Neuropeptide trefoil factor 3 attenuates naloxone-precipitated withdrawal in morphine-dependent mice.

Abstract

The persistence of physical dependence and craving in addicts is considered to contribute to relapse. Increasing evidence indicates that neuropeptide systems are associated with several phases of drug addiction, but little is known about whether the neuropeptide trefoil factor affects withdrawal symptoms. This study aims to investigate the potential effects of the neuropeptide trefoil factor 3 (TFF3) on naloxone-precipitated withdrawal symptoms in morphine-dependent mice. Mice received increasing doses of morphine over 3days. On day 4, the mice were injected with TFF3 (1.0mg/kg, i.p.) 30min after the last dose of morphine. Thirty minutes after TFF3 treatment, naloxone (1mg/kg, i.p.) was injected, and body weight, jumping behavior, wet-dog shakes, and locomotor activity were assessed 30min later. Naloxone caused significant weight loss and increased jumping behavior and wet-dog shakes in morphine-dependent mice. TFF3 (1.0mg/kg) reversed these behavioral symptoms caused by morphine withdrawal, suggesting that TFF3 might ameliorate physical dependence associated with opiate addiction. Furthermore, TFF3 pretreatment significantly reduced morphine withdrawal-induced increases in plasma corticosterone and adrenocorticotropic hormone levels. The glucocorticoid receptor agonist RU486 blocked the behavioral effects of TFF3 on morphine withdrawal symptoms. Finally, Fos expression in the medial prefrontal cortex which was decreased during morphine withdrawal was increased by TFF3 pretreatment. These findings indicate that TFF3 might be a potential therapeutic candidate for opiate addiction by regulating glucocorticoid secretion and neuronal activation in the prefrontal cortex.