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

Wu，Mingzheng1,2,3; Li，Zehua1,2; Liang，Lei2; Ma，Pingchuan1; Cui，Dong2; Chen，Peng1; Wu，Genhao1; Song，Xue Jun1,2

2020-03-01

10.1097/j.pain.0000000000001738

PAIN   影响因子和分区

0304-3959

1872-6623

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 elicits 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 increase 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) after 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.

Wnt signaling Morphine withdrawal mu-opioid receptor YAP TAZ Ryk receptor

SCI

英语

第一

Southern University of Science and Technology[G02416002]

Anesthesiology ; Neurosciences & Neurology

Anesthesiology ; Clinical Neurology ; Neurosciences

WOS:000524185000010

LIPPINCOTT WILLIAMS & WILKINS

NEUROSCIENCE & BEHAVIOR

2-s2.0-85079352928

Scopus

1.SUSTech Center for Pain Medicine and School of Medicine,Southern University of Science and Technology,Shenzhen,China
2.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education of China),Peking University Cancer Hospital and Institute,China
3.Department of Neurobiology,Northwestern University,Evanston,United States

Wu，Mingzheng,Li，Zehua,Liang，Lei,et al. Wnt signaling contributes to withdrawal symptoms from opioid receptor activation induced by morphine exposure or chronic inflammation[J]. PAIN,2020,161(3):532-544.

Wu，Mingzheng.,Li，Zehua.,Liang，Lei.,Ma，Pingchuan.,Cui，Dong.,...&Song，Xue Jun.(2020).Wnt signaling contributes to withdrawal symptoms from opioid receptor activation induced by morphine exposure or chronic inflammation.PAIN,161(3),532-544.

Wu，Mingzheng,et al."Wnt signaling contributes to withdrawal symptoms from opioid receptor activation induced by morphine exposure or chronic inflammation".PAIN 161.3(2020):532-544.