Different mu receptor subtypes mediate spinal and supraspinal analgesia in mice

To examine the relative roles of mu 1- and mu 2-receptors in spinal and supraspinal analgesia, we assessed the effects of naloxonazine, naloxone, beta-funaltrexamine (beta-FNA), and ICI-154,129 on tail-flick analgesia produced by intrathecal or intracerebroventricular injections of the highly mu-selective agonist, [D-Ala2,Me-Phe4,Gly(ol)5]enkephalin (DAGO; mu 1 and mu 2), [D-Ser2,Leu5]enkephalin-Thr6 (DSLET; mu 1 and delta), and the selective delta-receptor agonist [D-Pen2,D-Pen5]enkephalin (DPDPE) in mice. Both DAGO and DSLET supraspinal analgesia were mediated through mu 1-receptors. Naloxonazine shifted the supraspinal DAGO dose-response curve 4-fold to the right without changing the curve for spinal DAGO. Likewise, naloxonazine pretreatment shifted supraspinal DSLET analgesia 10-fold, whereas spinal DSLET analgesia was not affected. DPDPE analgesia was not antagonized spinally or supraspinally by naloxonazine pretreatment. These findings suggest that DAGO produces analgesia spinally and supraspinally through different sets of mu-receptors. Moreover, at least two distinct receptor subtypes mediated spinal analgesia. First, naloxone inhibited spinal DAGO analgesia more potently than DPDPE analgesia. Second, the irreversible mu-antagonist, beta-FNA, blocks spinal DAGO analgesia. Since spinal DAGO was insensitive to naloxonazine, ruling out a mu 1 mechanism, these results indicate a role for mu 2-receptors. Spinal DAGO analgesia also developed tolerance to morphine far more slowly than supraspinal DAGO analgesia even though mu-receptors mediate both, as indicated by their sensitivity towards beta-FNA. Finally, the delta-antagonist ICI-154,129 is a more potent inhibitor of spinal DPDPE analgesia than spinal DAGO analgesia. Thus, delta-receptors mediate spinal DPDPE analgesia.