Further studies on the involvement of the arachidonic acid cascade in the acute dependence produced by mu, kappa and delta opioid agonists in isolated tissues.
The effects of phospholipase A2, cyclooxygenase-1, cyclooxygenase-2, and 5-lipoxygenase inhibitors on acute opiate withdrawal induced by selective mu, kappa and delta receptor agonists was investigated in vitro. After a 4 min in vitro exposure to D-Ala2-N-methyl-Phe-Gly5-ol)enkephalin (DAMGO; a highly selective mu agonist) and trans(+/-)-3,4-dichloro-N-methyl-N-(2(1pyrrolidynyl)-cyclohexyl)-+ ++benzeneacetamid (U50-488H; a highly selective K agonist) a strong contraction of the guinea pig isolated ileum was observed after the addition of naloxone. This effect was also observed when rabbit isolated jejunum was pretreated with deltorphin (a highly selective delta agonist). Mepacrine (a phospholipase A2 inhibitor), tolmetin (a selective cyclooxygenase-1 inhibitor) and meloxicam (a selective cyclooxygenase-2 inhibitor) treatment before or after DAMGO or U50-488H were able to both prevent and reverse the naloxone-induced contraction after exposure to the opioid agonists, in a concentration-dependent fashion. In addition, nordihydroguaiaretic acid (a 5-lipooxygenase inhibitor) was able to block the naloxone-induced contraction following exposure to DAMGO or U50-488H if injected either before or after the opioid agonist. In contrast, mepacrine, tolmetin, meloxicam and nordihydroguaiaretic acid did not affect the naloxone-induced contraction after exposure to deltorphin. The results of the present study confirm and extend a previous study performed with morphine indicating that arachidonic acid and its metabolites (prostaglandins and leukotrienes) are involved in the development of opioid withdrawal induced by selective mu and kappa opioid agonists whereas no effects were observed on withdrawal induced by the selective delta opioid agonist deltorphin.
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Department of Pharmaceutical Sciences, University of Salerno, Italy. annacap@ponza.dia.unisa.it
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid / Q000502:physiology*; D044482:Benzeneacetamides; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007583:Jejunum / Q000187:drug effects*; D008297:Male; D009842:Oligopeptides / Q000009:adverse effects; D009293:Opioid-Related Disorders; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011758:Pyrroles / Q000009:adverse effects; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*
D044482:Benzeneacetamides; D004745:Enkephalins; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009842:Oligopeptides; D011758:Pyrroles; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C052660:3,4-dichloro-N-methyl-N-(2-(1-delta(3)-pyrrolinyl)-cyclohexyl)benzeneacetamide; C059567:deltorphin; D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2