Morphine-induced alterations in
sphingolipid metabolism in the spinal cord and increased formation of the bioactive
sphingolipid metabolite
sphingosine-1-phosphate (S1P) have been implicated in the development of
morphine-induced
hyperalgesia (OIH; increased
pain sensitivity) and antinociceptive tolerance. These adverse effects hamper
opioid use for treating
chronic pain and contribute to dependence and abuse. S1P produces distinct effects through 5
G-protein-coupled receptors (S1PR1-5) and several intracellular targets. How S1P exerts its effects in response to
morphine remains unknown. Here, we report that S1P contributes to the development of
morphine-induced
hyperalgesia and tolerance through
S1P receptor subtype 1 (S1PR1) signaling in uninjured male and female rodents, which can be blocked by targeting S1PR1 with S1PR1 antagonists or RNA silencing. In mouse
neuropathic pain models, S1PR1 antagonists blocked the development of tolerance to the antiallodynic effects of
morphine without altering
morphine pharmacokinetics and prevented prolonged
morphine-induced
neuropathic pain. Targeting S1PR1 reduced
morphine-induced neuroinflammatory events in the dorsal horn of the spinal cord: increased glial marker expression,
mitogen-activated protein kinase p38 and nuclear factor κB activation, and increased inflammatory
cytokine expression, such as interleukin-1β, a
cytokine central in the modulation of
opioid-induced neural plasticity. Our results identify S1PR1 as a critical path for S1P signaling in response to sustained
morphine and reveal downstream neuroinflammatory pathways impacted by S1PR1 activation. Our data support investigating S1PR1 antagonists as a clinical approach to mitigate
opioid-induced adverse effects and repurposing the functional S1PR1 antagonist
FTY720, which is FDA-approved for
multiple sclerosis, as an
opioid adjunct.