The present study examined the development of tolerance to morphine analgesia under conditions in which morphine was administered in the presence or absence of pain induced by subcutaneous injection of 50 μl of 2.5% formalin into the hind paw of rats. Animals were injected with morphine (25 mg/kg, i.p.) or saline for 3 consecutive days either in the presence of pain (10 min after formalin injection) or in the absence of pain (6 h prior to formalin injection). On the 4th day, tolerance to the analgesic effect of test doses of morphine (6 or 10 mg/kg) was assessed in the formalin and tail-flick tests, respectively. Significant tolerance in both tests was observed in animals receiving morphine in the absence of pain during the tolerance induction period, but not in animals receiving morphine in the presence of pain.