Mu antagonist and kappa agonist properties of β-funaltrexamine (β-FNA) in vivo: Long-lasting spinal analgesia in mice

It is now well established that compounds classified as kappa opioids can, in circumstances where they produce no measurable agonist effects, antagonize the actions of mu opioids. Largely on the basis of studies in vitro, β-funaltrexamine (β-FNA) has been classified as a reversible kappa agonist and long acting mu antagonist. The present study investigated the possibility that the mu antagonist profile of this compound could be related to its kappa agonist actions. We used two tests of analgesia (the acetic acid writhing test and the hot-water tail-flick test) and selective kappa agonists and antagonists given at supraspinal and spinal sites in mice. Intrathecal (i.t.) administration of β-FNA, but not the selective kappa agonist U50,488H, produced long-lasting and dose-related analgesia in the writhing test for periods up to 48 hr after a single dose. In contrast, i.t. β-FNA had no agonist actions in the tail-flick test. The kappa antagonist, nor-binaltorphimine (nor-BNI) produced no agonist effects in either analgesic test when given i.t. In the writhing test, nor-BNI produced a rightward displacement of the β-FNA dose-response line regardless of whether β-FNA was given 10 min or 4 hr before testing, indicating that i.t. β-FNA was acting as a kappa agonist in this test. As both i.t. morphine and β-FNA are active in the writhing test, the antagonist actions of i.t. β-FNA could be evaluated only in the tail-flick test, β-FNA, but not nor-BNI, blocked the effects of i.t. morphine in the tail-flick test. Neither the agonist actions of morphine nor the antagonism of morphine by β-FNA in this test was blocked by pretreatment with nor-BNI, suggesting that the β-FNA antagonist actions were not mediated by kappa receptors. Nonetheless, i.t. β-FNA antagonized morphine in the tail-flick test with a time course which was directly inverse to that observed for its analgesic actions in the writhing test. In contrast to the agonist actions of i.t. β-FNA in the writhing test, analgesic actions could not be detected in either test when β-FNA was given intracerebroventricularly (i.c.v.). Intracerebroventricular nor-BNI did not block the effects of i.c.v. morphine, but did antagonize i.c.v. U50,488H in the writhing test. Further, i.c.v. β-FNA blocked the effects of i.c.v. morphine in the writhing test, but this antagonist action was not blocked by nor-BNI, again suggesting that these antagonist actions were not mediated through kappa receptors. These data indicate that both at the level of the brain and the spinal cord, β-FNA produces its antagonist actions against morphine at mu, rather than kappa, receptors. Additionally, i.t., but not i.c.v., β-FNA produces a surprisingly long kappa-mediated analgesic effect which can be detected in the writhing test.