title: Blockade of neuronal dopamine D2 receptor attenuates morphine tolerance in mice spinal cord.
abstract: Tolerance induced by morphine remains a major unresolved problem and significantly limits its clinical use. Recent evidences have indicated that dopamine D2 receptor (D2DR) is likely to be involved in morphine-induced antinociceptive tolerance. However, its exact effect and molecular mechanism remain unknown. In this study we examined the effect of D2DR on morphine antinociceptive tolerance in mice spinal cord. Chronic morphine treatment significantly increased levels of D2DR in mice spinal dorsal horn. And the immunoreactivity of D2DR was newly expressed in neurons rather than astrocytes or microglia both in vivo and in vitro. Blockade of D2DR with its antagonist (sulpiride and L-741,626, i.t.) attenuated morphine antinociceptive tolerance without affecting basal pain perception. Sulpiride (i.t.) also down-regulated the expression of phosphorylation of NR1, PKC, MAPKs and suppressed the activation of astrocytes and microglia induced by chronic morphine administration. Particularly, D2DR was found to interact with μ opioid receptor (MOR) in neurons, and chronic morphine treatment enhanced the MOR/D2DR interactions. Sulpiride (i.t.) could disrupt the MOR/D2DR interactions and attenuate morphine tolerance, indicating that neuronal D2DR in the spinal cord may be involved in morphine tolerance possibly by interacting with MOR. These results may present new opportunities for the treatment and management of morphine-induced antinociceptive tolerance which often observed in clinic.
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
authors.forename: Wen-Ling
authors.initials: WL
authors.lastname: Dai
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xiong
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.
authors.forename: Zheng-Yu
authors.initials: ZY
authors.lastname: Cao
authors.affiliation: Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Jiangsu 211166, China.
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Liu
authors.affiliation: Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, Jiangsu 211198, China.|State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
authors.forename: Ji-Hua
authors.initials: JH
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
authors.forename: Bo-Yang
authors.initials: BY
authors.lastname: Yu
mesh_terms: D000818:Animals; D065127:Dopamine D2 Receptor Antagonists / Q000494:pharmacology*; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology*; D058748:Pain Perception / Q000187:drug effects*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism* / Q000473:pathology; D013469:Sulpiride / Q000494:pharmacology*
chemical_list: D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D009020:Morphine; D013469:Sulpiride