亨廷頓氏舞蹈症(Huntington's disease)是一種遺傳神經退化性疾病，目前已知此疾病會影響到神經系統並且導致智力和運動功能的障礙。由先前的研究顯示亨廷頓氏舞蹈症是由於亨廷頓基因上外顯子1區域中有擴展的CAG 三核苷酸重複序列累積，並導致N末端的多聚谷氨醯胺束鏈異長所引起的一種疾病，然而目前很少研究探討亨廷頓氏舞蹈症和疼痛之間的相關性。在我們的研究中，使用先前已經發表於突變亨廷頓基因外顯子含84個CAG三核苷酸重複序列的亨廷頓氏舞蹈症基因轉殖鼠(七到九週齡)來評估亨廷頓氏舞蹈症和疼痛的關係。經由在老鼠左後肢爪子注射福馬林或弗氏佐劑(CFA)來誘導建立發炎性疼痛模式；誘導發炎性疼痛後，收取脊髓、背根神經節(DRG)及局部後肢爪子的皮膚等組織來進行評估分析，之後則使用免疫螢光染色、西方墨點法與酵素連結免疫吸附分析(ELISA)等方法來鑑定組織中細胞及細胞因子的變化。我們的研究結果顯示，年輕與老年的未發病亨廷頓氏舞蹈症基因轉殖鼠產生較少的疼痛行為(包括機械異常疼痛及熱痛覺過敏)；西方墨點法與免疫螢光染色檢查則發現神經膠細胞和星狀細胞在年輕亨廷頓氏舞蹈症基因轉殖鼠的腰段脊髓與背根神經節中活化的情況較低；原癌基因c-Fos蛋白在腰段脊髓中表現量也較少。年輕亨廷頓氏舞蹈症基因轉殖鼠和野生型小鼠相比，發炎性細胞因子如腫瘤壞死因子TNF-α及白介素-1β (interleukin-1β，IL-1β)表現量較低；與疼痛相關的神經胜肽P物質(substance P)表現量也較少。最後我們在局部後肢爪子皮膚組織中也發現:年輕亨廷頓氏舞蹈症基因轉殖鼠的骨髓過氧化酶(MPO)和巨噬細胞標記物CD68的表現量也較低。亨廷頓蛋白可能參與發炎性疼痛與嗎啡鎮痛的作用機制，未來則需要再進一步探討其在各種疼痛模式中的角色。

Huntington's disease (HD), a genetically neurodegenerative disease, was well-known for affecting nervous system and lead to mental and motor dysfunctions. Previous studies had shown that Huntington's disease was caused by the exon 1 region of Huntington (HTT) gene with expanded CAG trinucleotide repeats and results in an abnormally long polyglutamine tract at N-terminus. However, little research focuses on the relationship of HD and pain. We used a previous published transgenic HD mice (7-9 weeks) carrying with mutant HTT exon 1 containing 84 CAG trinucleotide repeats to evaluate the relationship of HD and pain. Inflammatory pain models were induced by either formalin or Complete Freund’s adjuvant injection over left hind paw. Spinal cord, dorsal root ganglion (DRG) and local hind-paw skin tissues were harvested at the end of the inflammatory pain for evaluation. Immunofluorescence assay, Western blotting and ELISA were used to identify the change of cells and cytokines within tissues. Our data demonstrated that the pre-onset Huntington mice produced less pain behavior (both mechanical allodynia and heat sensitivity) in both young and aged mice. Western blotting and immunohistological examination of lumbar spinal cord tissue and DRG were also demonstrated less activation of glial cells and astrocyte in young HD mice. The expression of c-Fos was less in lumbar spinal cord. The production of inflammatory cytokine TNF-α and IL-1β were also less in young HD mice compared with wild type animals. The pain-related neuropeptide substance P was less in young HD mice. However, we also found that the expression of MPO and CD68 were also less in local hind-paw skin tissues of young HD mice. Huntington protein may be involved in the mechanism of inflammatory pain and morphine analgesia. Further studies were needed to investigate the possible role of HD in various pain models.

Andrich JE, Wobben M, Klotz P, Goetze O, Saft C. Upper gastrointestinal findings in Huntington's disease: patients suffer but do not complain. Journal of neural transmission 2009;116: 1607-1611.
Beal MF and Ferrante RJ. Experimental therapeutics in transgenic mouse models of Huntington's disease. Nature reviews Neuroscience 2004;5: 373-384.
Bjorkqvist M, Wild EJ, Thiele J, Silvestroni A, Andre R, Lahiri N, Raibon E, Lee RV, Benn CL, Soulet D, Magnusson A, Woodman B, Landles C, Pouladi MA, Hayden MR, Khalili-Shirazi A, Lowdell MW, Brundin P, Bates GP, Leavitt BR, Moller T, Tabrizi SJ. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease. The Journal of experimental medicine 2008;205: 1869-1877.
Block ML, Zecca L, Hong JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nature reviews Neuroscience 2007;8: 57-69.
Boecker H, Ceballos-Baumann A, Bartenstein P, Weindl A, Siebner HR, Fassbender T, Munz F, Schwaiger M, Conrad B. Sensory processing in Parkinson's and Huntington's disease: investigations with 3D H(2)(15)O-PET. Brain : a journal of neurology 1999;122 ( Pt 9): 1651-1665.
Bonica JJ. The need of a taxonomy. Pain 1979;6: 247-248.
Braz JM, Nassar MA, Wood JN, Basbaum AI. Parallel "pain" pathways arise from subpopulations of primary afferent nociceptor. Neuron 2005;47: 787-793.
Bullitt E, Lee CL, Light AR, Willcockson H. The effect of stimulus duration on noxious-stimulus induced c-fos expression in the rodent spinal cord. Brain research 1992;580: 172-179.
Caine ED and Shoulson I. Psychiatric syndromes in Huntington's disease. The American journal of psychiatry 1983;140: 728-733.
Calabrese V, Boyd-Kimball D, Scapagnini G, Butterfield DA. Nitric oxide and cellular stress response in brain aging and neurodegenerative disorders: the role of vitagenes. In vivo 2004;18: 245-267.
Calkins CM, Bensard DD, Shames BD, Pulido EJ, Abraham E, Fernandez N, Meng X, Dinarello CA, McIntyre RC, Jr. IL-1 regulates in vivo C-X-C chemokine induction and neutrophil sequestration following endotoxemia. Journal of endotoxin research 2002;8: 59-67.
Cattaneo E, Zuccato C, Tartari M. Normal huntingtin function: an alternative approach to Huntington's disease. Nature reviews Neuroscience 2005;6: 919-930.
Cha JH, Kosinski CM, Kerner JA, Alsdorf SA, Mangiarini L, Davies SW, Penney JB, Bates GP, Young AB. Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington disease gene. Proceedings of the National Academy of Sciences of the United States of America 1998;95: 6480-6485.
Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. Journal of neuroscience methods 1994;53: 55-63.
Cheng PH, Li CL, Her LS, Chang YF, Chan AW, Chen CM, Yang SH. Significantly differential diffusion of neuropathological aggregates in the brain of transgenic mice carrying N-terminal mutant huntingtin fused with green fluorescent protein. Brain structure & function 2013;218: 283-294.
Cisbani G and Cicchetti F. An in vitro perspective on the molecular mechanisms underlying mutant huntingtin protein toxicity. Cell death & disease 2012;3: e382.
Coggeshall RE. Fos, nociception and the dorsal horn. Progress in neurobiology 2005;77: 299-352.
Craufurd D, Thompson JC, Snowden JS. Behavioral changes in Huntington Disease. Neuropsychiatry, neuropsychology, and behavioral neurology 2001;14: 219-226.
Crotti A, Benner C, Kerman BE, Gosselin D, Lagier-Tourenne C, Zuccato C, Cattaneo E, Gage FH, Cleveland DW, Glass CK. Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nature neuroscience 2014;17: 513-521.
De Tommaso M, Serpino C, Difruscolo O, Cormio C, Sciruicchio V, Franco G, Farella I, Livrea P. Nociceptive inputs transmission in Huntington's disease: a study by laser evoked potentials. Acta neurologica Belgica 2011;111: 33-40.
Deckel AW. Nitric oxide and nitric oxide synthase in Huntington's disease. Journal of neuroscience research 2001;64: 99-107.
Ferrini F and De Koninck Y. Microglia control neuronal network excitability via BDNF signalling. Neural plasticity 2013;2013: 429815.
Fusco FR, Zuccato C, Tartari M, Martorana A, De March Z, Giampa C, Cattaneo E, Bernardi G. Co-localization of brain-derived neurotrophic factor (BDNF) and wild-type huntingtin in normal and quinolinic acid-lesioned rat brain. The European journal of neuroscience 2003;18: 1093-1102.
Gauthier LR, Charrin BC, Borrell-Pages M, Dompierre JP, Rangone H, Cordelieres FP, De Mey J, MacDonald ME, Lessmann V, Humbert S, Saudou F. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 2004;118: 127-138.
Giorgini F and Muchowski PJ. Connecting the dots in Huntington's disease with protein interaction networks. Genome biology 2005;6: 210.
Gittins R and Harrison PJ. Neuronal density, size and shape in the human anterior cingulate cortex: a comparison of Nissl and NeuN staining. Brain research bulletin 2004;63: 155-160.
Gutekunst CA, Li SH, Yi H, Mulroy JS, Kuemmerle S, Jones R, Rye D, Ferrante RJ, Hersch SM, Li XJ. Nuclear and neuropil aggregates in Huntington's disease: relationship to neuropathology. The Journal of neuroscience : the official journal of the Society for Neuroscience 1999;19: 2522-2534.
Hardy JD, Wolff HG, Goodell H. Studies on Pain. A New Method for Measuring Pain Threshold: Observations on Spatial Summation of Pain. The Journal of clinical investigation 1940;19: 649-657.
Hargreaves K, Dubner R, Brown F, Flores C, Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 1988;32: 77-88.
Hsiao HY and Chern Y. Targeting glial cells to elucidate the pathogenesis of Huntington's disease. Molecular neurobiology 2010;41: 248-255.
Hunt SP, Pini A, Evan G. Induction of c-fos-like protein in spinal cord neurons following sensory stimulation. Nature 1987;328: 632-634.
Leavitt BR, van Raamsdonk JM, Shehadeh J, Fernandes H, Murphy Z, Graham RK, Wellington CL, Raymond LA, Hayden MR. Wild-type huntingtin protects neurons from excitotoxicity. Journal of neurochemistry 2006;96: 1121-1129.
Li JY, Plomann M, Brundin P. Huntington's disease: a synaptopathy? Trends in molecular medicine 2003;9: 414-420.
Li S and Li XJ. Multiple pathways contribute to the pathogenesis of Huntington disease. Molecular neurodegeneration 2006;1: 19.
Li SH, Gutekunst CA, Hersch SM, Li XJ. Interaction of huntingtin-associated protein with dynactin P150Glued. The Journal of neuroscience : the official journal of the Society for Neuroscience 1998;18: 1261-1269.
Lin CH, Tallaksen-Greene S, Chien WM, Cearley JA, Jackson WS, Crouse AB, Ren S, Li XJ, Albin RL, Detloff PJ. Neurological abnormalities in a knock-in mouse model of Huntington's disease. Human molecular genetics 2001;10: 137-144.
Luszczki JJ and Czuczwar SJ. Isobolographic characterization of interactions between vigabatrin and tiagabine in two experimental models of epilepsy. Progress in neuro-psychopharmacology & biological psychiatry 2007;31: 529-538.
MacDonald ME, M. AC, Duyao MP, Myers RH, Carol Lin, Srinidhi L, Barnes G, Taylor SA, James M, Groot N, MacFarlane H, Jenkins B, Anderson MA, Wexler NS, Gusella JF. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell 1993;72: 971-983.
Medzhitov R. Inflammation 2010: new adventures of an old flame. Cell 2010;140: 771-776.
Mennicken F, Maki R, de Souza EB, Quirion R. Chemokines and chemokine receptors in the CNS: a possible role in neuroinflammation and patterning. Trends in pharmacological sciences 1999;20: 73-78.
Metzler M, Legendre-Guillemin V, Gan L, Chopra V, Kwok A, McPherson PS, Hayden MR. HIP1 functions in clathrin-mediated endocytosis through binding to clathrin and adaptor protein 2. The Journal of biological chemistry 2001;276: 39271-39276.
Middleton FA and Strick PL. Basal ganglia and cerebellar loops: motor and cognitive circuits. Brain research Brain research reviews 2000;31: 236-250.
Millecamps S and Julien JP. Axonal transport deficits and neurodegenerative diseases. Nature reviews Neuroscience 2013;14: 161-176.
Mizoguchi Y, Kato TA, Seki Y, Ohgidani M, Sagata N, Horikawa H, Yamauchi Y, Sato-Kasai M, Hayakawa K, Inoue R, Kanba S, Monji A. BDNF induces sustained intracellular Ca2+ elevation through the upregulation of surface TRPC3 channels in rodent microglia. The Journal of biological chemistry 2014.
Mizoguchi Y, Monji A, Kato TA, Horikawa H, Seki Y, Kasai M, Kanba S, Yamada S. Possible role of BDNF-induced microglial intracellular Ca(2+) elevation in the pathophysiology of neuropsychiatric disorders. Mini reviews in medicinal chemistry 2011;11: 575-581.
Mogil JS. Animal models of pain: progress and challenges. Nature reviews Neuroscience 2009;10: 283-294.
Mogil JS and Crager SE. What should we be measuring in behavioral studies of chronic pain in animals? Pain 2004;112: 12-15.
Mogil JS, Ritchie J, Sotocinal SG, Smith SB, Croteau S, Levitin DJ, Naumova AK. Screening for pain phenotypes: analysis of three congenic mouse strains on a battery of nine nociceptive assays. Pain 2006;126: 24-34.
Parent JM, Valentin VV, Lowenstein DH. Prolonged seizures increase proliferating neuroblasts in the adult rat subventricular zone-olfactory bulb pathway. The Journal of neuroscience : the official journal of the Society for Neuroscience 2002;22: 3174-3188.
Parpura V and Zorec R. Gliotransmission: Exocytotic release from astrocytes. Brain research reviews 2010;63: 83-92.
Paulsena JS, Ready RE, Hamiltond JM, Mega MS, Cummings JL. Neuropsychiatric aspects of Huntington's disease. J Neurol Neurosurg Psychiatry 2001;71: 310-314.
Perrotta A, Serpino C, Cormio C, Serrao M, Sandrini G, Pierelli F, de Tommaso M. Abnormal spinal cord pain processing in Huntington's disease. The role of the diffuse noxious inhibitory control. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology 2012;123: 1624-1630.
Piomelli D and Sasso O. Peripheral gating of pain signals by endogenous lipid mediators. Nature neuroscience 2014;17: 164-174.
Pouladi MA, Morton AJ, Hayden MR. Choosing an animal model for the study of Huntington's disease. Nature reviews Neuroscience 2013;14: 708-721.
Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science 2000;288: 1769-1772.
Reiner A, Albin RL, Anderson KD, D'Amato CJ, Penney JB, Young AB. Differential loss of striatal projection neurons in Huntington disease. Proceedings of the National Academy of Sciences of the United States of America 1988;85: 5733-5737.
Roos RA, Bots GT, Hermans J. Neuronal nuclear membrane indentation and astrocyte/neuron ratio in Huntington's disease. A quantitative electron microscopic study. Journal fur Hirnforschung 1985;26: 689-693.
Saft C, Schuttke A, Beste C, Andrich J, Heindel W, Pfleiderer B. fMRI reveals altered auditory processing in manifest and premanifest Huntington's disease. Neuropsychologia 2008;46: 1279-1289.
Scherder E and Statema M. Huntington's disease. Lancet 2010;376: 1464.
Scholz J and Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nature neuroscience 2007;10: 1361-1368.
Shiwach R. Psychopathology in Huntington's disease patients. Acta psychiatrica Scandinavica 1994;90: 241-246.
Simmons DA, Casale M, Alcon B, Pham N, Narayan N, Lynch G. Ferritin accumulation in dystrophic microglia is an early event in the development of Huntington's disease. Glia 2007;55: 1074-1084.
Stone LS, MacMillan LB, Kitto KF, Limbird LE, Wilcox GL. The alpha2a adrenergic receptor subtype mediates spinal analgesia evoked by alpha2 agonists and is necessary for spinal adrenergic-opioid synergy. The Journal of neuroscience : the official journal of the Society for Neuroscience 1997;17: 7157-7165.
Tai YF, Pavese N, Gerhard A, Tabrizi SJ, Barker RA, Brooks DJ, Piccini P. Microglial activation in presymptomatic Huntington's disease gene carriers. Brain : a journal of neurology 2007;130: 1759-1766.
Tjolsen A, Berge OG, Hunskaar S, Rosland JH, Hole K. The formalin test: an evaluation of the method. Pain 1992;51: 5-17.
Trang T, Beggs S, Salter MW. Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain. Neuron glia biology 2011;7: 99-108.
Walker FO. Huntington's Disease. Seminars in neurology 2007;27: 143-150.
Weiss A, Trager U, Wild EJ, Grueninger S, Farmer R, Landles C, Scahill RI, Lahiri N, Haider S, Macdonald D, Frost C, Bates GP, Bilbe G, Kuhn R, Andre R, Tabrizi SJ. Mutant huntingtin fragmentation in immune cells tracks Huntington's disease progression. The Journal of clinical investigation 2012;122: 3731-3736.
Zhang H and Dougherty PM. Acute inhibition of signalling phenotype of spinal GABAergic neurons by tumour necrosis factor-alpha. The Journal of physiology 2011;589: 4511-4526.