Resensitization of blood pressure response to mu-opioid peptide agonists after acute desensitization

IV administration of mu-opioid peptide agonists (DAMGO, DALDA, and [Dmt(1)]DALDA) results in a transient, naloxone-sensitive, increase in blood pressure in awake sheep. Despite significant differences in pharmacokinetics, these blood pressure responses all last < 15 min. The lack of correlation between half-life and duration of action suggested rapid desensitization. When a second dose of the same agonist was repeated 30 min later, the response was completely abolished. An increase in blood pressure and rapid desensitization was also observed with the kappa-opioid agonist (U50488H), whereas delta-agonists (DPDPE and DELT) had no effect on blood pressure. The response to DAMGO was abolished after prior exposure to DAMGO or DALDA, but there was no evidence of cross-desensitization between mu and delta, or mu and kappa, opioid agonists. Full resensitization of the blood pressure response occurred by 4 h for DAMGO (t(1/2) = 15 min) and by 48 h for [Dmt(1)]DALDA (t(1/2) = 1.8 h). These data support our hypothesis that the transient nature of the blood pressure response to mu-opioid agonists is caused by rapid desensitization and suggest that the rate of resensitization is dependent on the pharmacokinetics of the agonist.