Neuroinflammation mediated by toll-like receptors (TLRs) signaling pathway has a substantial role to morphine addiction. Αlpha-pinene is a member of the monoterpene family that has exhibited anti-inflammatory effects. This study aimed to examine the anti-inflammatory effects of alpha-pinene treatment on TLRs signaling pathway in the rat hippocampus after morphine dependence and withdrawal. Six groups of male Wistar rats were used in two categories, including dependent and withdrawal. Morphine (10 mg/kg) was intraperitoneally injected twice daily for 10 consecutive days to induce dependence. Alpha-pinene (20 mg/kg) was injected once daily either during 10 days of morphine treatment (in dependent category) or over a 30-day withdrawal period. The results revealed that protein expression of TLR4, TLR10, and MyD88 increased, but PI3K and p-AKT1B levels decreased in the hippocampus after both morphine dependence and withdrawal period. The results also revealed that treatment with alpha-pinene during either 10 days of the induction of dependence or 30 days of withdrawal period partially restored the alterations observed after dependence, but almost completely reinstated most of the examined factors after withdrawal. It can be concluded that alpha-pinene has a notable effect on the neuroinflammation induced by chronic use of morphine by controlling the changes in the expression of the TLR signaling pathway, thereby modulating the onset and progression of morphine addiction and withdrawal complications. These results can serve as a valuable insight to guide future therapeutic approaches in the treatment of complications caused by repeated use of morphine such as tolerance, dependence and addiction.
