Effects of κ-Agonist on the Antinociception and Locomotor EnhancingAction Induced by Morphine in Mice

The antinociception of intracerebroventricular injection (i.c.v.) of morphine was markedly abolished by pretreatment with naloxonazine (μ1-antagonist), s.c.; β-funaltrexamine (μ1/μ2-antagonist), i.c.v.; DSP-4 (noradrenaline neurotoxin), s.c.; or p-chlorophenylalanine (serotonin synthesis inhibitor), s.c. in the mouse 55°C hot-plate assay. Pretreatment with nor-binaltorphimine (κ-antagonist), i.c.v. or PCPA, s.c. drastically blocked the κ-agonist U-50,488H-induced supraspinal antinociception. These findings indicate either noradrenergic or serotonergic involvement in the mediation of the antinociception of i.c.v.-morphine through μ-receptors. On the contrary, the antinociception of i.c.v.- U-50.488H through κ-receptors appears to depend on the serotonergic but not noradrenergic systems. The antinociceptive interaction between the i.c.v.-morphine and -U-50,488H was an additive effect. On the other hand, i.c.v.-morphine dose-dependently increased the locomotion in mice, and this hyperlocomotion of morphine was drastically blocked by pretreatment with either β-funaltrexamine, i.c.v. or 6-hydroxydopamine (dopamine depletor), i.c.v. I.C.V.-U-50,488H dose-dependently reduced the increasing locomotion of i.c.v.-morphine, but not that of s.c.-apomorphine (dopamine receptor agonist), and this effect of U-50,488H was completely reversed by pretreatment with nor-binaltorphimine, i.c.v. These results suggest that coadministration of κ-agonists can suppress the dopamine-related hyperlocomotion of μ-agonists without decreasing the antinociception of μ-agonists in mice.