title: Dezocine exhibits antihypersensitivity activities in neuropathy through spinal μ-opioid receptor activation and norepinephrine reuptake inhibition.
abstract: Dezocine is the number one opioid painkiller prescribed and sold in China, occupying 44% of the nation's opioid analgesics market today and far ahead of the gold-standard morphine. We discovered the mechanisms underlying dezocine antihypersensitivity activity and assessed their implications to antihypersensitivity tolerance. Dezocine, given subcutaneously in spinal nerve-ligated neuropathic rats, time- and dose-dependently produced mechanical antiallodynia and thermal antihyperalgesia, significantly increased ipsilateral spinal norepinephrine and serotonin levels, and induced less antiallodynic tolerance than morphine. Its mechanical antiallodynia was partially (40% or 60%) and completely (100%) attenuated by spinal μ-opioid receptor (MOR) antagonism or norepinephrine depletion/α2-adrenoceptor antagonism and combined antagonism of MORs and α2-adenoceptors, respectively. In contrast, antagonism of spinal κ-opioid receptors (KORs) and δ-opioid receptors (DORs) or depletion of spinal serotonin did not significantly alter dezocine antiallodynia. In addition, dezocine-delayed antiallodynic tolerance was accelerated by spinal norepinephrine depletion/α2-adenoceptor antagonism. Thus dezocine produces antihypersensitivity activity through spinal MOR activation and norepinephrine reuptake inhibition (NRI), but apparently not through spinal KOR and DOR activation, serotonin reuptake inhibition or other mechanisms. Our findings reclassify dezocine as the first analgesic of the recently proposed MOR-NRI, and reveal its potential as an alternative to as well as concurrent use with morphine in treating pain.
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Wang
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Mao
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Teng-Fei
authors.initials: TF
authors.lastname: Li
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Nian
authors.initials: N
authors.lastname: Gong
authors.affiliation: Department of Anesthesiology and Pediatric Clinical Pharmacology Laboratory, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, 1678 Dongfang Road, Shanghai 200127, China.
authors.forename: Ma-Zhong
authors.initials: MZ
authors.lastname: Zhang
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D051381:Rats; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
chemical_list: D000700:Analgesics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D017450:Receptors, Opioid, mu; D013764:Tetrahydronaphthalenes; C010827:dezocine; D009638:Norepinephrine