title: Mother root of Aconitum carmichaelii Debeaux exerts antinociceptive effect in Complet Freund's Adjuvant-induced mice: roles of dynorpin/kappa-opioid system and transient receptor potential vanilloid type-1 ion channel.
abstract: BACKGROUND
  Processed Chuanwu (PCW), the mother root of Aconitum carmichaelii Debeauxv, has been widely used as a classic Traditional Chinese Medicine for pain relieve for over two millennia clinically. However, its action on chronic inflammatory pain has not been clarified. Here, we investigated the antinociceptive effect of PCW in complete freund's adjuvant (CFA)-induced mice and its possible mechanisms associated with opioid system and TRPV1 ion channel.
  
  
  METHODS
  Male ICR mice were intraplantarly injected with CFA. PCW (0.34, 0.68 and 1.35 g/kg) was orally given to mice once a day for 7 days. Von frey hairs and planter test were assessed to evaluate the antinociceptive effect of PCW. To investigate the participation of dynorphin/opioid system in PCW antinociception, subtype-specific opioid receptor antagonists or anti-dynorphin A antiserum were used. To eliminate other central mechanisms that contribute to PCW antinociception, hot plate (50 °C) test were performed. Further, involvements of TRPV1 in PCW antinociception were evaluated in CFA-induced TRPV1(-/-) and TRPV1(+/+) C57BL/6 male mice, and in capsaicin-induced nociception ICR naive mice pretreated with nor-BNI. Meanwhile, calcium imaging was performed in HEK293T-TRPV1 cells. Finally, rotarod, open-field tests and body temperature measurement were carried out to assess side effects of PCW.
  
  
  RESULTS
  PCW dose-dependently attenuated mechanical and heat hypersensitivities with no tolerance, which could be partially attenuated by coadministration of k-opioid receptor antagonist nor-binaltorphimine (nor-BNI) or anti-dynorphin A (1-13) antiserum. And PCW antinociception was totally erased by pretreatment with nor-BNI in the hot plate test. In addition, PCW antinociception was decreased in TRPV1(-/-) mice compared to TRPV1(+/+) group. And PCW still manifested inhibitory effects in capsaicin-induced nociception with nor-BNI pretreatment. PCW significantly inhibited capsaicin-induced calcium influx in HEK293T-TRPV1 cells. Finally, no detectable side effects were found in naive mice treated with PCW.
  
  
  CONCLUSIONS
  This study shows PCW's potent antinociceptive effect in inflammatory conditions without obvious side effects. This effect may result from the activation of κ-opioid receptor via dynorpin release and the inhibition of TRPV1. These findings indicate that PCW might be a potential agent for the management of chronic inflammatory pain.
authors: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China. lyb506@126.com.
authors: Chao
authors: C
authors: Wang
authors: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China. 554785365@qq.com.
authors: Danni
authors: D
authors: Sun
authors: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China. chunfang666@126.com.
authors: Chunfang
authors: C
authors: Liu
authors: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China. xijiangyue3013@163.com.
authors: Chunyan
authors: C
authors: Zhu
authors: Institute Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China. jxhtjb@263.com.
authors: Xianghong
authors: X
authors: Jing
authors: Institute Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China. 809107218@qq.com.
authors: Shuping
authors: S
authors: Chen
authors: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China. liucuiling0912@foxmail.com.
authors: Cuiling
authors: C
authors: Liu
authors: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China. zhikai-by@hotmail.com.
authors: Kai
authors: K
authors: Zhi
authors: National Center for Mass Spectrometry in Changchun and Jilin province Key Laboratory for Traditional Chinese Medicine Chemistry and Mass Spectrometry and Chemical Biology Laboratory, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China. mslab11@ciac.ac.cn.|University of Chinese Academy of Sciences, Beijing, 100049, China. mslab11@ciac.ac.cn.
authors: Tengfei
authors: T
authors: Xu
authors: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China. 65435307@qq.com.
authors: Hui
authors: H
authors: Wang
authors: Institute Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, 100700, China. 13521898023@163.com.
authors: Junling
authors: J
authors: Liu
authors: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China. xu_ying1978@163.com.
authors: Ying
authors: Y
authors: Xu
authors: National Center for Mass Spectrometry in Changchun and Jilin province Key Laboratory for Traditional Chinese Medicine Chemistry and Mass Spectrometry and Chemical Biology Laboratory, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China. liuzq@ciac.jl.cn.
authors: Zhiqiang
authors: Z
authors: Liu
authors: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16, Nanxiaojie, Dongzhimennei, Beijing, 100700, China. nlin@icmm.ac.cn.
authors: Na
authors: N
authors: Lin
mesh_terms: D031841:Aconitum / Q000737:chemistry*; D000284:Administration, Oral; D000700:Analgesics / Q000737:chemistry*; D000701:Analgesics, Opioid / Q000737:chemistry; D000818:Animals; D001831:Body Temperature; D002138:Calibration; D002470:Cell Survival; D002851:Chromatography, High Pressure Liquid; D004399:Dynorphins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D005620:Freund's Adjuvant / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D010936:Plant Extracts / Q000737:chemistry*; D018517:Plant Roots / Q000737:chemistry; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D000700:Analgesics; D000701:Analgesics, Opioid; D010936:Plant Extracts; D017473:Receptors, Opioid, kappa; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C116587:kappa(1) opioid receptor; D004399:Dynorphins; D005620:Freund's Adjuvant