Spinal interactions between opioid and noradrenergic agonists in mice: multiplicativity involves delta and alpha-2 receptors.

The nature of the interaction between spinally administered opioid and alpha-2 agonists was investigated using the substance P behavioral test in mice. Morphine and agonists which more selectively activate mu or delta opioid receptors were co-administered intrathecally with direct and indirect acting adrenergic agonists norepinephrine, cocaine or clonidine and the behavioral responses to intrathecally coadministered substance P were evaluated. The ED50 values for agonists administered separately and concurrently were computed and drug interactions were evaluated using isobolographic analyses. After separate administration, all the opioid and adrenergic agonists inhibited the substance P-induced behavioral responses. Upon coadministration of opioid and adrenergic agonists, a multiplicative interaction was observed between morphine or the delta agonist D-Pen2-D-Pen-5-enkephalin and the adrenergic agonists. Additive or antagonistic interactions were found between the mu agonist Tyr-D-Ala-NMe-Phe-Gly(ol) and the same adrenergic agonists. The opioid antagonist naloxone and the alpha-2 adrenergic antagonist idazoxan were given as intrathecal pretreatments at doses chosen to shift the dose-response curves of their corresponding agonist (given alone) 4- to 10-fold to the right; this always resulted in a smaller, but significant (2- to 4-fold) shift in the dose-response curve of the other agonist given alone. Intrathecal pretreatment with naloxone or idazoxan altered some interactions between the opioids and clonidine. Although naloxone blocked completely the multiplicative interaction between morphine and clonidine, idazoxan did not. Both naloxone and idazoxan changed the antagonistic interaction between Tyr-D-Ala-NMe-Phe-Gly(ol) and clonidine to a multiplicative interaction. Neither antagonist blocked the multiplicative interaction between D-Pen2-D-Pen5-enkephalin and clonidine. These results suggest that: 1) interactions between opioid and adrenergic agonists in mouse spinal cord are mediated by delta and alpha-2 receptor subtypes; 2) the synergistic interaction between morphine and alpha-2 adrenergic agonists may involve action at delta opioid receptors; and 3) antagonist action on these drug interactions is complex.