Opioids, such as morphine, are potent analgesic drugs that are commonly used to treat moderate to severe acute pain. There is also increasing reliance on opioids for managing chronic pain, a pervasive condition that afflicts approximately one in five Canadians. However, prolonged opioid usage can lead to the development of opioid analgesic tolerance, which is characterized by diminished pain-relieving effects. The A3 adenosine receptor (A3AR) is a novel target that produces antinociceptive and anti-inflammatory effects in animal models of chronic neuropathic pain, a condition that shares similar mechanisms with opioid tolerance. We determined that spinal A3AR acutely potentiates morphine antinociception without preventing the development of tolerance. Chronic morphine increased microglia reactivity, MAP kinase activity within the lumbar spinal cord, and cell-surface A3AR protein density on microglia, while spinal A3AR activation abrogated these changes. Overall, these findings have significant implications for improving opioid efficacy in chronic pain management.