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
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.