PREVENTING MORPHINE ANTINOCICEPTIVE TOLERANCE BY IRREVERSIBLE MU-OPIOID ANTAGONISTS BEFORE THE ONSET OF THEIR ANTAGONISM

Irreversible opioid antagonists, when administered at small doses, require several hours to display their antagonism of antinociception mediated by opioid receptors. However, most opioid affinity ligands only need a few minutes to produce wash-resistant inhibition of opioid binding to brain membranes. Our study investigated whether the irreversible antagonists, beta-funaltrexamine (beta-FNA), 14 alpha,14'beta-[dithiobis[(2-oxo-2,1-ethanediyl)imino]]bis-7,8-dihydro-N-(cyclopropylmethyl)nor-morphinone (N-CPM-TAMO), and N-cyclopropylmethyl-5 beta-methyl-14 beta-(p-nitrocinnamoylamino)-7,8-dihydromophinone (N-CPM-MET-CAMO) had any effect on morphine-induced antinociceptive tolerance before the appearance of their antagonism in the mouse tail-flick assay. All opioids were given by i.c.v. administration. The irreversible antagonists, beta-FNA (20 nmol), N-CPM-TAMO (0.5 nmol) and N-CPM-MET-CAMO (1 nmol) did not produce any antagonism of morphine-induced analgesia until at least 8 hr after administration. Pretreatment with morphine (3 nmol, -140 min) produced acute antinociceptive tolerance as demonstrated by a 45-fold rightward shift of the morphine dose-response curve. When coadministered with morphine, beta-FNA, N-CPM-TAMO and N-CPM-MET-CAMO completely prevented the development of morphine tolerance 140 min after administration in a dose-dependent manner. This preventive effect lasted for up to 420 min, during which time, morphine was given repeatedly up to four times. This antinociception produced by morphine after coadministration with irreversible antagonists was antagonized by naloxone, demonstrating that morphine-induced analgesia was still mediated by opioid receptors. The kappa- and delta-selective opioid antagonists, nor-binaltorphimine and ICI 174,864, respectively, did not block the preventive effect produced by the irreversible antagonists. In addition, the affinity ligands did not reverse morphine antinociceptive tolerance after the tolerance had been developed. These data demonstrate that the irreversible antagonists, beta-FNA, N-CPM-TAMO and N-CPM-MET-CAMO prevented the development of acute morphine tolerance before the appearance of their antagonism. The data also suggest that the mechanism of long-term antagonism of mu opioid receptors by irreversible antagonists is more complex than the direct binding of the irreversible antagonists to the mu opioid binding site.