Chronic morphine-induced changes in signaling at the A3adenosine receptor contribute to morphine-induced hyperalgesia, tolerance, and withdrawal

Timothy M. Doyle, Tally M. Largent-Milnes, Zhoumou Chen, Vasiliki Staikopoulos, Emanuela Esposito, Rebecca Dalgarno, Churmy Fan, Dilip K. Tosh, Cuzzocrea Salvatore Cuzzocrea, Kenneth A. Jacobson, Tuan Trang, Mark R. Hutchinson, Gary J. Bennett, Todd W. Vanderah, Daniela Salvemini

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Treating 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 ofmorphine, but the extent of their interaction remains poorly understood. Here, we demonstrate that morphineinduced 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 domaincontaining 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-dependentwithdrawal behaviors by greater than 50%. These findings suggest A3AR-dependent adenosine signaling is compromised during sustained morphine to allow the development ofmorphine-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.

Original languageEnglish (US)
Pages (from-to)331-341
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - Aug 1 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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