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.
Szeto
H H
HH
Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10021, USA. hhszeto@mail.med.cornell.edu
Soong
Y
Y
Wu
D
D
Fasolo
J
J
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D005260:Female; D009842:Oligopeptides / Q000494:pharmacology; D018847:Opioid Peptides / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000819:agonists; D017473:Receptors, Opioid, kappa / Q000819:agonists; D017450:Receptors, Opioid, mu / Q000819:agonists*; D012756:Sheep
D000700:Analgesics; D009842:Oligopeptides; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C063076:tyrosyl-arginyl-phenylalanyl-lysinamide; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D020881:Enkephalin, D-Penicillamine (2,5)-