Wnt signaling contributes to withdrawal symptoms from opioid receptor activation

Induced by morphine exposure or chronic inflammation


Patients are prescribed opioids for analgesic purposed but sometimes abusing opioids for their euphoric effects. Opiate tolerance and dependence are commonly due to repetitive use of opioids which cause limited opioid use in the clinical practices. One of the major clinical challenges is preventing and treating opioid dependence and withdrawal, which have a complex mechanism. Even though decades of research, the molecular and cellular mechanisms of opioids actions are still baffling. In the development of nervous system, receptors and ligands of Wnt signaling are essential factors and it is regulating the neuronal and synaptic plasticity, during the adulthood.

Wnt protein family is a secreted lipid-modified signaling molecules in the regulation of proliferation, differentiation, and migration during the development of nervous systems. Poor post-injury axon regeneration, some mental disorders, and neuropathic pain can be caused by the dysregulation of Wnt signaling. Despite some adverse drug reactions have been indicated, there are many compounds in clinical trials targeting Wnt pathways to modulate Wnt signaling in clinical practice.

In this view, researchers at Southern University of Science and Technology and Peking University Cancer Hospital and Institute: Mingzheng Wu, Zehua Li, Pingchuan Ma, Dr. Peng Chen, Genhao Wu, Lei Liang, Dong Cui, and Professor Xue-Jun Song demonstrated the critical role of Wnt expression in opioid dependency and naloxone-precipitated withdrawal. Their work is now published in the research journal, Pain.

The research team repeatedly injected morphine for prolonged time and observed naloxone-precipitated opioid withdrawal and chronic inflammation symptoms. They then analyzed activity of Wnt signaling in primary sensory neurons and the spinal cord by techniques of quantitative real-time polymerase chain reaction, western blotting, immunohistochemistry, and calcium imaging, etc.

The authors demonstrated that lengthy morphine treatment induces Wnt gathering in dorsal root ganglion and after morphine withdrawal, Wnt proteins are transferred to the spinal dorsal horn, where it enhances morphine withdrawal neurochemical and behavioral alterations in animals. After naloxone-precipitated withdrawal, activation of the canonical and non-canonical Ryk receptor is mediating these alterations. Moreover, YAP and TAZ, which are also mediate the effects of Wnt ligands on cell migration and osteogenic differentiation, are involved in development of morphine withdrawal but may have different regulatory effects as well as β-catenin.  Furthermore, Wnt signaling also plays essential roles in latent sensitization following chronic inflammation.

The findings of Professor Xue-Jun Song and colleagues provided compelling evidence on the vital role of Wnt signaling. Consequently, they propose a potential novel pathway for opioid-induced sensitization and offer a possible target for naloxone-precipitated opioid withdrawal syndromes as well as for avoiding the transition from acute to chronic pain in future clinical trials.

About the author

Xue-Jun Song, MD, PhD, Professor and Director of SUSTech Center for Pain Medicine at Southern University of Science and Technology (SUSTech), Shenzhen, China.

Dr. Song obtained his MD and PhD in neurobiology in Chinese Academy of Sciences in 1995 and had his postdoctoral training at Yale University. He then served as a faculty at the University of Texas Medical Center, Parker University, and Peking University, respectively. Dr. Song currently also serves on several committees of IASP, Chinese societies of neuroscience, pain medicine and pharmacology, as well as Senior/Executive Editors for several prestigious including J Neurophysiol and Biochem, Pain Med, etc.

Current research interests in Dr. Song’s group include 1) sensory neuron excitability, synaptic plasticity, and intracellular signal transduction; 2) cellular and molecular mechanisms underlying chronic pain after nerve injury, cancer, and diabetes, and opiate actions; 3) neural mechanisms underlying general anesthesia. Dr. Song is a leading scientist in understanding neuropathic pain, cancer pain, and opiate actions, particularly regarding roles of WNT signaling and ephrinB-EphB receptor signaling.

His research has been funded by the key national and international research grants and resulted in high-quality original research articles published in the peer-reviewed journals including Anesthesiology, Brain, Cancer Res, FASEB J, J Clin Invest, J Neurosci, Nat Neurosci, and Pain, etc., as well as patent publications. He has also been recognized by several prestigious scientific awards including AAPM’s Robert Adison Award, The Scott Haldeman Award, The Louis Sportelli NCMIC Award, and several outstanding scientific awards from Chinese organizations of science and technology.


Wu M, Li Z, Liang L, Ma P, Cui D, Chen P, Wu G, Song XJ. Wnt signaling contributes to withdrawal symptoms from opioid receptor activation induced by morphine exposure or chronic inflammation. Pain. 2020;161(3):532-544. doi:10.1097/j.pain.0000000000001738

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