Determination of cross tolerance in rat spinal cord using intrathecal infusion via sequential mini-osmotic pumps

Continuous intrathecal (IT) infusion via ALZET ® mini-osmotic pumps was used to induce spinal tolerance to morphine in the rat. Naloxone (1 mg/kg IP), injected on day 3 of continuous IT morphine (10 μg/hr), produced mild withdrawal symptoms in all morphine-treated animals. In rats pretreated with continuous IT morphine (10 μg/hr) or saline, systemic morphine (2, 4, 8, 10 and 15 mg/kg IP) produced equivalent, dose-dependent antinociception using the tail-flick and paw pressure tests. The rostral and caudal distribution of methylene blue dye in rat spinal cord was determined on days 1–7 of continouus IT infusion. The dye remained localized near the catheter tip through infusion; maximum distribution was 1.5 cm rostrally and 1.0 cm caudally. The data indicate that morphine, infused at the rate of 10 μg/hr, does not undergo extensive redistribution in the spinal cord. A sequential, double mini-osmotic pump technique for cross tolerance studies in rat spinal cord is described. In rats pretreated with continuous IT norepinephrine for 4 days, the antinociceptive actions of continuous IT morphine were reduced but not significantly different from saline-pretreated animals. These data suggest that morphine, injected into the spinal cord, does not produce behavioural analgesia by activation of local adrenergic systems.