Cerebral cortical 5-HT 1, and 5-HT 2, receptors of morphine tolerant-dependent rats

Abstract

The effect of chronic administration of morphine to rats on 5-HT 1 and 5-HT 2 receptors in the cerebral cortex was determined. Male Sprague-Dawley rats were implanted subcutaneously with 6 pellets of morphine (each containing 75 mg of morphine free base) during a 7 day period. Animals which served as controls were implanted with placebo pellets. The procedure for implantation of pellets produced a high degree of tolerance to and physical dependence on morphine in the rat. The tolerance to the analgesic and hyperthermic effects of morphine was demonstrated by decreased responses in the rats implanted with morphine pellet in comparison to the placebo-treated controls. The physical dependence was shown by the greater weight loss after removal of the pellet in the rats implanted with morphine pellets when compared to rats implanted with placebo pellets. The pellets were removed (withdrawn) and, after 6–8 h, the rats were sacrificed and the cerebral cortex was isolated. In another experiment the pellets were left in place (tolerant-dependent rats). The 5-HT 1 and 5-HT 2 receptors were characterized by using [ 3H]5-HT and [ 3H]spiroperidol as the ligands and unlabelled 5-HT and ketanserin, respectively, to determine non-specific binding. The [ 3H]5-HT bound to 5-HT 1 receptors on membranes from the cerebral cortex of rats implanted with placebo pellets, at a single high affinity site, with a B max of 102 ± 10 fmol/ mg protein and a K d of 6.02 ± 0.98 nM. Implantation of morphine pellets, followed by removal of the pellets resulted in a 50% increase in the B max value of [ 3 H ]5- HT but the K d values did not change. In rats from which the pellets were not removed, the B max and K d values of [ 3H]5-HT in placebo- and morphine-treated groups did not differ. [ 3H]Spiroperidol bound to 5-HT 2 receptors on cortical membranes of rats implanted with placebo pellet at a single high affinity site with B max and K d values of 131 ± 5 fmol/mg protein and 0.22 ± 0.01 nM, respectively. The implantation of pellets of morphine followed by removal of the pellets did not alter the characteristics of 5-HT 2, receptors, however in rats with the pellets in place, the B max for 5-HT 2 receptors in placebo- and morphine-treated groups did not differ but the K d values were much smaller in morphine-treated rats compared to rats implanted with placebo pellets. It is concluded that the development of tolerance to, and physical dependence on, morphine by implantation of pellets results in up-regulation of 5-HT 2 receptors whereas in morphine-abstinent rats there is a selective up-regulation of 5-HT 1 receptors on the membranes in the cerebral cortex.