INDEPENDENT EXPRESSION OF 2 PHARMACOLOGICALLY DISTINCT SUPRASPINAL MU-ANALGESIC SYSTEMS IN GENETICALLY DIFFERENT MOUSE STRAINS

Morphine coadministered at the level of the brainstem and the spinal c ord in rodents elicits a profound synergism with a combined analgesic potency almost 10-fold greater than that seen with morphine in either region alone. In the present study, we demonstrate that supraspinal mu 2 receptors mediate this synergy, whereas morphine given only within t he brainstem elicits analgesia through mu1 receptors. In the mu1-defic ient CXBK strain of mice, morphine given intracerebroventricularly (i. c.v.) alone at doses up to 10 mug fails to produce greater than 20% an algesia in marked contrast to CD-1 mice (ED50 0.51 mug i.c.v.). At the spinal level, both the CXBK and CD-1 strains are equally sensitive to morphine (ED50 0.91 and 0.94 mug intrathecally, respectively), a mu2 action. Morphine administered i.c.v. potentiates a fixed low dose of i ntrathecal morphine as effectively in the CXBK mice as the CD-1 mice. Additional studies using selective mu antagonists differentiated these two analgesic responses pharmacologically. The mu1-selective drug nal oxonazine (35 mg/kg s.c.) antagonizes the analgesic actions of morphin e given only supraspinally without diminishing the potency of i.c.v. m orphine in the synergy model. Beta-Funaltrexamine, which blocks both m u1 and mu2 receptors, given i.c.v. antagonizes the analgesia after sup raspinal morphine alone (ID50 2.5 mug i.c.v.) or its potentiation of i ntrathecal morphine (ID50 2.4 mug i.c.v.) equally well, confirming the involvement of mu receptors in both actions. In contrast, naloxonazin e reverses the analgesia after supraspinal morphine alone (ID50 2.8 mu g i.c.v.) almost 6-fold more potently than the synergy between i.c.v. and intrathecal morphine (ID50 18.3 mug i.c.v.). Together our results indicate the presence of two genetically and pharmacologically distinc t populations of supraspinal mu receptors capable of mediating analges ia.