Abstract
The antinociceptive effects of morphine are mediated in part by activation of the S1P1 receptor as indicated by attenuation of morphine‐induced antinociception by a S1P1 receptor antagonist VPC44116 in mice. In addition, as tested in SphK2 knockout mice, activation of sphingosine kinase2, the kinase responsible (along with SphK1) in the phosphorylation and activation of S1P is required for the fully efficacious effect of morphine in antinociceptive testing in mice. The antinociceptive effects of morphine are enhanced by the administration of subactive doses of the S1P analog FTY720 (fingolimod) and the S1P1 receptor‐selective drug, CYM‐ 5442. Morphine‐induced antinociception and G‐protein activation via [35S]GTPγS autoradiography in several brain regions are not attenuated in FTY720‐tolerant mice. Thus, S1P and opioid receptors appear to have distinct receptor signaling systems. However, these data indicate that opioid and S1P1 receptor‐activated processes are highly dependent upon one another in the production of antinociception. The Presidential Research Incentive Grant (VCU) and NIDA RO3DA‐05274 supported this work.
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