Inhibition of opioid-degrading enzymes potentiates delta9-tetrahydrocannabinol-induced antinociception in mice.
Delta9-tetrahydrocannabinol (delta9-THC) elicits antinociception in rodents through the central CB1 cannabinoid receptor subtype. In addition. Delta9-THC stimulates the release of dynorphin-related peptides leading to kappa-opioid spinal antinociception. In this work we describe the effect of a mixture of thiorphan (a neutral endopeptidase EC3.4.24.11 inhibitor) and bestatin (an aminopeptidase inhibitor), administered i.c.v., on the antinociceptive effect of peripherally administered delta9-THC in mice. As in the case of morphine or DAMGO ([D-Ala2.N-Me-Phe4,Gly-ol]enkephalin), a mu-selective opioid receptor agonist, the mixture of enkephalin-degrading enzyme inhibitors also enhanced the antinociceptive effect of delta9-THC. This effect was blocked by the CB1 cannabinoid receptor antagonist, SR-141,716-A, as well as by naloxone. The kappa-opioid receptor antagonist nor-binaltorphimine, administered i.t., also antagonized the effect of this combination. Similar results were obtained with the mu-opioid receptor antagonist beta-funaltrexamine after i.c.v. administration. These results demonstrate the involvement of both mu-opioid supraspinal and kappa-opioid spinal receptors in the interaction of both opioid and cannabinoid systems regulating nociception in mice.
Reche
I
I
Departamento de Farmacologia, Facultad de Farmacia, Universidad Complutense de Madrid, Ciudad Universitaria, Spain.
Ruiz-Gayo
M
M
Fuentes
J A
JA
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D013759:Dronabinol / Q000494:pharmacology*; D007276:Injections, Intraventricular; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D009292:Narcotic Antagonists / Q000494:pharmacology*; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D017288:Pain Threshold / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology*; D015244:Thiorphan / Q000494:pharmacology*
D009292:Narcotic Antagonists; D011480:Protease Inhibitors; D013759:Dronabinol; D015244:Thiorphan; D000626:Aminopeptidases; D015260:Neprilysin; D007930:Leucine; C012211:ubenimex