Alpha-pinene modulates hippocampal MAPKs/c-Fos pathways during morphine dependence and withdrawal in rats.

RATIONALE: A potential strategy for managing morphine addiction is preventing mitogen-activated protein kinases (MAPKs) activation and neuroinflammation. The molecular basis of inflammation involves inflammatory cytokines, whose production and activity are modulated by the MAPKs signaling pathways. OBJECTIVES: This study investigated how alpha-pinene (APN), an anti-inflammatory monoterpene, influences hippocampal MAPKs levels during chronic morphine exposure and the subsequent prolonged withdrawal phase. METHODS: Three experimental groups as dependent model groups intraperitoneally received 10 days of saline + DMSO, morphine (10 mg/kg) + DMSO, and morphine + APN (20 mg/kg). Three additional groups were designated as withdrawal models, treating them with either saline (group 1) or morphine (groups 2 and 3) for 10 days before subjecting them to a 30-day withdrawal period. During the withdrawal, the first and second groups were administered daily 5% DMSO injections, whereas the third group received daily APN (20 mg/kg) treatment. Results: The results revealed that Hippocampal expression of MAPKs, including p38, ERK1/2, and JNK remained largely unchanged subsequent to both the chronic morphine exposure and the 30-day morphine wash-out phase. However, hippocampal levels of the phosphorylated form of the MAPKs significantly increased after both the morphine exposure and withdrawal phase. Interestingly, APN treatment during morphine exposure or over the 30-day of withdrawal phase significantly restored hippocampal levels of the phosphorylated MAPKs and decreased c-Fos expression. CONCLUSIONS: It can be concluded that APN treatment may contribute to preventing hippocampal MAPK overactivation and decreasing c-Fos expression resulting from chronic morphine exposure and the subsequent withdrawal phase.