title: Bullatine A stimulates spinal microglial dynorphin A expression to produce anti-hypersensitivity in a variety of rat pain models.
abstract: Aconiti brachypodi Radix (Xue-shang-yi-zhi-hao) has been prescribed to manage chronic pain, arthritis, and traumatic injuries. Bullatine A, a C20-diterpenoid alkaloid, is one of its principle effective compounds. This study aimed to investigate the anti-hypersensitivity of bullatine A in a variety of rat pain models and explore its mechanisms of action.
  
  
  
  Rat neuropathic pain, inflammatory pain, diabetic neuropathic pain, and bone cancer pain models were used. Dynorphin A and pro-inflammatory cytokines were measured in the spinal cord and cultured primary microglia. Double immunofluorescence staining of dynorphin A and glial and neuronal cellular markers was also measured in the spinal cord.
  
  
  
  Subcutaneous and intrathecal injection of bullatine A dose-dependently attenuated spinal nerve ligation-, complete Freud's adjuvant-, diabetes-, and bone cancer-induced mechanical allodynia and thermal hyperalgesia, with the efficacies of 45-70 % inhibition, and half-effective doses of 0.9-1.9 mg/kg for subcutaneous injection. However, bullatine A was not effective in blocking acute nociceptive response in the normal condition. Bullatine A specifically stimulated dynorphin A expression in microglia in the spinal cord in vivo and cultured primary microglia in vitro; the stimulatory effects were completely inhibited by the microglial inhibitor minocycline. In contrast, bullatine A did not have an inhibitory effect on peripheral nerve injury- or lipopolysaccharide-induced pro-inflammatory cytokine expression. The spinal anti-allodynic effects of bullatine A were entirely blocked by intrathecal injection of minocycline, the specific dynorphin A antiserum, and the selective k-opioid receptor antagonist.
  
  
  
  We, for the first time, demonstrate that bullatine A specifically attenuates pain hypersensitivity, regardless of the pain models employed. The results also suggest that stimulation of spinal microglial dynorphin A expression mediates bullatine A anti-nociception in pain hypersensitivity conditions.
authors: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai, 200240, China.
authors: Qian
authors: Q
authors: Huang
authors: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai, 200240, China.
authors: Xiao-Fang
authors: XF
authors: Mao
authors: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai, 200240, China.
authors: Hai-Yun
authors: HY
authors: Wu
authors: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai, 200240, China.
authors: Teng-Fei
authors: TF
authors: Li
authors: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai, 200240, China.
authors: Ming-Li
authors: ML
authors: Sun
authors: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai, 200240, China.
authors: Hao
authors: H
authors: Liu
authors: King's Lab, Shanghai Jiao Tong University School of Pharmacy, 800 Dongchuan Road, Shanghai, 200240, China. yxwang@sjtu.edu.cn.
authors: Yong-Xiang
authors: YX
authors: Wang
mesh_terms: D000470:Alkaloids / Q000494:pharmacology / Q000627:therapeutic use*; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004224:Diterpenes / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004399:Dynorphins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism*; D007279:Injections, Subcutaneous; D008297:Male; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D000700:Analgesics; D004224:Diterpenes; C587049:bullatine A; D004399:Dynorphins
keywords: Anti-hypersensitivity; Bullatine A; Dynorphin A; Microglia; Pro-inflammatory cytokines; Spinal cord