Cynomolgus monkeys do not develop tolerance to opioids

In order to examine the development of tolerance to opioids, eight cynomolgus and two rhesus monkeys were trained to press a lever for food reinforcement and then were catheterized so that drugs could be infused. Three doses of hydromorphone and six different interdose intervals were studied. Hydromorphone infusions initially suppressed lever pressing for food in both species. The rhesus monkeys acquired tolerance to these sedative effects after 14 exposures to the opioid. However, the cynomolgus monkeys failed to acquire tolerance after more than 100 exposures. Naloxone challenge elicited withdrawal symptoms from the rhesus monkeys but not from the cynomolgus monkeys. This differential response to sustained opioid administration in these closely related species suggests that a genetic mechanism may underlie tolerance to and physical dependence on opioids.