PMID- 29662325
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220317
IS  - 1178-7090 (Print)
IS  - 1178-7090 (Electronic)
IS  - 1178-7090 (Linking)
VI  - 11
DP  - 2018
TI  - Sonic hedgehog signaling in spinal cord contributes to morphine-induced 
      hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor 
      expression.
PG  - 649-659
LID - 10.2147/JPR.S153544 [doi]
AB  - PURPOSE: Preventing opioid-induced hyperalgesia and tolerance continues to be a 
      major clinical challenge, and the underlying mechanisms of hyperalgesia and 
      tolerance remain elusive. Here, we investigated the role of sonic hedgehog (Shh) 
      signaling in opioid-induced hyperalgesia and tolerance. METHODS: Shh signaling 
      expression, behavioral changes, and neurochemical alterations induced by morphine 
      were analyzed in male adult CD-1 mice with repeated administration of morphine. 
      To investigate the contribution of Shh to morphine-induced hyperalgesia (MIH) and 
      tolerance, Shh signaling inhibitor cyclopamine and Shh small interfering RNA 
      (siRNA) were used. To explore the mechanisms of Shh signaling in MIH and 
      tolerance, brain-derived neurotrophic factor (BDNF) inhibitor K252 and anti-BDNF 
      antibody were used. RESULTS: Repeated administration of morphine produced obvious 
      hyperalgesia and tolerance. The behavioral changes were correlated with the 
      upregulation and activation of morphine treatment-induced Shh signaling. 
      Pharmacologic and genetic inhibition of Shh signaling significantly delayed the 
      generation of MIH and tolerance and associated neurochemical changes. Chronic 
      morphine administration also induced upregulation of BDNF. Inhibiting BDNF 
      effectively delayed the generation of MIH and tolerance. The upregulation of BDNF 
      induced by morphine was significantly suppressed by inhibiting Shh signaling. In 
      naive mice, exogenous activation of Shh signaling caused a rapid increase of BDNF 
      expression, as well as thermal hyperalgesia. Inhibiting BDNF significantly 
      suppressed smoothened agonist-induced hyperalgesia. CONCLUSION: These findings 
      suggest that Shh signaling may be a critical mediator for MIH and tolerance by 
      regulating BDNF expression. Inhibiting Shh signaling, especially during the early 
      phase, may effectively delay or suppress MIH and tolerance.
FAU - Liu, Su
AU  - Liu S
AD  - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, 
      Xuzhou, Jiangsu, China.
AD  - Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, 
      Xuzhou, Jiangsu, China.
FAU - Yao, Jun-Li
AU  - Yao JL
AD  - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, 
      Xuzhou, Jiangsu, China.
AD  - Department of Anesthesiology, Xuzhou Children's Hospital, Xuzhou, Jiangsu, China.
FAU - Wan, Xin-Xin
AU  - Wan XX
AD  - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, 
      Xuzhou, Jiangsu, China.
FAU - Song, Zhi-Jing
AU  - Song ZJ
AD  - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, 
      Xuzhou, Jiangsu, China.
FAU - Miao, Shuai
AU  - Miao S
AD  - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, 
      Xuzhou, Jiangsu, China.
AD  - Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, 
      Xuzhou, Jiangsu, China.
FAU - Zhao, Ye
AU  - Zhao Y
AD  - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, 
      Xuzhou, Jiangsu, China.
AD  - Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, 
      Xuzhou, Jiangsu, China.
FAU - Wang, Xiu-Li
AU  - Wang XL
AD  - Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, 
      Xuzhou, Jiangsu, China.
AD  - Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, 
      Xuzhou, Jiangsu, China.
FAU - Liu, Yue-Peng
AU  - Liu YP
AD  - Center of Clinical Research and Translational Medicine, Lianyungang Oriental 
      Hospital, Lianyungang, Jiangsu, China.
LA  - eng
PT  - Journal Article
DEP - 20180403
PL  - New Zealand
TA  - J Pain Res
JT  - Journal of pain research
JID - 101540514
PMC - PMC5892616
OTO - NOTNLM
OT  - brain-derived neurotrophic factor
OT  - hyperalgesia
OT  - sonic hedgehog
OT  - spinal cord
OT  - tolerance
COIS- Disclosure The authors report no conflicts of interest in this work.
EDAT- 2018/04/18 06:00
MHDA- 2018/04/18 06:01
PMCR- 2018/04/03
CRDT- 2018/04/18 06:00
PHST- 2018/04/18 06:00 [entrez]
PHST- 2018/04/18 06:00 [pubmed]
PHST- 2018/04/18 06:01 [medline]
PHST- 2018/04/03 00:00 [pmc-release]
AID - jpr-11-649 [pii]
AID - 10.2147/JPR.S153544 [doi]
PST - epublish
SO  - J Pain Res. 2018 Apr 3;11:649-659. doi: 10.2147/JPR.S153544. eCollection 2018.