• Timothy M Doyle, Tally M Largent-Milnes, Zhoumou Chen, Vasiliki Staikopoulos, Emanuela Esposito, Rebecca Dalgarno, Churmy Fan, Dilip K Tosh, Salvatore Cuzzocrea, Kenneth A Jacobson, Tuan Trang, Mark R Hutchinson, Gary J Bennett, Todd W Vanderah, and Daniela Salvemini.
• Department of Pharmacology and Physiology and Henry and Amelia Nasrallah Center for Neuroscience, Saint Louis University School of Medicine, St. Louis, Missouri (T.M.D., Z.C., D.S.); Department of Pharmacology, University of Arizona College of Medicine, Tucson, Arizona (T.M.L.-M., T.W.V.); Discipline of Physiology, Institute for Photonics and Advanced Sensing, ARC Centre of Excellence for Nanoscale BioPhotonics, University of Adelaide, Adelaide, Australia (V.S., M.R.H.); Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy (E.E., S.C.); Departments of Comparative Biology and Experimental Medicine and Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada (R.D., C.F., T.T.); Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (D.K.T., K.A.J.); and Department of Anesthesiology, University of California San Diego, La Jolla, California (G.J.B.).
• J. Pharmacol. Exp. Ther. 2020 Aug 1; 374 (2): 331-341.

AbstractTreating chronic pain by using opioids, such as morphine, is hampered by the development of opioid-induced hyperalgesia (OIH; increased pain sensitivity), antinociceptive tolerance, and withdrawal, which can contribute to dependence and abuse. In the central nervous system, the purine nucleoside adenosine has been implicated in beneficial and detrimental actions of morphine, but the extent of their interaction remains poorly understood. Here, we demonstrate that morphine-induced OIH and antinociceptive tolerance in rats is associated with a twofold increase in adenosine kinase (ADK) expression in the dorsal horn of the spinal cord. Blocking ADK activity in the spinal cord provided greater than 90% attenuation of OIH and antinociceptive tolerance through A3 adenosine receptor (A3AR) signaling. Supplementing adenosine signaling with selective A3AR agonists blocked OIH and antinociceptive tolerance in rodents of both sexes. Engagement of A3AR in the spinal cord with an ADK inhibitor or A3AR agonist was associated with reduced dorsal horn of the spinal cord expression of the NOD-like receptor pyrin domain-containing 3 (60%-75%), cleaved caspase 1 (40%-60%), interleukin (IL)-1β (76%-80%), and tumor necrosis factor (50%-60%). In contrast, the neuroinhibitory and anti-inflammatory cytokine IL-10 increased twofold. In mice, A3AR agonists prevented the development of tolerance in a model of neuropathic pain and reduced naloxone-dependent withdrawal behaviors by greater than 50%. These findings suggest A3AR-dependent adenosine signaling is compromised during sustained morphine to allow the development of morphine-induced adverse effects. These findings raise the intriguing possibility that A3AR agonists may be useful adjunct to opioids to manage their unwanted effects. SIGNIFICANCE STATEMENT: The development of hyperalgesia and antinociceptive tolerance during prolonged opioid use are noteworthy opioid-induced adverse effects that reduce opioid efficacy for treating chronic pain and increase the risk of dependence and abuse. We report that in rodents, these adverse effects are due to reduced adenosine signaling at the A3AR, resulting in NOD-like receptor pyrin domain-containing 3-interleukin-1β neuroinflammation in spinal cord. These effects are attenuated by A3AR agonists, suggesting that A3AR may be a target for therapeutic intervention with selective A3AR agonist as opioid adjuncts.U.S. Government work not protected by U.S. copyright.

27 keywords...

hide…