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Wnt signaling contributes to withdrawal symptoms from opioid receptor activation induced by morphine exposure or chronic inflammation.
Pain 2019PAIN

Abstract

Preventing and treating opioid dependence and withdrawal is a major clinical challenge, and the underlying mechanisms of opioid dependence and withdrawal remain elusive. We hypothesized that prolonged morphine exposure or chronic inflammation-induced μ-opioid receptor activity serves as a severe stress that elicit neuronal alterations and recapitulates events during development. Here, we report that Wnt signaling, which is important in developmental processes of the nervous system, plays a critical role in withdrawal symptoms from opioid receptor activation in mice. Repeated exposures of morphine or peripheral inflammation produced by intraplantar injection of Complete Freund's Adjuvant significantly increases the expression of Wnt5b in the primary sensory neurons in dorsal root ganglion (DRG). Accumulated Wnt5b in DRG neurons quickly transmits to the spinal cord dorsal horn (DH) following naloxone treatment. In the DH, Wnt5b, acts through the atypical Wnt-Ryk receptor and alternative Wnt-YAP/TAZ signaling pathways, contributing to the naloxone-precipitated opioid withdrawal-like behavioral symptoms and hyperalgesia. Inhibition of Wnt synthesis and blockage of Wnt signaling pathways greatly suppress the behavioral and neurochemical alterations after naloxone-precipitated withdrawal. These findings reveal a critical mechanism underlying naloxone-precipitated opioid withdrawal, suggesting that targeting Wnt5b synthesis in DRG neurons and Wnt signaling in DH may be an effective approach for prevention and treatment of opioid withdrawal syndromes, as well as the transition from acute to chronic pain.

Authors+Show Affiliations

SUSTech Center for Pain Medicine and School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education of China), Peking University Cancer Hospital & Institute, Beijing 100142, China. Department of Neurobiology, Northwestern University, Evanston, IL, USA.SUSTech Center for Pain Medicine and School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education of China), Peking University Cancer Hospital & Institute, Beijing 100142, China.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education of China), Peking University Cancer Hospital & Institute, Beijing 100142, China.SUSTech Center for Pain Medicine and School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education of China), Peking University Cancer Hospital & Institute, Beijing 100142, China.SUSTech Center for Pain Medicine and School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.SUSTech Center for Pain Medicine and School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.SUSTech Center for Pain Medicine and School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education of China), Peking University Cancer Hospital & Institute, Beijing 100142, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31738230

Citation

Wu, Ming-Zheng, et al. "Wnt Signaling Contributes to Withdrawal Symptoms From Opioid Receptor Activation Induced By Morphine Exposure or Chronic Inflammation." Pain, 2019.
Wu MZ, Li ZH, Liang L, et al. Wnt signaling contributes to withdrawal symptoms from opioid receptor activation induced by morphine exposure or chronic inflammation. Pain. 2019.
Wu, M. Z., Li, Z. H., Liang, L., Ma, P. C., Cui, D., Chen, P., ... Song, X. J. (2019). Wnt signaling contributes to withdrawal symptoms from opioid receptor activation induced by morphine exposure or chronic inflammation. Pain, doi:10.1097/j.pain.0000000000001738.
Wu MZ, et al. Wnt Signaling Contributes to Withdrawal Symptoms From Opioid Receptor Activation Induced By Morphine Exposure or Chronic Inflammation. Pain. 2019 Nov 5; PubMed PMID: 31738230.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Wnt signaling contributes to withdrawal symptoms from opioid receptor activation induced by morphine exposure or chronic inflammation. AU - Wu,Ming-Zheng, AU - Li,Ze-Hua, AU - Liang,Lei, AU - Ma,Ping-Chuan, AU - Cui,Dong, AU - Chen,Peng, AU - Wu,Gen-Hao, AU - Song,Xue-Jun, Y1 - 2019/11/05/ PY - 2019/11/19/entrez JF - Pain JO - Pain N2 - Preventing and treating opioid dependence and withdrawal is a major clinical challenge, and the underlying mechanisms of opioid dependence and withdrawal remain elusive. We hypothesized that prolonged morphine exposure or chronic inflammation-induced μ-opioid receptor activity serves as a severe stress that elicit neuronal alterations and recapitulates events during development. Here, we report that Wnt signaling, which is important in developmental processes of the nervous system, plays a critical role in withdrawal symptoms from opioid receptor activation in mice. Repeated exposures of morphine or peripheral inflammation produced by intraplantar injection of Complete Freund's Adjuvant significantly increases the expression of Wnt5b in the primary sensory neurons in dorsal root ganglion (DRG). Accumulated Wnt5b in DRG neurons quickly transmits to the spinal cord dorsal horn (DH) following naloxone treatment. In the DH, Wnt5b, acts through the atypical Wnt-Ryk receptor and alternative Wnt-YAP/TAZ signaling pathways, contributing to the naloxone-precipitated opioid withdrawal-like behavioral symptoms and hyperalgesia. Inhibition of Wnt synthesis and blockage of Wnt signaling pathways greatly suppress the behavioral and neurochemical alterations after naloxone-precipitated withdrawal. These findings reveal a critical mechanism underlying naloxone-precipitated opioid withdrawal, suggesting that targeting Wnt5b synthesis in DRG neurons and Wnt signaling in DH may be an effective approach for prevention and treatment of opioid withdrawal syndromes, as well as the transition from acute to chronic pain. SN - 1872-6623 UR - https://www.unboundmedicine.com/medline/citation/31738230/Wnt_signaling_contributes_to_withdrawal_symptoms_from_opioid_receptor_activation_induced_by_morphine_exposure_or_chronic_inflammation L2 - http://dx.doi.org/10.1097/j.pain.0000000000001738 DB - PRIME DP - Unbound Medicine ER -