Cerebral cortical 5-HT1 and 5-HT2 receptors of morphine tolerant-dependent rats

The effect of chronic administration of morphine to rats on 5-HT₁ and 5-HT₂ 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 The pellets were removed (withdrawn) and, after 6–8 h, the rats were sacrificed and the cerebral cortex was isolated.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-HT₁ and 5-HT₂ 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-HT₁ 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 [^3H]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-HT₂ 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-HT₂, receptors, however in rats with the pellets in place, the B_max for 5-HT₂ 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-HT₂ receptors whereas in morphine-abstinent rats there is a selective up-regulation of 5-HT₁ receptors on the membranes in the cerebral cortex.