Neuropharmacology: Effects on Rat Brain K1- and K2-Opioid Receptors after Chronic Treatment with Non-peptide K-Agonists

Injection of K-agonist dynorphins and non-peptide K-agonists into the hippocampus induces a reduction in blood pressure. It has been postulated that K-opioid agonists and K-receptors are important in one mechanism of antihypertension and might have clinical potential for the treatment of hypertension. We have investigated whether chronic treatment with U-50488H and U-62066E, two non-peptide K-agonists, effects brain K₁- or K₂-receptor numbers or affinities in areas that might correlate with changes in blood pressure. K₁- and K₂-Opioid receptor affinities and densities were determined in cortex, hippocampus, hypothalamus, midbrain and pons after 14 days subcutaneous infusion of two non-peptide K-agonists, U-50488H and U-62066E, 9.6 mg kg day^?1, by means of osmotic minipumps, to spontaneously hypertensive rats (SHR) and to Wistar-Kyoto (WKY) rats. This infusion significantly reduced blood pressure. Brains were removed within 48 h of the end of drug infusion and K-receptor binding studies were performed on homogenates from each brain area using [³H]U-69593 to assay K₁-receptors and [³H]bremazocine to assay K₂-receptors. U-62066E treatment seemed to cause a slight decrease in the number of [³H]bremazocine binding sites (K₂-receptors) from 98.2 ± 9 to 74.9 ± 8 fmol (mg protein)^?1 in the hippocampus when compared with SHR controls. A small decrease in K₂-receptor density in the pons of WKY rats was also observed after U-50488H treatment (control, 51.2±5; U-50488H-treated, 24.3±9 fmol (mg protein)^?1). Although SHR blood pressure values were consistently reduced by treatment with K-agonists, there was little if any significant change in apparent numbers of K₁- or K₂-receptors or their affinities in any of the brain regions examined. These data indicate that although chronic treatment with K-agonists reduces blood pressure in SHR, the treatment does not elicit major changes in brain K-receptors either in SHR or in WKY rats. The potential use of K-agonists for treating hypertension might not cause receptor changes in the brain and might, therefore, result in fewer side effects or negligible rebound hypertension.