A comparative study in rats of the respiratory depression and analgesia induced by mu- and delta-opioid agonists.
A comparison was made in awake rats between the analgesic and the respiratory depressant actions induced by the mu-opiate agonists morphine and Tyr-D-Ala-Gly-N-Me-Phe-Met-(O)-ol (FK-33824), and the delta-agonists Tyr-D-Ala-Gly-Phe-D-Leu ( DADLE ) and Tyr-D-Ser-Gly-Phe-D-Leu-Thr (D-Ser2- Thr6 ), injected into the cerebral ventricles. The four opioids caused a dose-dependent analgesia (tail-flick); FK-33824 was the most potent, followed by morphine, DADLE and D-Ser2- Thr6 , and the duration of the analgesic effect of D-Ser2- Thr6 was very short. Respiratory frequency was dose-dependently depressed by FK-33824 and DADLE ; dose-response curves with morphine and D-Ser2- Thr6 could not be obtained for technical reasons. The in vivo apparent pA2 values for naloxone against the mu-agonist FK-33824 and the delta-agonist DADLE were similar in analgesia suggesting an interaction with the same type of receptor. On the other hand, in respiration studies the pA2 value for the interaction of naloxone with DADLE was significantly higher than with FK-33824. The ratio between the ED50 required to induce respiratory depression and analgesia was 1,500 times higher for FK-33824 than for DADLE . It was concluded that agonist interaction with mu-receptors can result in antinociceptive effect in the tail-flick test, whereas respiratory depression seems to require a prominent, but non-exclusive, interaction with delta-receptors.
D000698:Analgesia; D000818:Animals; D005405:D-Ala(2),MePhe(4),Met(0)-ol-enkephalin / Q000494:pharmacology; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine; D004745:Enkephalins / Q000494:pharmacology*; D005260:Female; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012119:Respiration / Q000187:drug effects*
D004745:Enkephalins; D009842:Oligopeptides; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; D005405:D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; C034318:enkephalin, Ser(2), Leu(5), Thr(6)-; D009020:Morphine