Although opiates are effective in the treatment of chronic pain, many patients are under-treated due to the common belief that tolerance is an inevitable consequence of prolonged opiate use and may result in increased adverse side effects. Yet, careful clinical observations suggest that less tolerance than expected develops to the opiate's analgesic effects in most chronic pain patients. Data from animal studies are conflicting and the effect of pain on the development of tolerance to the opiate's adverse effects has not been systematically examined. This proposal will test the hypothesis that the presence of a persistent pain state will attenuate the development of tolerance to the analgesic, but not to the respiratory depressant effects of opiates. The proposed experiments will utilize a partial sciatic nerve ligature as a model of neuropathic pain and the Freund's adjuvant-induced arthritis model of chronic nociceptive pain. Tolerance will be established using continuous subcutaneous morphine infusions via implanted minipumps. Antinociception will be tested with ratings of spontaneous pain behavior and paw withdrawal to noxious thermal stimulation while the respiratory effects of morphine will be assessed with plethysmography. A parallel control factorial design will permit quantitative comparisons between treatment effects. As previous studies have shown that tolerance to different opiate effects may develop at different rates and to different extents, initial experiments will characterize the time course of tolerance development to both morphine effects in the same animals. Subsequent experiments will employ a morphine cumulative dosing regimen to determine the magnitude of analgesia and respiratory tolerance in chronic pain vs. pain-free groups. The results will clarify the effects of chronic pain on the development of tolerance, enhance our understanding of differential tolerance, and lead to future studies examining the underlying mechanisms of these important phenomena.
