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-Ala(2)-N-methyl-Phe-Gly(5)-ol)enkephalin (DAMGO; a highly selective mu agonist) and trans(+/-)-3,4-dichloro-N-methyI-N-(2(1pyr rolidynyl)- cyclohexyl)-benzeneacetamid (U50-488H; a highly selective kappa agonist) a strong contraction of the guinea pig isolated ileum was observe d 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 c yclooxygenase-1 inhibitor) and meloxicam (a selective cyclooxygenase-2 inhi bitor) treatment before or after DAMGO or U50-488H were able to both preven t and reverse the naloxone-induced contraction after exposure to the opioid agonists, in a concentration-dependent fashion. In addition, nordihydrogua iaretic acid (a 5-lipooxygenase inhibitor) was able to block the naloxone-i nduced contraction following exposure to DAMGO or U50-488H if injected eith er before or after the opioid agonist. In contrast, mepacrine, tolmetin, me loxicam and nordihydroguaiaretic acid did not affect the naloxone-induced c ontraction after exposure to deltorphin. The results of the present study c onfirm 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 an d kappa opioid agonists whereas no effects were observed on withdrawal indu ced by the selective delta opioid agonist deltorphin. (C) 1999 Elsevier Sci ence Ltd. All rights reserved.