Treating chronic pain 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 2-fold increase in adenosine kinase (ADK) expression in the dorsal horn of the spinal cord (DH-SC). Blocking ADK activity in the spinal cord provided greater than 90% attenuation of OIH and antinociceptive tolerance through A adenosine receptor (AAR) signaling. Supplementing adenosine signaling with selective AAR agonists blocked OIH and antinociceptive tolerance in rodents of both sexes. Engagement of AAR in the spinal cord with an ADK inhibitor or AAR agonist was associated with reduced DH-SC expression of the NOD-like receptor pyrin domain-containing 3 (NLRP3; 60-75%), cleaved caspase 1 (40-60%), interleukin (IL)-1β (76-80%) and tumor necrosis factor (TNF; 50-60%). In contrast, the neuroinhibitory and anti-inflammatory cytokine IL-10 increased 2-fold. In mice, AAR 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 AAR-dependent adenosine signaling is compromised during sustained morphine to allow the development of morphine-induced adverse effects. These findings raise the intriguing possibility that AAR agonists may be useful adjunct to opioids to manage their unwanted effects.