Bhilawanol Reduces Morphine Conditioned Place Preference and Anxiety by Modulating Antioxidant, Anti-Inflammatory, and Nitric Oxide Pathways

Abstract

Opioid addiction is characterized by persistent drug seeking; the main objective of addiction treatment is to prevent relapses, which remains the primary limitation of pharmacological therapy. In the present work, the role of bhilawanol (BWL) on morphine conditioned place preference (CPP) and the anxiety-like behavior during the abstinence period in the mice model was investigated. Morphine CPP was induced with an increasing dose of morphine (MOR) from 5 mg/kg bid to 25 mg/kg bid for 5 days during the conditioning schedule. The effect of BWL (0.25, 0.5, and 1 mg/kg) was tested on the rewarding effects of MOR. BWL 1 mg/kg significantly reduced MOR acquisition and reinstatement and accelerated extinction of MOR CPP. BWL 1 mg/kg also markedly reduced anxiety-like behavior on the last extinction day, as measured by the open-field (OF) and elevated plus maze (EPM) tests. BWL significantly preserved the antioxidant enzymes in the brain and modulated the expression of tumor necrosis factor (TNF-α), inducible nitric oxide synthase (iNOS), and neuronal nitric oxide synthase (nNOS) in both the cortex and hippocampus regions of the brain. Further, BWL also modulated the expression of TNF-α and brain-derived neurotrophic factor (BDNF) in MOR-treated mice, measured through ELISA. In addition, BWL displayed a significant reduction in total nitric oxide in the cortex and hippocampal region. These findings show the beneficial effects of BWL in MOR-induced CPP, extinction, and reinstatement, as well as reducing anxiety during abstinence from MOR through modulation of antioxidant, inflammatory, and NO pathways.