Do morphine and its metabolites morphine-6-glucuronide and morphine-3-glucuronide affect dopamine release in nucleus accumbens in mice?

Opiates have been used for centuries both as recreational drugs and for medical purposes. Opioids are substances that bind opioid receptors that are present throughout the nervous system. These receptors are the primary mediators of the pharmacological effects of opioids. However, their addiction potential is due to their rewarding/reinforcing effects conveyed by activation of dopaminergic neurons in the ventral tegmental area (VTA). Activation of VTA neurons leads to an increased release of dopamine in the nucleus accumbens (NAc), which is an important mechanism related to the reward/reinforcing effect of a variety of drugs and natural stimuli. Heroin is rapidly metabolized to 6-monoacetylmorphine after intake, which is further converted to morphine. Morphine is metabolized to morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). M6G has recently been showed to have rewarding effects similar to morphine, while M3G has not showed such effects. It is well known that morphine, has rewarding effects and increase dopamine release in the NAc. The effects of the morphine metabolites on mesocorticolimbic dopamine release have not yet been studied. The present study thus aims to investigate how morphine, M6G and M3G affect extracellular concentrations of dopamine in the NAc by using the in vivo microdialysis technique in freely moving mice. Microdialysis samples were analyzed for dopamine by high performance liquid chromatography (HPLC) with electrochemical detection (ED) after injection of different doses of morphine, M6G and M3G. Both morphine and M6G treatment significantly increase extracellular dopamine concentrations in NAc, but a dose-response relationship was not seen for the two doses used. Administration of M3G shows no significant increase in extracellular dopamine. This study therefore confirm previous results indicating that M6G, but not M3G, have addictive properties and thus might play an important role in development of dependence after heroin or morphine administration