Opioid drugs as reinforcing stimuli in rhesus monkeys

Working in a laboratory at the University of Michigan that was originally designed in the 1960s by Dr. Tomoji Yanagita, we have been evaluating opioid drugs for their ability to maintain behavior in rhesus monkeys. The animals are prepared with intravenous catheters that can be accessed from the outside of the cage. Inside the cage are two response levers and several stimulus lights. When one of the lights is turned on, it signals to the monkey that it can receive an intravenous injection of a centrally acting drug as a consequence of responses on the lever. Mu opioid agonists, particularly heroin, present serious human abuse problems in the United States and other countries. These drugs also maintain lever responding by monkeys. Kappa opioid agonists do not maintain responding and may be aversive to animals and to humans. Delta opioid agonists also fail to maintain lever responding by monkeys. By using pA 2 analysis we have determined that the same opioid receptor (mu) mediates the analgesic, respiratory depressant, and reinforcing effects of opioid drugs, making it unlikely that abuse liability and analgesic effects can be effectively separated. It is commonly acknowledged that human heroin addicts take increasing amounts of heroin over time. A similar pattern of increasing opioid intake was shown many years ago in both rats and rhesus monkeys. Although this increasing intake may be the result of tolerance development, it is not clear that the tolerance was to the reinforcing effects, as compared with the rate-suppressing effects, of the opioid. In our studies, we found that daily administration of morphine produced a slight decrease in the potency of morphine and heroin as reinforcers, a much larger decrease in the potency of the partial agonists buprenorphine and nalbuphine, and no change in the potency of alfentanil. This suggests that tolerance to the reinforcing effects of opioids depends on the efficacy of the individual agents. We have evaluated the ability of a new treatment agent, the partial agonist buprenorphine, to modify the reinforcing effects of alfentanil. Although buprenorphine is an effective reinforcer, it is also able to decrease the potency of alfentanil as a reinforcer