Sphingosine-1-phosphate receptor subtype 1 activation in the central nervous system contributes to morphine withdrawal in rodents

Daniela Salvemini,Kali Janes,Zhoumou Chen,Mark R Hutchinson,William L Neumann,Sarah Spiegel,Timothy M Doyle,Vicky Staikopoulos,Kathryn Braden

doi:10.1186/s12974-020-01975-2

Abstract

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.

Highlights

Chronic neuropathic pain is difficult to treat and sufferers are often left with opioids as the only option for some pain relief
We found that repeated administration of morphine in rodents altered sphingolipid metabolism in the central nervous system (CNS) and increased the levels of ceramide and S1P, which directly contributed to the development of Opioid-induced hyperalgesia (OIH) and tolerance [5]
LC-ESI-MS/MS analysis of multiple sphingolipid species in the dorsal horn of the spinal cord harvested 1 h after naloxone or vehicle revealed that sphingolipid metabolism was dramatically altered in mice given naloxone after morphine than mice given the vehicle after morphine (Fig. 1)

Summary

Introduction

Chronic neuropathic pain is difficult to treat and sufferers are often left with opioids as the only option for some pain relief. The long-term use of opioids, such as morphine, is limited by the development of paradoxical. Emerging evidence shows that long-term morphine exposure can lead to dysregulation of sphingolipid metabolism within the dorsal horn spinal cord [4, 5]. Our recent work uncovered an important link within the central nervous system (CNS) between opioids and sphingolipids in the neurobiology of OIH and antinociceptive tolerance [4, 5]. We found that repeated administration of morphine in rodents altered sphingolipid metabolism in the CNS and increased the levels of ceramide and S1P, which directly contributed to the development of OIH and tolerance [5]. We have recently identified that S1PR1 was responsible for transducing the effects of S1P in the development of OIH and tolerance [4]. Its inhibition with S1PR1 functional and competitive antagonists significantly attenuated the development of OIH and tolerance, identifying S1PR1 as a target for therapeutic intervention for OIH and tolerance [4]

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Results

Conclusion