Independent expression of two pharmacologically distinct supraspinal mu analgesic systems in genetically different...

Morphine coadministered at the level of the brainstem and the spinal cord 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 mu2 receptors mediate this synergy, whereas morphine given only within the brainstem elicits analgesia through mu1 receptors. In the mu1-deficient CXBK strain of mice, morphine given intracerebroventricularly (i.c.v.) alone at doses up to 10 micrograms fails to produce greater than 20% analgesia in marked contrast to CD-1 mice (ED50 0.51 micrograms 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 micrograms intrathecally, respectively), a mu2 action. Morphine administered i.c.v. potentiates a fixed low dose of intrathecal 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 naloxonazine (35 mg/kg s.c.) antagonizes the analgesic actions of morphine given only supraspinally without diminishing the potency of i.c.v. morphine in the synergy model. beta-Funaltrexamine, which blocks both mu1 and mu2 receptors, given i.c.v. antagonizes the analgesia after supraspinal morphine alone (ID50 2.5 micrograms i.c.v.) or its potentiation of intrathecal morphine (ID50 2.4 micrograms i.c.v.) equally well, confirming the involvement of mu receptors in both actions. In contrast, naloxonazine reverses the analgesia after supraspinal morphine alone (ID50 2.8 micrograms i.c.v.) almost 6-fold more potently than the synergy between i.c.v. and intrathecal morphine (ID50 18.3 micrograms i.c.v.). Together our results indicate the presence of two genetically and pharmacologically distinct populations of supraspinal mu receptors capable of mediating analgesia.