Dose- and time-dependent bimodal effects of kappa-opioid agonists on locomotor activity in mice

Citation
A. Kuzmin et al., Dose- and time-dependent bimodal effects of kappa-opioid agonists on locomotor activity in mice, J PHARM EXP, 295(3), 2000, pp. 1031-1042
Citations number
33
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
0022-3565 → ACNP
Volume
295
Issue
3
Year of publication
2000
Pages
1031 - 1042
Database
ISI
SICI code
0022-3565(200012)295:3<1031:DATBEO>2.0.ZU;2-N
Abstract
The kappa -opioid agonists U50488H, bremazocine, and BRL52537, and the mu - opioid agonist morphine were compared in their ability to modify spontaneou s motor activity in male NMRI mice. Higher, analgesic doses of the kappa -a gonists reduced rearing, motility, and locomotion in nonhabituated mice. Th ese effects, as well as the analgesic action of U50488H, were blocked by th e selective kappa -opioid antagonists nor-binaltorphimine and DIPPA. In con trast, lower, subanalgesic doses (1.25 and 2.5 mg/kg for U50488H; 0.15 and 0.075 mg/kg for bremazocine, and 0.1 mg/kg for BRL52537) time dependently i ncreased motor activity. The stimulatory effects of U50488H and bremazocine were not observed in habituated animals and were reduced by dopamine deple tion. Surprisingly, the stimulatory effects of U50488H and bremazocine were not blocked by nor-binaltorphimine and DIPPA but they were completely elim inated by naloxone (0.1 mg/kg). The effects of morphine were dose-dependent ; an initial limited suppression was followed by increased motility and loc omotion (but not rearing) with a peak effect at 20 mg/kg both in habituated and nonhabituated mice. The selective mu -opioid antagonist beta -funaltre xamine blocked morphine-induced motor stimulation and analgesia but failed to affect the analgesic and motor stimulatory effects of U50488H. The resul ts indicate that kappa -opioid agonists interact with different functional subtypes of opioid receptors. A stimulatory, naloxone-sensitive but nor-bin altorphimine- and DIPPA-insensitive subtype of opioid receptor appears to o perate only when the dopamine system is tonically active in nonhabituated a nimals. At higher doses, kappa -agonists produce analgesia and motor suppre ssion, effects mediated by a "classic" (inhibitory) kappa -opioid receptor.