title: Concurrent bullatine A enhances morphine antinociception and inhibits morphine antinociceptive tolerance by indirect activation of spinal κ-opioid receptors.
abstract: BACKGROUND
  Bullatine A, a C20-diterpenoid alkaloid and one of the major effective ingredients in Aconiti brachypodi Radix (Xue-shang-yi-zhi-hao), can block pain hypersensitivity in a variety of rodent models through expression of spinal microglial dynorphin A.
  
  
  OBJECTIVE
  To assess the interaction between bullatine A and morphine on antinociception in acute nociception and pain hypersensitivity states, with the exogenous synthetic dynorphin A as a comparison MATERIALS AND METHODS: Spinal nerve ligation-induced neuropathic rats and naïve mice were used for assessing the acute and chronic interactions of bullatine A/dynorphin A with morphine.
  
  
  RESULTS
  Single subcutaneous injection of bullatine A or dynorphin A(1-17) did not either alter formalin- and thermally (hot-plate and water immersion tests)-induced acute nociception or potentiate morphine antinociception in naïve mice. In contrast, bullatine A dose-dependently inhibited formalin-induced tonic pain with the efficacy of 54% inhibition and the half-effective dose of 0.9mg/kg. Concurrent bullatine A additively enhanced morphine antinociception. In neuropathic rats, the antinociceptive effects of multiple bidaily intrathecal injections of bullatine A and dynorphin A remained consistent over 13 days, whereas morphine produced progressive and complete tolerance to antinociception, which was completely inhibited by concurrent bullatine A and dynorphin A. A single intrathecal injection of bullatine A and dynorphin A immediately reversed established morphine tolerance in neuropathic rats, although the blockade was a less degree in the thermally induced mouse acute nociceptive tests. The inhibitory effects of bullatine A and dynorphin A on morphine tolerance were immediately and completely attenuated by intrathecal dynorphin A antibody and/or selective κ-opioid receptor antagonist GNTI.
  
  
  CONCLUSIONS
  These results suggest that bullatine A produces antinociception without induction of tolerance and inhibits morphine antinociceptive tolerance, and provide pharmacological basis for concurrent bullatine A and morphine treatment for chronic pain and morphine analgesic tolerance.
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Ming-Li
authors.initials: ML
authors.lastname: Sun
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China.
authors.forename: Xin-Yan
authors.initials: XY
authors.lastname: Li
authors.affiliation: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai 200240, China. Electronic address: yxwang@sjtu.edu.cn.
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Wang
mesh_terms: D000470:Alkaloids / Q000494:pharmacology / Q000627:therapeutic use; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004361:Drug Tolerance; D004399:Dynorphins / Q000494:pharmacology / Q000627:therapeutic use; D005557:Formaldehyde; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D017208:Rats, Wistar; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D013131:Spine / Q000187:drug effects / Q000378:metabolism
chemical_list: D000470:Alkaloids; D000700:Analgesics; D004224:Diterpenes; D004338:Drug Combinations; D017473:Receptors, Opioid, kappa; C587049:bullatine A; D005557:Formaldehyde; D004399:Dynorphins; D009020:Morphine
keywords: Bullatine A; Bullatine A (PubChem CID: 102004922); Dynorphin A; Interaction; Morphine; Nociceptive tolerance; dynorphin A(1−17) (PubChem CID: 91928823); morphine (PubChem CID: 5464110)