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

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.

S1P/S1PR1 signaling is involved in the development of nociceptive pain

“…On this basis, we verified by Western blotting that the phosphorylation of STAT3, ERK, and p38MAPK decreased significantly after S1PR1 was knocked down ( Figures 5A–F ). Previous studies have found that activation of glial cell S1PR1 contributes to the development of neuropathic pain, specifically knocking out the S1PR1 allele in GFAP-positive astrocytes, and no SNL-induced neuropathic pain occurs ( Chen et al, 2019 ; Doyle et al, 2020a ). Increasing evidence has shown that microglia and astrocytes play an important role in the development of inflammatory pain caused by CFA ( Ji et al, 2016 ).…”

Dysregulation of sphingolipid metabolism in pain

“…Subsequently, Bryant et al demonstrated that ceramide also induces oxidative DNA damage and activation of the nuclear enzyme poly adenosine diphosphate-ribose polymerase (PARP) via the nitrite-mediated nitrogen oxidative stress pathway, leading to apoptosis and participation in tolerance generation (Bryant et al, 2009). In addition, S1P inhibitors have likewise been shown to block the development of morphine tolerance by improving neuroglial cell function and decreasing the associated proinflammatory cytokine production (Muscoli et al, 2010;Doyle et al, 2020a). In a mouse model of neuropathic pain, S1PR1 antagonists blocked the development of morphine tolerance and prevented morphineinduced neuropathic pain by reversing S1P-induced neuroinflammation including activation of mitogen-activated protein kinase p38 and NF-κB, and increased expression of inflammatory cytokines (Doyle et al, 2020b).…”