release.J Neurosci 2011,31:7563-7567.
51.Zhou FM,Cheng RX,Wang S,Huang Y,Gao YJ,Zhou Y,et al.Antioxidants attenuate acute and chronic itch:peripheral and central mechanisms of oxidative stress in pruritus.Neurosci Bull2016.doi:10.1007/s12264-016-0076-z.
52.Chen Y,Fang Q,Wang Z,Zhang JY,MacLeod AS,Hall RP,et al.Transient receptor potential vanilloid 4 ion channel functions as a pruriceptor in epidermal keratinocytes to evoke histaminergic itch.J Biol Chem 2016,291:10252-10262.
53.Akiyama T,Ivanov M,Nagamine M,Davoodi A,Carstens MI,Ikoma A,et al.Involvement of TRPV4 in serotonin-evoked scratching.J Invest Dermatol 2016,136:154-160.
54.Wang XL,Tian B,Huang Y,Peng XY,Chen LH,Li JC,et al.Hydrogen sulfide-induced itch requires activation of Cav3.2T-type calcium channel in mice.Sci Rep 2015,5:16768.
55.Lei Z,Sami Shaikh A,Zheng W,Yu X,Yu J,Li J.Non-proton ligand sensing domain of acid sensing ion channel 3 is required for itch sensation.J Neurochem 2016,139:1093-1101.
56.Chatterjea D,Paredes L,Martinov T,Balsells E,Allen J,Sykes A,et al.TNF-alpha neutralizing antibody blocks thermal sensitivity induced by compound 48/80-provoked mast cell degranulation.F1000Res 2013,2:178.
57.Wheeler MA,Heffner DL,Kim S,Espy SM,Spano AJ,Cleland CL,et al.TNF-alpha/TNFR1 signaling is required for the development and function of primary nociceptors.Neuron 2014,82:587-602.
58.Zhang Y,Dun SL,Chen YH,Luo JJ,Cowan A,Dun NJ.Scratching activates microglia in the mouse spinal cord.J Neurosci Res 2015,93:466-474.
59.Zhang Y,Yan J,Hu R,Sun Y,Ma Y,Chen Z,et al.Microglia are involved in pruritus induced by DNFB via the CX3CR1/p38MAPK pathway.Cell Physiol Biochem 2015,35:1023-1033.
60.Torigoe K,Tominaga M,Ko KC,Takahashi N,Matsuda H,Hayashi R,et al.Intrathecal minocycline suppresses itch-related behavior and improves dermatitis in a mouse model of atopic dermatitis.J Invest Dermatol 2016,136:879-881.
61.Berta T,Park CK,Xu ZZ,Xie RG,Liu T,Lu N,et al.Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-alpha secretion.J Clin Invest 2014,124:1173-1186.
62.Sun YG,Chen ZF.A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord.Nature 2007,448:700-703.
63.Mishra SK,Hoon MA.The cells and circuitry for itch responses in mice.Science 2013,340:968-971.
2.LaMotte RH,Dong X,Ringkamp M.Sensory neurons and circuits mediating itch.Nat Rev Neurosci 2014,15:19-31.
3.Yosipovitch G,Bernhard JD.Clinical practice.Chronic pruritus.N Engl J Med 2013,368:1625-1634.
4.Bieber T.Atopic dermatitis.N Engl J Med 2008,358:1483-1494.
5.Wilson SR,The L,Batia LM,Beattie K,Katibah GE,McClain SP,et al.The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch.Cell 2013,155:285-295.
6.Kremer AE,Oude Elferink RP,Beuers U.Pathophysiology and current management of pruritus in liver disease.Gastroenterol Clin Biol 2011,35:89-97.
7.Kremer AE,Martens JJ,Kulik W,Rueff F,Kuiper EM,van Buuren HR,et al.Lysophosphatidic acid is a potential mediator of cholestatic pruritus.Gastroenterology 2010,139:1008-1018.
8.Yamaoka H,Sasaki H,Yamasaki H,Ogawa K,Ohta T,Furuta H,et al.Truncal pruritus of unknown origin may be a symptom of diabetic polyneuropathy.Diabetes Care 2010,33:150-155.
9.Mettang T,Kremer AE.Uremic pruritus.Kidney Int 2015,87:685-691.
10.Berger TG,Steinhoff M.Pruritus and renal failure.Semin Cutan Med Surg 2011,30:99-100.
11.Dhand A,Aminoff MJ.The neurology of itch.Brain 2014,137:313-322.
12.Stander S,Schmelz M.Chronic itch and pain-similarities and differences.Eur J Pain 2006,10:473-478.
13.Liu T,Ji RR.New insights into the mechanisms of itch:are pain and itch controlled by distinct mechanisms?Pflugers Arch 2013,465:1671-1685.
14.Luo J,Feng J,Liu S,Walters ET,Hu H.Molecular and cellular mechanisms that initiate pain and itch.Cell Mol Life Sci 2015,72:3201-3223.
15.Ji RR,Xu ZZ,Gao YJ.Emerging targets in neuroinflammationdriven chronic pain.Nat Rev Drug Discov 2014,13:533-548.
16.Zhang ZJ,Cao DL,Zhang X,Ji RR,Gao YJ.Chemokine contribution to neuropathic pain:respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons.Pain 2013,154:2185-2197.
17.Gao YJ,Ji RR.Chemokines,neuronal-glial interactions,and central processing of neuropathic pain.Pharmacol Ther 2010,126:56-68.
18.Ji RR,Berta T,Nedergaard M.Glia and pain:is chronic pain a gliopathy?Pain 2013,154 Suppl 1:S10-S28.
19.Ji RR,Chamessian A,Zhang YQ.Pain regulation by non-neuronal cells and inflammation.Science 2016,354:572-577.
20.Storan ER,O'Gorman SM,McDonald ID,Steinhoff M.Role of cytokines and chemokines in itch.Handb Exp Pharmacol 2015,226:163-176.
21.Cevikbas F,Wang X,Akiyama T,Kempkes C,Savinko T,Antal A,et al.A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch:Involvement of TRPV1 and TRPA1.J Allergy Clin Immunol 2014,133:448-460.
22.Dillon SR,Sprecher C,Hammond A,Bilsborough J,RosenfeldFranklin M,Presnell SR,et al.Interleukin 31,a cytokine produced by activated T cells,induces dermatitis in mice.Nat Immunol 2004,5:752-760.
23.Qu L,Fu K,Yang J,Shimada SG,LaMotte RH.CXCR3 chemokine receptor signaling mediates itch in experimental allergic contact dermatitis.Pain 2015,156:1737-46.
24.Oh MH,Oh SY,Lu J,Lou H,Myers AC,Zhu Z,et al.TRPA1-dependent pruritus in IL-13-induced chronic atopic dermatitis.J Immunol 2013,191:5371-5382.
25.McDermott MF.TNF and TNFR biology in health and disease.Cell Mol Biol(Noisy-le-grand)2001,47:619-635.
26.Leung L,Cahill CM.TNF-alpha and neuropathic pain-a review.J Neuroinflammation 2010,7:27.
27.Hehlgans T,Mannel DN.The TNF-TNF receptor system.Biol Chem 2002,383:1581-1585.
28.Zhang L,Berta T,Xu ZZ,Liu T,Park JY,Ji RR.TNF-alpha contributes to spinal cord synaptic plasticity and inflammatory pain:distinct role of TNF receptor subtypes 1 and 2.Pain 2011,152:419-427.
29.Junger H,Sorkin LS.Nociceptive and inflammatory effects of subcutaneous TNFalpha.Pain 2000,85:145-151.
30.Vogel C,Stallforth S,Sommer C.Altered pain behavior and regeneration after nerve injury in TNF receptor deficient mice.J Peripher Nerv Syst 2006,11:294-303.
31.Geis C,Graulich M,Wissmann A,Hagenacker T,Thomale J,Sommer C,et al.Evoked pain behavior and spinal glia activation is dependent on tumor necrosis factor receptor 1 and 2 in a mouse model of bone cancer pain.Neuroscience 2010,169:463-474.
32.Constantin CE,Mair N,Sailer CA,Andratsch M,Xu ZZ,Blumer MJ,et al.Endogenous tumor necrosis factor alpha(TNFalpha)requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model.J Neurosci 2008,28:5072-5081.
33.Rozas P,Lazcano P,Pina R,Cho A,Terse A,Pertusa M,et al.Targeted overexpression of tumor necrosis factor-alpha increases cyclin-dependent kinase 5 activity and TRPV1-dependent Ca~(2+)influx in trigeminal neurons.Pain 2016,157:1346-1362.
34.Russell FA,Fernandes ES,Courade JP,Keeble JE,Brain SD.Tumour necrosis factor alpha mediates transient receptor potential vanilloid 1-dependent bilateral thermal hyperalgesia with distinct peripheral roles of interleukin-lbeta,protein kinase C and cyclooxygenase-2 signalling.Pain 2009,142:264-274.
35.Jin X,Gereau RWt.Acute p38-mediated modulation of tetrodotoxin-resistant sodium channels in mouse sensory neurons by tumor necrosis factor-alpha.J Neurosci 2006,26:246-255.
36.Gudes S,Barkai O,Caspi Y,Katz B,Lev S,Binshtok AM.The role of slow and persistent TTX-resistant sodium currents in acute tumor necrosis factor-alpha-mediated increase in nociceptors excitability.J Neurophysiol 2015,113:601-619.
37.Schafers M,Svensson CI,Sommer C,Sorkin LS.Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons.J Neurosci 2003,23:2517-2521.
38.Wilson SR,Gerhold KA,Bifolck-Fisher A,Liu Q,Patel KN,Dong X,et al.TRPA1 is required for histamine-independent,Mas-related G protein-coupled receptor-mediated itch.Nat Neurosci 2011,14:595-602.
39.Liu T,Xu ZZ,Park CK,Berta T,Ji RR.Toll-like receptor 7mediates pruritus.Nat Neurosci 2010,13:1460-1462.
40.Liu T,Ji RR.Oxidative stress induces itch via activation of transient receptor potential subtype ankyrin 1 in mice.Neurosci Bull 2012,28:145-154.
41.Schlosburg JE,Boger DL,Cravatt BF,Lichtman AH.Endocannabinoid modulation of scratching response in an acute allergenic model:a new prospective neural therapeutic target for pruritus.J Pharmacol Exp Ther 2009,329:314-323.
42.Gao Y,Fang X,Sun H,Wang Y,Yao LJ,Li JP,et al.Toll-like receptor 4-mediated myeloid differentiation factor 88-dependent signaling pathway is activated by cerebral ischemia-reperfusion in hippocampal CA1 region in mice.Biol Pharm Bull 2009,32:1665-1671.
43.Liu T,Han Q,Chen G,Huang Y,Zhao LX,Berta T,et al.Tolllike receptor 4 contributes to chronic itch,alloknesis,and spinal astrocyte activation in male mice.Pain 2016,157:806-817.
44.Liu T,Gao YJ,Ji RR.Emerging role of Toll-like receptors in the control of pain and itch.Neurosci Bull 2012,28:131-144.
45.Baral P,Mills K,Pinho-Ribeiro FA,Chiu IM.Pain and itch:beneficial or harmful to antimicrobial defense?Cell Host Microbe 2016,19:755-759.
46.Shim WS,Oh U.Histamine-induced itch and its relationship with pain.Mol Pain 2008,4:29.
47.McNeil B,Dong X.Peripheral mechanisms of itch.Neurosci Bull2012,28:100-110.
48.Shimizu K,Andoh T,Yoshihisa Y,Shimizu T.Histamine released from epidermal keratinocytes plays a role in alpha-melanocyte-stimulating hormone-induced itching in mice.Am J Pathol 2015,185:3003-3010.
49.Liu Q,Tang Z,Surdenikova L,Kim S,Patel KN,Kim A,et al.Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus.Cell 2009,139:1353-1365.
50.Sikand P,Dong X,LaMotte RH.BAM8-22 peptide produces itch and nociceptive sensations in humans independent of histamine release.J Neurosci 2011,31:7563-7567.
51.Zhou FM,Cheng RX,Wang S,Huang Y,Gao YJ,Zhou Y,et al.Antioxidants attenuate acute and chronic itch:peripheral and central mechanisms of oxidative stress in pruritus.Neurosci Bull2016.doi:10.1007/s12264-016-0076-z.
52.Chen Y,Fang Q,Wang Z,Zhang JY,MacLeod AS,Hall RP,et al.Transient receptor potential vanilloid 4 ion channel functions as a pruriceptor in epidermal keratinocytes to evoke histaminergic itch.J Biol Chem 2016,291:10252-10262.
53.Akiyama T,Ivanov M,Nagamine M,Davoodi A,Carstens MI,Ikoma A,et al.Involvement of TRPV4 in serotonin-evoked scratching.J Invest Dermatol 2016,136:154-160.
54.Wang XL,Tian B,Huang Y,Peng XY,Chen LH,Li JC,et al.Hydrogen sulfide-induced itch requires activation of Cav3.2T-type calcium channel in mice.Sci Rep 2015,5:16768.
55.Lei Z,Sami Shaikh A,Zheng W,Yu X,Yu J,Li J.Non-proton ligand sensing domain of acid sensing ion channel 3 is required for itch sensation.J Neurochem 2016,139:1093-1101.
56.Chatterjea D,Paredes L,Martinov T,Balsells E,Allen J,Sykes A,et al.TNF-alpha neutralizing antibody blocks thermal sensitivity induced by compound 48/80-provoked mast cell degranulation.F1000Res 2013,2:178.
57.Wheeler MA,Heffner DL,Kim S,Espy SM,Spano AJ,Cleland CL,et al.TNF-alpha/TNFR1 signaling is required for the development and function of primary nociceptors.Neuron 2014,82:587-602.
58.Zhang Y,Dun SL,Chen YH,Luo JJ,Cowan A,Dun NJ.Scratching activates microglia in the mouse spinal cord.J Neurosci Res 2015,93:466-474.
59.Zhang Y,Yan J,Hu R,Sun Y,Ma Y,Chen Z,et al.Microglia are involved in pruritus induced by DNFB via the CX3CR1/p38MAPK pathway.Cell Physiol Biochem 2015,35:1023-1033.
60.Torigoe K,Tominaga M,Ko KC,Takahashi N,Matsuda H,Hayashi R,et al.Intrathecal minocycline suppresses itch-related behavior and improves dermatitis in a mouse model of atopic dermatitis.J Invest Dermatol 2016,136:879-881.
61.Berta T,Park CK,Xu ZZ,Xie RG,Liu T,Lu N,et al.Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-alpha secretion.J Clin Invest 2014,124:1173-1186.
62.Sun YG,Chen ZF.A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord.Nature 2007,448:700-703.
63.Mishra SK,Hoon MA.The cells and circuitry for itch responses in mice.Science 2013,340:968-971.