Effects of (-)-Epigallocatechin Gallate on the Development of Morphine-induced Physical Dependence

Among the various nervous systems and signaling components involved in the development of morphine withdrawal symptoms, sensitization of the brain dopaminergic nervous system and an increase in the cAMP levels in the locus coeruleus are believed to be the most important cellular events. This study tested the effects of (-)-epigallocatechin gallate (EGCG), a major compound of green tea, on the development of morphine-induced withdrawal symptoms. All the naloxone-precipitated withdrawal symptoms in morphine-dependent animals were inhibited by an EGCG pretreatment in a dose-dependent manner, being forepaw tremor, rearing, teeth chattering, urination, and wet dog shake were more sensitive than jumping and ptosis. In addition, EGCG showed moderate inhibitory effects on the morphine-induced increase in the cAMP levels in the locus coeruleus at 100 mg/kg and the signaling of the dopamine $D_2$ receptor at 100 ${\mu}M$. Effects of EGCG on the sequestration of $D_2$ receptor were inconclusive. These results suggest that EGCG has strong pharmacological activity against the development of morphine dependence, which can be partly explained by its inhibitory effects on the morphine-induced increase in the cAMP levels in the locus coeruleus and the signaling of the dopamine $D_2$ receptor.