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Dose- and time-dependent bimodal effects of kappa-opioid agonists on locomotor activity in mice
A Kuzmin1, J Sandin, L Terenius
1Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Alexander.Kuzmin@fyfa.ki.se
Abstract:
The kappa-opioid agonists U50488H, bremazocine, and BRL52537, and the mu-opioid agonist morphine were compared in their ability to modify spontaneous motor activity in male NMRI mice. Higher, analgesic doses of the kappa-agonists reduced rearing, motility, and locomotion in nonhabituated mice. These effects, as well as the analgesic action of U50488H, were blocked by the selective kappa-opioid antagonists nor-binaltorphimine and DIPPA. In contrast, 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 increased motor activity. The stimulatory effects of U50488H and bremazocine were not observed in habituated animals and were reduced by dopamine depletion. Surprisingly, the stimulatory effects of U50488H and bremazocine were not blocked by nor-binaltorphimine and DIPPA but they were completely eliminated by naloxone (0.1 mg/kg). The effects of morphine were dose-dependent; an initial limited suppression was followed by increased motility and locomotion (but not rearing) with a peak effect at 20 mg/kg both in habituated and nonhabituated mice. The selective mu-opioid antagonist beta-funaltrexamine blocked morphine-induced motor stimulation and analgesia but failed to affect the analgesic and motor stimulatory effects of U50488H. The results indicate that kappa-opioid agonists interact with different functional subtypes of opioid receptors. A stimulatory, naloxone-sensitive but nor-binaltorphimine- and DIPPA-insensitive subtype of opioid receptor appears to operate only when the dopamine system is tonically active in nonhabituated animals. At higher doses, kappa-agonists produce analgesia and motor suppression, effects mediated by a "classic" (inhibitory) kappa-opioid receptor.
Insights
Kappa-opioid agonists show dual effects on mouse motor activity. Low doses stimulate, while high doses suppress activity, indicating interaction with distinct opioid receptor subtypes.
Area of Science:
- Pharmacology
- Neuroscience
- Behavioral Science
Background:
- Opioid receptors, specifically kappa-opioid receptors, are known to modulate motor activity and pain.
- Previous research suggests complex interactions between opioid agonists and motor function, but the precise mechanisms and receptor subtypes involved require further elucidation.
Purpose of the Study:
- To compare the effects of kappa-opioid agonists (U50488H, bremazocine, BRL52537) and a mu-opioid agonist (morphine) on spontaneous motor activity in mice.
- To investigate the receptor subtypes and mechanisms underlying the observed motor effects of these opioid agonists.
Main Methods:
- Administration of various kappa- and mu-opioid agonists and their selective antagonists to male NMRI mice.
- Assessment of spontaneous motor activity, including rearing, motility, and locomotion, in both habituated and nonhabituated animals.
- Dopamine depletion and blockade of opioid receptors using specific antagonists (nor-binaltorphimine, DIPPA, naloxone, beta-funaltrexamine) to elucidate mechanisms.
Main Results:
- Higher doses of kappa-opioid agonists reduced motor activity and produced analgesia, blocked by kappa-opioid antagonists.
- Lower doses of kappa-opioid agonists dose-dependently increased motor activity, an effect sensitive to naloxone but not kappa-antagonists, and dependent on dopamine activity and habituation.
- Morphine's effects were dose-dependent, with initial suppression followed by stimulation, mediated by mu-opioid receptors.
Conclusions:
- Kappa-opioid agonists interact with at least two functional opioid receptor subtypes: a classic inhibitory receptor mediating analgesia and motor suppression at high doses, and a stimulatory, naloxone-sensitive receptor involved in motor activation under specific conditions.
- The stimulatory kappa-opioid effects are distinct from mu-opioid receptor-mediated effects and appear to involve a novel opioid receptor subtype that interacts with the dopaminergic system.