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

摘要

Sphingolipid metabolism is enhanced in the spinal cord during naloxone-precipitated withdrawal and contributes to withdrawal behaviors. (a) Schematic of treatment paradigms. (b) Schematic of sphingolipid metabolic pathways. (c-e) LC-ESI-MS/MS analysis of multiple sphingolipid species of lipids extracted from the mouse spinal cord 1 h after intraperitoneal naloxone (Mor+naloxone, n = 5) or its vehicle (Mor; n = 6) administration to mice treated with 3 days of escalating morphine treatments (c). Naloxone-precipitated withdrawal was associated with significant enhancements of sphingolipid metabolite levels, including S1P and dihydro-S1P, when compared to its vehicle. Individual ceramide (d) and dihydroceramide (e) species are shown. (f) Naloxone-precipitated withdrawal behaviors (e.g., jumping, front paw shaking, and hunched/prayer postures) in mice treated with morphine and naloxone (Mor+naloxone; n = 6) were attenuated in mice administered a single daily intrathecal myriocin (300 nM; Mor+naloxone+myriocin; n = 6) given 15 min before first dose of morphine of the day. Jumping [t(5.8) = 3.9, p = 0.008, d = 2.28, n = 6], front paw shaking [t(9.3) = 4.2, p = 0.002, d = 2.45, n = 6], and hunching [t(9.9) = 4.4, p = 0.0014, d = 2.54, n = 6]. Data are mean ± SEM and analyzed by two-tailed Welch’s corrected t test and Benjamini-Hochberg analysis (b-d) or two-tailed Welch’s corrected t test (e). *q < 0.04 (b) or q < 0.046 (c, d) vs. Mor and #p < 0.05 vs. Mor