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Opioid therapies for chronic pain are undermined by many adverse side effects that reduce their efficacy and lead to dependence, abuse, reduced quality of life, and even death. We have recently reported that sphingosine-1-phosphate (S1P) 1 receptor (S1PR1) antagonists block the development of morphine-induced hyperalgesia and analgesic tolerance. However, the impact of S1PR1 antagonists on other undesirable side effects of opioids, such as opioid-induced dependence, remains unknown. Here, we demonstrate that naloxone-precipitated morphine withdrawal in mice altered de novo sphingolipid metabolism in the dorsal horn of the spinal cord and increased S1P that accompanied the manifestation of several withdrawal behaviors. Blocking de novo sphingolipid metabolism with intrathecal administration of myriocin, an inhibitor of serine palmitoyltransferase, blocked naloxone-precipitated withdrawal. Noteworthy, we found that competitive (NIBR-15) and functional (FTY720) S1PR1 antagonists attenuated withdrawal behaviors in mice. Mechanistically, at the level of the spinal cord, naloxone-precipitated withdrawal was associated with increased glial activity and formation of the potent inflammatory/neuroexcitatory cytokine interleukin-1β (IL-1β); these events were attenuated by S1PR1 antagonists. These results provide the first molecular insight for the role of the S1P/S1PR1 axis during opioid withdrawal. Our data identify S1PR1 antagonists as potential therapeutics to mitigate opioid-induced dependence and support repurposing the S1PR1 functional antagonist FTY720, which is FDA-approved for multiple sclerosis, as an opioid adjunct.

Peripheral neuropathy accompanied by chronic neuropathic pain is the most common dose-limiting complication associated with several first-line chemotherapeutics regardless of their mechanism of action. Symptoms can persist long after the cessation of treatment thereby reducing the patient's quality of life and limiting the ability to treat cancer effectively. Adenosine has been shown to be protective in models of pain. Its actions are mediated by four G-protein coupled adenosine receptors (ARs): A1, A2A, A2B, and A3. While agonists to A1AR and A2AAR have been tested in pain, they have adverse cardiovascular side effects that make them unattractive for use. The role(s) of A3AR agonists in pain has yet to be explored. The objective of this study was to examine the potential beneficial effects of selective A3AR agonists as adjuncts in a model of chemotherapy-induced neuropathic pain and identify possible pathways that A3AR may be modulating. It is shown herein that 1) A3AR agonists protect against the development of chemotherapy-induced neuropathic pain via beneficial effects in the periphery (mito-protection in peripheral nerve sensory axons) and the spinal cord (release of anti-inflammatory cytokines/suppression of pro-inflammatory cytokines) and 2) A3AR agonists can reverse established chemotherapy-induced neuropathic pain via an IL-10 dependent mechanism. This dissertation provides the pharmacological basis for targeting A3AR as adjuncts to chemotherapeutics for the management of resulting neuropathies. These findings could potentially have a significant impact on patients with various forms of cancer.