Effect of chronic administration of U-50,488H on tolerance to its pharmacological actions and on multiple opioid receptors in rat brain regions and spinal cord.

The effects of chronic administration of U-50,488H (trans-3,4-dichloro-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeacetamide ), a selective kappa opioid agonist, on the development of tolerance to its analgesic and hypothermic effects and on mu, delta and kappa opioid receptors in brain regions and spinal cord of male Sprague-Dawley rats were determined. Rats were injected i.p. twice daily with 25 mg/kg of U-50,488H for 4 days. The development of tolerance to the analgesic and hypothermic effects of U-50,488H was almost complete after 4 days of treatment. [3H]Tyr-D-Ala-Gly-MePhe-Gly-ol (DAMGO), [3H]Tyr-D-Ser-Gly-Phe-Leu-Thr (DSTLE) and [3H]ethylketocyclazocine (EK) were used as ligands for mu, delta and kappa opioid receptors, respectively. The binding of [3H]DAMGO to membranes prepared from various brain regions (pons + medulla, midbrain, hypothalamus, corpus striatum and cortex) and spinal cord was unaffected by chronic administration of U-50,488H. The binding of [3H]DSTLE in U-50,488H-treated rats was decreased in spinal cord and increased in corpus striatum. The binding of [3H]EK to membranes prepared from pons + medulla, midbrain, cortex and spinal cord was decreased whereas it was increased in the corpus striatum. The changes in the binding of [3H]DSTLE and [3H]EK after chronic treatment with U-50,488H were due to changes in the maximum binding values and not in the Kd values. The results indicate that, in the rat, chronic administration of U-50,488H results in the development of tolerance to its analgesic and hypothermic effects and down-regulation of kappa and delta opioid receptors in the spinal cord and an up-regulation in the corpus striatum.(ABSTRACT TRUNCATED AT 250 WORDS)