title: Exogenous induction of HO-1 alleviates vincristine-induced neuropathic pain by reducing spinal glial activation in mice.
abstract: Chemotherapy drugs such as vincristine can produce painful peripheral neuropathy for which is still lack of effective treatment. Recent studies have demonstrated that neuroinflammation plays an important role in the pathogenesis of neuropathic pain. Heme oxygenase 1 (HO-1) was shown to mediate the resolution of inflammation. In this study, we investigated the contribution of HO-1 in the modulation of vincristine-induced pain and the mechanisms implicated. Injection of vincristine induced persistent mechanical allodynia and thermal hyperalgesia in mice. The expression of HO-1 mRNA and protein was increased in 2 weeks in the spinal cord. Immunostaining showed that HO-1 was mainly expressed in neurons of spinal cord dorsal horn in naïve animals, but induced in astrocytes and microglia after vincristine injection. Intraperitoneal injection of HO-1 inducer increased HO-1 expression in the spinal cord and attenuated vincristine-induced pain. Persistent induction of HO-1 by intraspinal injection of HO-1-expressing lentivirus alleviated vincristine-induced pain for more than 2 weeks. Furthermore, vincristine induced activation of glial cells (astrocytes and microglia), phosphorylation of MAPKs (JNK, ERK, and p38), and production of TNF-α and monocyte chemoattractant protein-1 in the spinal cord, which were all reduced by intrathecal injection of HO-1 inducer. Taken together, our data provide the first evidence that induction of HO-1 attenuates vincristine-induced neuropathic pain via inhibition of glia-mediated neuroinflammation in the spinal cord. This suggests that exogenously induced HO-1 may have potential as therapy in chemotherapy-induced neuropathic pain.
authors.affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Jiangsu 226001, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Jiangsu 226001, China; Department of Human Anatomy, School of Medicine, Nantong University, Jiangsu 226001, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
authors.forename: Zhi-Jun
authors.initials: ZJ
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, The Affiliated Hospital of Nantong University, Jiangsu 226001, China.
authors.forename: Ming-Di
authors.initials: MD
authors.lastname: Zhu
authors.affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Jiangsu 226001, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
authors.forename: Bao-Chun
authors.initials: BC
authors.lastname: Jiang
authors.affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Jiangsu 226001, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Yang
authors.affiliation: Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Jiangsu 226001, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China. Electronic address: gaoyongjing@hotmail.com.
authors.forename: Yong-Jing
authors.initials: YJ
authors.lastname: Gao
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D004195:Disease Models, Animal; D020536:Enzyme Activators / Q000494:pharmacology; D015316:Genetic Therapy; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006930:Hyperalgesia / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000628:therapy; D016086:Lentivirus / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008813:Mice, Inbred ICR; D009437:Neuralgia / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D014750:Vincristine / Q000633:toxicity*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000972:Antineoplastic Agents, Phytogenic; D020536:Enzyme Activators; D008565:Membrane Proteins; D011524:Protoporphyrins; D012333:RNA, Messenger; D014750:Vincristine; C028025:protoporphyrin IX; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse
keywords: Astrocytes; Chemotherapy-induced pain; Heme oxygenase 1; Mice; Microglia; Mitogen-activated protein kinase; Neuroinflammation; Spinal cord; Vincristine