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Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
Modification of morphine sensitization by opioid and dopamine receptor antagonists: evaluation by studying ambulation
1Department of Neurobiology and Behavior, Gunma University School of Medicine, Maebashi, Japan.
Abstract:
The repeated administration of morphine (10 mg/kg s.c.) at 3- to 4-day intervals caused sensitization to its ambulation-increasing effect. A mu-opioid receptor antagonist naloxone (0.03-1 mg/kg s.c.), and dopamine D1 and D2 receptor antagonists SCH 23390; R-(+)-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine HCl (0.01-0.1 mg/kg s.c.) and YM-09151-2 (nemonapride); cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4- methylaminobenzamide (0.003-0.1 mg/kg s.c.), respectively, dose dependently reduced the ambulation increase caused by morphine as well as the sensitization to morphine, when one of them was combined with morphine in the repeated administration. Treatment with SCH 23390 or YM-09151-2, but not naloxone, 3 h after each morphine administration tended to enhance the morphine sensitization. Furthermore, when YM-09151-2 (0.1 mg/kg) was repeatedly administered to the morphine-naive mice 5 times at 3- to 4-day intervals, these mice showed a significant increase in morphine sensitivity. Although the morphine sensitization was partially reversible, repeated (5 times) treatment of the morphine-sensitized mice with SCH 23390 (0.1 mg/kg) resulted in a further enhancement in morphine sensitivity. The same treatment with YM-09151-2 (0.03 and 0.1 mg/kg) tended to increase the sensitivity. These results suggest that, in terms of ambulation in mice, an enhancement of dopaminergic neurotransmission through the agonistic action on mu-opioid receptors is responsible for induction of morphine sensitization.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Repeated morphine administration sensitizes mice to its effects. Dopamine receptor antagonists partially reversed this, while blocking dopamine after morphine enhanced sensitization, suggesting dopamine
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Repeated morphine administration can lead to sensitization, an increase in drug effect with repeated exposure.
- The precise mechanisms underlying morphine sensitization, particularly the role of dopaminergic pathways, require further elucidation.
Purpose of the Study:
- To investigate the role of mu-opioid and dopamine D1/D2 receptors in morphine-induced sensitization of ambulation in mice.
- To explore the impact of dopamine receptor antagonists on the development and reversal of morphine sensitization.
Main Methods:
- Mice received repeated subcutaneous administrations of morphine (10 mg/kg) at 3- to 4-day intervals to induce sensitization.
- The effects of co-administered mu-opioid (naloxone) and dopamine D1/D2 receptor antagonists (SCH 23390, YM-09151-2) on morphine-induced ambulation and sensitization were assessed.
- The impact of administering dopamine antagonists after morphine, or repeatedly to naive mice, on subsequent morphine sensitivity was also examined.
Main Results:
- Repeated morphine administration led to sensitization of its ambulation-increasing effect.
- Dopamine D1 and D2 receptor antagonists, but not a mu-opioid antagonist, dose-dependently reduced morphine-induced ambulation and sensitization when co-administered.
- Administering dopamine antagonists after morphine, or repeatedly to naive mice, enhanced subsequent morphine sensitivity, indicating a role for dopamine in the induction and maintenance of sensitization.
Conclusions:
- Dopaminergic neurotransmission plays a crucial role in the induction of morphine sensitization.
- Enhancement of dopaminergic activity, possibly downstream of mu-opioid receptor agonism, is implicated in the development of morphine sensitization.
- Targeting dopaminergic pathways may offer strategies for modulating opioid-induced behavioral plasticity.
