The opioid mu receptor antagonist beta-funaltrexamine (beta-FNA) blocked the development of physical dependence in rats when infused simultaneously with morphine for 6 days. In addition, beta-FNA given s.c. 24 h prior to the initiation and on day 3 of a 6 day period of morphine infusion in rats reduced the development of physical dependence in a dose-dependent manner. In morphine-dependent rhesus monkeys, beta-FNA precipitated a prompt and long-lasting withdrawal, which was not reversed within 30 h by subsequent injections of morphine. In contrast, naloxone-induced withdrawal lasted approximately 90 min. These results provide further evidence that beta-FNA is a long-acting antagonist of the opioid mu receptor, and that this receptor has a major role in the development of morphine-induced physical dependence.