title: Sensitization of P2X3 receptors by cystathionine β-synthetase mediates persistent pain hypersensitivity in a rat model of lumbar disc herniation.
abstract: Lumbar disc herniation (LDH) is a major cause of discogenic low back pain and sciatica, but the underlying mechanisms remain largely unknown. Hydrogen sulfide (H2S) is becoming recognized for its involvement in a wide variety of processes including inflammation and nociception. The present study was designed to investigate the roles of the H2S signaling pathway in the regulation of expression and function of purinergic receptors (P2XRs) in dorsal root ganglion (DRG) neurons from rats with LDH. LDH was induced by implantation of autologous nucleus pulposus (NP), harvested from rat tail, in lumbar 5 and 6 spinal nerve roots. Implantation of autologous NP induced persistent pain hypersensitivity, which was partially reversed by an intrathecal injection of A317491, a potent inhibitor of P2X3Rs and P2X2/3Rs. The NP induced persistent pain hypersensitivity was associated with the increased expression of P2X3Rs, but not P2X1Rs and P2X2Rs, receptors in L5-6 DRGs. NP implantation also produced a 2-fold increase in ATP-induced intracellular calcium signals in DRG neurons when compared to those of controls (P < 0.05). Interestingly, NP implantation significantly enhanced expression of the endogenous hydrogen sulfide producing enzyme, cystathionine-β-synthetase (CBS). Systematic administration of O-(Carboxymethyl) hydroxylamine hemihydrochloride (AOAA), an inhibitor of CBS, suppressed the upregulation of P2X3R expression and the potentiation of ATP-induced intracellular calcium signals in DRG neurons (P < 0.05). Intrathecal injection of AOAA markedly attenuated NP induced- persistent pain hypersensitivity. Our results suggest that sensitization of P2X3Rs, which is likely mediated by CBS-H2S signaling in primary sensory neurons, contributes to discogenic pain. Targeting CBS/H2S-P2X3R signaling may represent a potential treatment for neuropathic pain caused by LDH.
authors.affiliation: Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou, 215004, Peoples Republic of China. 45681392@qq.com.
authors.forename: Qianliang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, 215123, Peoples Republic of China. hongyanzhuhyz@163.com.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou, 215004, Peoples Republic of China. 379251092@qq.com.
authors.forename: Kang
authors.initials: K
authors.lastname: Zou
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, 215123, Peoples Republic of China. yuan163bo@163.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, 215123, Peoples Republic of China. youlangzhou@163.com.
authors.forename: You-Lang
authors.initials: YL
authors.lastname: Zhou
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, 215123, Peoples Republic of China. jiangxinghong@suda.edu.cn.
authors.forename: Xinghong
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Orthopedics, the Second Affiliated Hospital of Soochow University, Suzhou, 215004, Peoples Republic of China. cxyanjun@hotmail.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, 215123, Peoples Republic of China. guangyinxu@suda.edu.cn.|Laboratory for Translational Pain Medicine, Institute of Neuroscience, Soochow University, 199 Ren-Ai Road, Suzhou, 215123, China. guangyinxu@suda.edu.cn.
authors.forename: Guang-Yin
authors.initials: GY
authors.lastname: Xu
mesh_terms: D000818:Animals; D003541:Cystathionine beta-Synthase / Q000378:metabolism*; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000378:metabolism; D006930:Hyperalgesia / Q000503:physiopathology; D006967:Hypersensitivity / Q000378:metabolism*; D007405:Intervertebral Disc Displacement / Q000378:metabolism*; D008297:Male; D009437:Neuralgia / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism*; D013126:Spinal Nerve Roots / Q000378:metabolism
chemical_list: D058477:Receptors, Purinergic P2X3; D003541:Cystathionine beta-Synthase