Spinal A₃ adenosine receptor activation acutely restores morphine antinociception in opioid tolerant male rats

Abstract

Opioids are potent analgesics, but their pain-relieving effects diminish with repeated use. The reduction in analgesic potency is a hallmark of opioid analgesic tolerance, which hampers opioid pain therapy. In the central nervous system, opioid analgesia is critically modulated by adenosine, a purine nucleoside implicated in the beneficial and detrimental actions of opioid medications. Here, we focus on the A 3 adenosine receptor (A 3 AR) in opioid analgesic tolerance. Intrathecal administration of the A 3 AR agonist MRS5698 with daily systemic morphine in male rats attenuated the reduction in morphine antinociception over 7 days. In rats with established morphine tolerance, intrathecal MRS5698 partially restored the antinociceptive effects of morphine. However, when MRS5698 was discontinued, these animals displayed a reduced antinociceptive response to morphine. Our results suggest that MRS5698 acutely and transiently potentiates morphine antinociception in tolerant rats. By contrast, in morphine-naïve rats MRS5698 treatment did not impact thermal nociceptive threshold or affect antinociceptive response to a single injection of morphine. Furthermore, we found that morphine-induced adenosine release in cerebrospinal fluid was blunted in tolerant animals, but total spinal A 3 AR expression was not affected. Collectively, our findings indicate that spinal A 3 AR activation acutely potentiates morphine antinociception in the opioid tolerant state.

The Agonist of Adenosine A1 Receptor Induced Desensitization of delta Opioid receptor-mediated Raf-1/MEK/ERK Signaling by Feedback Phosphorylation of Raf-1-Ser289/296/301

“…Our ndings regarding the crosstalk between A 1 R-and DOR-mediated signaling pathways represent a new mechanism that control physiologic functions related to opioid receptors, including their nociceptive and non-nociceptive roles. For example, it has been discovered that activation of adenosine receptors was able to modulate the effect and tolerance of the opioid receptor system, which result in potentiation of morphine antinociception [23], visceral antinociception [24] and spinal cord nociceptive re exes [25]. Moreover, since DOR has emerged as a promising target for pain treatment [26] due to the analgesic potency of its own agonists [27] or contribution to the antinociception effects of other drugs [18], investigations on mechanisms that control DOR activity, such as its interaction with A 1 R, is of great value in development of novel strategies for pain management.…”