Tolerance to morphine analgesia: Influence of pain and method of morphine delivery

Whether some kinds of pain can modify the development of tolerance to morphine analgesia is a controversial issue. Clinically, the development of tolerance is often difficult to establish because many factors can contribute to a decline in analgesic coverage, including disease progression. Basic animal research designed to examine tolerance provides the experimental control necessary to differentiate 'real' tolerance from other variables that can influence morphine analgesia. The present study examines the effects of inflammation induced by complete Freund's adjuvant (CFA) on the development of tolerance to morphine analgesia produced by two different methods of morphine delivery - repeated bolus injections and continuous infusion. Male Long-Evans hooded rats were injected with CFA (0.2 mL) into the right hind paw under sodium pentobarbital anesthesia or were given anesthesia alone. Starting 24 h later, rats either received an injection of morphine (20 mg/kg, intraperitoneal) on four consecutive days or were implanted with a 72 h osmotic minipump that delivered 80 mg/kg morphine over a similar time period. Control animals received saline injections or were implanted with empty minipumps. After 24 h, sensitivity to morphine-induced analgesia was measured by the tail-immersion test (water maintained at 52°C) using a cumulative dosing procedure. It was found that CFA attenuated tolerance to the morphine analgesia that was induced by intraperitoneal injections of morphine. In contrast, when morphine was delivered via osmotic minipumps, significant analgesic tolerance was observed in animals that received morphine in the presence of CFA but not in those that received morphine in the absence of CFA. These results show the importance of the method used to deliver morphine in determining the effects of pain on the development of tolerance to morphine analgesia.