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Sonic hedgehog signaling in spinal cord contributes to morphine-induced hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor expression

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...

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Autores principales: Liu, Su, Yao, Jun-Li, Wan, Xin-Xin, Song, Zhi-Jing, Miao, Shuai, Zhao, Ye, Wang, Xiu-Li, Liu, Yue-Peng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892616/
https://www.ncbi.nlm.nih.gov/pubmed/29662325
http://dx.doi.org/10.2147/JPR.S153544
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author Liu, Su
Yao, Jun-Li
Wan, Xin-Xin
Song, Zhi-Jing
Miao, Shuai
Zhao, Ye
Wang, Xiu-Li
Liu, Yue-Peng
author_facet Liu, Su
Yao, Jun-Li
Wan, Xin-Xin
Song, Zhi-Jing
Miao, Shuai
Zhao, Ye
Wang, Xiu-Li
Liu, Yue-Peng
author_sort Liu, Su
collection PubMed
description 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 naïve 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.
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spelling pubmed-58926162018-04-16 Sonic hedgehog signaling in spinal cord contributes to morphine-induced hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor expression Liu, Su Yao, Jun-Li Wan, Xin-Xin Song, Zhi-Jing Miao, Shuai Zhao, Ye Wang, Xiu-Li Liu, Yue-Peng J Pain Res Original Research 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 naïve 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. Dove Medical Press 2018-04-03 /pmc/articles/PMC5892616/ /pubmed/29662325 http://dx.doi.org/10.2147/JPR.S153544 Text en © 2018 Liu et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Liu, Su
Yao, Jun-Li
Wan, Xin-Xin
Song, Zhi-Jing
Miao, Shuai
Zhao, Ye
Wang, Xiu-Li
Liu, Yue-Peng
Sonic hedgehog signaling in spinal cord contributes to morphine-induced hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor expression
title Sonic hedgehog signaling in spinal cord contributes to morphine-induced hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor expression
title_full Sonic hedgehog signaling in spinal cord contributes to morphine-induced hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor expression
title_fullStr Sonic hedgehog signaling in spinal cord contributes to morphine-induced hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor expression
title_full_unstemmed Sonic hedgehog signaling in spinal cord contributes to morphine-induced hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor expression
title_short Sonic hedgehog signaling in spinal cord contributes to morphine-induced hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor expression
title_sort sonic hedgehog signaling in spinal cord contributes to morphine-induced hyperalgesia and tolerance through upregulating brain-derived neurotrophic factor expression
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892616/
https://www.ncbi.nlm.nih.gov/pubmed/29662325
http://dx.doi.org/10.2147/JPR.S153544
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