Intracerebroventricular N-ethylmaleimide differentially reduces supraspinal opioid analgesia in mice.
I.c.v. injection of 1 nmol N-ethylmaleimide (NEM) into mice interfered with opioid-induced supraspinal analgesia, as assessed in the warm water tail-flick test. This effect of NEM was long-lasting (more than 3 days), non-competitive and differentially inhibited by the opioids studied. The analgesia induced by [D-Ala2,D-Leu5]enkephalin (DADLE), [D-Ala2,Met5]enkephalinamide (DAME) and [D-Pen2,D-Pen5]enkephalin (DPDPE) was greatly reduced in NEM-treated mice. The antinociception elicited by [D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAGO) was also impaired although to a lesser extent. In contrast, the activity of morphine and etorphine remained unchanged. NEM-sensitive opioids coadministered with morphine antagonized the analgesia elicited by the alkaloid in NEM-treated mice. The administration of naltrexone or DADLE, DAGO, [D-Ala2,N-MePhe4,Met-(O)5-ol]enkephalin (FK-33824) and morphine in doses equivalent to the ED90 doses for inducing analgesia, a few minutes before NEM prevented it from interfering with DADLE-elicited supraspinal analgesia when evaluated 24 h later. In contrast, the selective delta antagonist, ICI 174864, did not protect the DADLE-induced analgesia against the effect of NEM. We suggest that NEM produced its effect by acting upon a site that appears to be distal to the receptor binding site, presumably located on the guanine nucleotide binding regulatory proteins, Gi/Go. Therefore, these transducer proteins might play a key role in the effects displayed by opioids when acting via the mu receptor-Gi/Go complexes.
Sánchez-Blázquez
P
P
Cajal Institute, C.S.I.C., Madrid, Spain.
Ulibarri
I
I
Garzón
J
J
D000700:Analgesics; D000818:Animals; D004723:Endorphins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine; D004745:Enkephalins / Q000494:pharmacology; D005033:Ethylmaleimide / Q000008:administration & dosage / Q000494:pharmacology*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D013439:Sulfhydryl Reagents / Q000494:pharmacology
D000700:Analgesics; D004723:Endorphins; D004745:Enkephalins; D009292:Narcotic Antagonists; D013439:Sulfhydryl Reagents; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004743:Enkephalin, Leucine; D009271:Naltrexone; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-; C040643:N,N-diallyl-tyrosyl-alpha-aminoisobutyric acid-phenylalanyl-leucine; D005033:Ethylmaleimide