Effects of kappa-agonist on the antinociception and locomotor enhancing action induced by morphine in mice.

The antinociception of intracerebroventricular injection (i.c.v.) of morphine was markedly abolished by pretreatment with naloxonazine (micro 1-antagonist), s.c.; beta-funaltrexamine (micro 1/micro 2-antagonist), i.c.v.; DSP-4 (noradrenaline neurotoxin), s.c.; or p-chlorophenylalanine (serotonin synthesis inhibitor), s.c. in the mouse 55 degrees C hot-plate assay. Pretreatment with nor-binaltorphimine (kappa-antagonist), i.c.v. or PCPA, s.c. drastically blocked the kappa-agonist U-50,488H-induced supraspinal antinociception. These findings indicate either noradrenergic or serotonergic involvement in the mediation of the antinociceptio of i.c.v.-morphine through mu-receptors. On the contrary, the antinociception of i.c.v.- U-50,488H through kappa-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 beta-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 kappa-agonists can suppress the dopamine-related hyperlocomotion of mu-agonists without decreasing the anti-nociception of mu-agonists in mice.