Effects of continuous opioid receptor blockade on alcohol intake and up-regulation of opioid receptor subtype signalling in a genetic model of high alcohol drinking

Effects of a continuous naloxone infusion via osmotic pumps on alcohol drin king and opioid receptor density and function in the high-drinking AA (ALko , Alcohol) rats were examined. AA rats were trained to drink 10% (v/v) etha nol in a 1-h limited access procedure and implanted with subcutaneous osmot ic pumps delivering either saline, a low dose (0.3 mg/kg per hour), or a hi gh dose (3.0 mg/kg per hour) of naloxone for 7 days. The pumps were then re moved and alcohol, food and water intakes were measured for another 4 days. Compared with saline, both naloxone doses significantly suppressed 1-h alco hol intake during the 7-day infusion. The suppression was smaller than that by a bolus injection of the same daily dose 15 min before the session, alt hough a complete blockade of morphine-induced antinociception was achieved even with the smaller naloxone infusion. Significant decreases were also se en in daily food and water intake during the first days, but they quickly r eturned to their previous baselines. After pump removal, rats of both nalox one-treated groups rapidly increased their alcohol drinking and reached the pretreatment baseline, while their food and water intakes significantly su rpassed their baselines. Naloxone infusion at 3.0 mg/kg per hour for 7 days significantly decreased 24-h alcohol drinking without affecting alcohol preference. Twenty-four hou rs after pump removal, autoradiography with [H-3]DAMGO, [H-3]DPDPE and [H-3 ]U-69,543 revealed an up-regulation of mu-, delta- and kappa-opioid recepto r binding sites in many brain areas of these animals. This receptor up-regu lation was functional, because receptor coupling to G-protein activation wa s enhanced by agonist ligands, as revealed by [S-35]GTP gamma S autoradiogr aphy. A good correlation existed between ligand binding densities and G-pro tein activation for mu- and kappa-receptors in control and naloxone-treated brain sections. Furthermore, morphine-induced analgesia in a hot-plate tes t showed a leftward shift in the morphine dose-response curve after naloxon e treatment. These results suggest that the usefulness of a chronic opioid antagonist dosing regime could be limited by nonspecific effects of the ant agonist on ingestive behaviour, an up-regulation of opioid receptors with h igh antagonist doses, and the resulting supersensitivity to opioid agonists after the discontinuation of the treatment.