Role of delta-opioid receptor subtypes in anxiety-related behaviors in the elevated plus-maze in rats.

Rationale: Recent studies have shown that endogenous opioid systems are associated with the regulation of emotional responses. In particular, it has been reported that delta-opioid receptors act naturally to inhibit stress and anxiety.

Objective: The present study was designed to examine the possible involvement of opioid delta-receptor subtypes in the anxiety-related behavior in the elevated-plus-maze test.

Methods: Six-week-old male Lewis rats were used. The total numbers of visits to the closed and open arms and the cumulative time spent and visits in the open arms were determined. Plasma corticosterone levels were measured by enzyme immunoassay.

Results: Naltrindole (NTI), a delta-opioid receptor antagonist (3 mg/kg s.c.), induced a significant decrease in the percentages of time spent and visits in the open arms. Naltriben (NTB), a delta2-opioid receptor antagonist (3 mg/kg s.c.), but not 7-benzylidenenaltrexone, a delta1-opioid receptor antagonist, produced similar anxiety-related behaviors in the elevated plus-maze. These effects of NTI and NTB were antagonized by pretreatment with (+)-4-[(aR)-a-((2S,5R)-4-allyl-2,5-dimethyl-1piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80), a delta-opioid receptor agonist. Furthermore, after exposure to the elevated plus-maze, the maximal increase in the plasma corticosterone level in NTI-treated rats was clearly higher than that in vehicle-treated rats. However, when NTI and SNC80 were coadministered, higher levels of plasma corticosterone were not seen after exposure to the elevated plus-maze.

Conclusion: These results suggest that endogenous delta2-opioid-receptor-mediated systems are involved in the regulation of anxiety-related behaviors and might play a physiologically important role in the regulation of adrenocortical activity.