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Involvement of the opioid system in the anxiolytic effect of diazepam in mice
1Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan.
Abstract:
In the present study, the anticonflict effect of diazepam was significantly abolished by pretreatment with naloxone, beta-funaltrexamine or nor-binaltorphimine but not naltrindole, using a Vogel-type conflict paradigm in mice. However, naloxone alone had a significant proconflict effect, and beta-funaltrexamine alone tended to produce a proconflict effect. Spontaneous drinking behavior was not affected by treatment with diazepam and nor-binaltorphimine. In addition, nor-binaltorphimine had no effect on diazepam-induced motor incoordination, hypothermia or anticonvulsant action, respectively. Moreover, the stable dynorphin analog E2078 ([N-methyl-Tyr1, N-alpha-methyl-Arg7-D-Leu8]dynorphin A-(1-8) ethylamide) and the highly selective kappa-opioid receptor agonist U50,488H (trans-3,4-dichloro-N-(2-(1-pyrrolidinyl)cyclohexyl)benzenacetamide++ + methanesulfonate hydrochloride) produced a significant anticonflict effect, which was completely antagonized by pretreatment with nor-binaltorphimine. These findings suggested that the kappa-opioid system may play an important role in the anxiolytic effect of benzodiazepine and the regulation of anxiety.
Insights
The kappa-opioid system influences benzodiazepine
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Benzodiazepines are commonly prescribed for anxiety.
- The role of opioid systems in anxiety regulation is not fully understood.
Purpose of the Study:
- To investigate the involvement of the kappa-opioid system in the anxiolytic effects of diazepam.
- To explore the interaction between benzodiazepines and opioid receptors in anxiety.
Main Methods:
- Utilized a Vogel-type conflict paradigm in mice.
- Administered diazepam alone and in combination with opioid receptor antagonists (naloxone, beta-funaltrexamine, nor-binaltorphimine, naltrindole).
- Assessed the effects of kappa-opioid receptor agonists (E2078, U50,488H) and their interaction with nor-binaltorphimine.
Main Results:
- Diazepam's anticonflict effect was blocked by naloxone, beta-funaltrexamine, and nor-binaltorphimine, but not naltrindole.
- Kappa-opioid receptor agonists (E2078, U50,488H) demonstrated anxiolytic effects.
- Nor-binaltorphimine antagonized the anticonflict effects of kappa-opioid agonists.
- Naloxone alone showed a proconflict effect, while beta-funaltrexamine tended towards a proconflict effect.
Conclusions:
- The kappa-opioid system plays a significant role in mediating the anxiolytic effects of benzodiazepines.
- This system is implicated in the regulation of anxiety.
- Findings suggest potential therapeutic targets for anxiety disorders by modulating the kappa-opioid system.
