Studies of Morphine and D-ala2-D-leu5-enkephalin (DADLE) Cross-tolerance after Continuous Intrathecal Infusion in the Rat

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Abstract
To determine the cross tolerance to the antinociceptive effects of μ and δ opioids In the spinal cord, rats received a 7-day infusion of one of three concentrations each of morphine (2, 6, or 20 nmol/h) or D-ala2-D-leu5-enkephalin (DADLE) (2, 6, or 20 nmol/h). A constant-rate (1 μ1/h), constant-dose intrathecal infusion pump was used. On day 7, the magnitude of tolerance was assessed by establishing dose-response curves for the effect of the chronic drug given as an intrathecal bolus. Cross-tolerance was assessed in separate groups of animals with identical infusions by establishing morphine dose–response curves in DADLE-tolerant animals and DADLE dose–response curves in morphine-tolerant animals. Each infused animal was used for a single bolus injection. For morphine and DADLE tolerance, a parallel rightward shift in the dose–response curve was produced with the degree of shift proportional to the log of the infusion dose. Thus, at the infusion rate of 6 nmol/h for either morphine or DADLE, the shift of the tolerance dose–response curves was 55− and 33-fold, respectively. Morphine and DADLE cross-tolerance was also detected as shown by rightward shifts of the cross-tolerance dose–response curves; however, these shifts were relatively minor compared to the shifts seen in the tolerance dose–response curves of animals tested with the same agent as infused. At the infusion dose of 6 nmol/h for either morphine or DADLE, the shift of the cross-tolerance curve for DADLE in morphine-tolerant rats was only 2.7-fold, whereas that of morphine in DADLE-tolerant rats was only 1.3-fold. These data are interpreted as supporting separate sites of spinal antinociceptive action for morphine and DADLE in the rat and emphasize the importance of a dose-dependent induction and assessment of tolerance in studies of tolerance and cross-tolerance.

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