Lack of mixed agonist-antagonist properties of [Gln8-Gly31]-beta h-EP-Gly-Gly-NH2 and [Arg9,19,24,28,29]-beta h-EP in the rat vas deferens neuroeffector junction: studies with naloxone, beta-funaltrexamine and ICI 174,864.
The 1-27 truncated fragment of beta h-endorphin (beta h-EP) as well as [Gln8,Gly31]-beta h-EP-Gly-Gly-NH2 or [Arg9,19,24,28,29]-beta h-EP exhibited opiate agonist activity in the rat vas deferens bioassay; the potency of these peptides was 3 to 6 times less than that of beta h-EP. None of these compounds exhibited any degree of antagonism towards the inhibitory action of beta h-EP. Naloxone antagonized and reversed the inhibitory action of beta h-EP and its analogues though with varying potencies. The apparent naloxone-pA2 value for beta h-EP was 8.94; that for [Gln8-Gly31]-beta h-EP-Gly-Gly-NH2 was 8.08 and that for [Arg9,19,24,28,29]-beta h-EP was 8.38. beta-Funaltrexamine (beta-FNA) potently antagonized the inhibitory action of beta h-EP following non-equilibrium kinetics. Tissue preincubation with 10 nM beta-FNA for 60 min followed by extensive washing caused a 10-fold increase in the beta h-EP IC50. However, 10 nM beta-FNA caused only a 1.2 increase in the IC50 of [Gln8,Gly31]-beta h-EP-Gly-Gly-NH2 and a 4.1-fold increase in the IC50 of [Arg9,19,24,28,29]-beta h-EP. In contrast, preincubation of the tissue with 3 microM ICI 174,864 did not modify the potency of beta h-EP or its structural analogues. However, a 60 min pretreatment with 10 microM beta-FNA followed by the addition of 3 microM ICI 174,864 revealed a further decrease in the potency of the opiopeptins compared with tissues exposed to beta-FNA alone or ICI 174,864 alone. In conclusion, the inhibitory action of these peptides is remarkably sensitive to beta-FNA antagonism; in addition the peptides act as pure opiate agonists in marked contrast with the agonist-antagonist properties described in the CNS.
Valenzuela
R
R
Department of Physiology, Neurohumoral Regulatory Unit, Faculty of Biological Sciences, Catholic University of Chile, Casilla, Santiago.
Li
C H
CH
Huidobro-Toro
J P
JP
D000818:Animals; D004723:Endorphins / Q000494:pharmacology*; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009451:Neuroeffector Junction / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D014649:Vas Deferens / Q000187:drug effects; D001615:beta-Endorphin / Q000031:analogs & derivatives* / Q000494:pharmacology
D004723:Endorphins; D009292:Narcotic Antagonists; D009270:Naloxone; D004743:Enkephalin, Leucine; D009271:Naltrexone; D001615:beta-Endorphin; C024524:beta-funaltrexamine; C045429:beta-endorphin, Gln(8),Gly(31)-Gly-Gly-NH2-; C060384:beta-endorphin, Arg(9,19,24,28,29)-; C040643:N,N-diallyl-tyrosyl-alpha-aminoisobutyric acid-phenylalanyl-leucine