ABSTRACT
BACKGROUND: The opioid peptide beta-endorphin (beta-E) is synthesized and released in response to stressful stimuli as well as acute alcohol administration. The release of beta-E following exposure to an inescapable aversive situation may mediate behaviors that contribute to allostasis of the stress response. The present study examines the effects of beta-E on immobility in assays involving inescapable stress, both under basal conditions and after acute administration of EtOH. METHODS: Female and male transgenic mice with varying capacities to translate beta-E were subjected to either the forced swim (FST, Experiment 1) or the tail suspension test (TST, Experiment 2). In Experiment 3, mice were divided into three groups based on hormonal status (male, female-estrous, and female-nonestrous) and injected with either 1 g/kg EtOH or equivolume saline 14 minutes prior to behavioral assessment on the TST. RESULTS: Experiments 1 and 2 demonstrated a direct relationship between beta-E levels and immobility. There were also sex differences in behavior in these tests, with males displaying more immobility than females. A main effect of genotype in Experiment 3 replicated findings in Experiments 1 and 2. There was also an effect of EtOH (increasing immobility) and a significant interaction reflecting a particularly robust effect of the drug in mice with low beta-E. In addition, there were interactions between beta-E, EtOH effects, and hormonal status. CONCLUSIONS: These findings support the contention that beta-E moderates behavioral responses to stressful stimuli and suggest a role for this peptide in coping behavior. Furthermore, the effects of EtOH on the response to stress may be mediated by beta-E. Sex differences in this influence may contribute to sex differences in disease susceptibility and expression.
Subject(s)
Behavior, Animal/physiology , Depression/physiopathology , Ethanol/pharmacology , Hindlimb Suspension/psychology , Stress, Psychological/physiopathology , Stress, Psychological/psychology , beta-Endorphin/physiology , Adaptation, Psychological/physiology , Animals , Central Nervous System Depressants/pharmacology , Female , Male , Mice , Mice, Transgenic , Models, Animal , Sex Characteristics , beta-Endorphin/geneticsABSTRACT
RATIONALE: The opioid peptide beta-endorphin (beta-E) is synthesized by the pro-opiomelanocortin gene in response to environmental stressors and alcohol administration and is implicated in the behavioral sequelae associated with these stimuli. OBJECTIVES: We sought to determine the influence of beta-E on the stress response by evaluating basal measures of anxiety as well as on EtOH-induced anxiolytic behavior using transgenic mice that differ with respect to beta-E. METHODS: Anxious behavior was evaluated for male and female heterozygous, wild-type, and beta-E knockout mice using the Light-Dark Box and Plus Maze assays. Subsequent tests evaluated behavior 20 min after administration of intraperitoneal saline or EtOH (0.5, 1.0, and 1.5 g/kg). RESULTS: We observed a direct relationship between beta-E levels and the percentage of entries into open arms of the Plus Maze as well as the time spent in either the open arms or the light compartment of the Light-Dark box during basal conditions, suggesting that this peptide normally inhibits anxious behavior. However, mice lacking beta-E demonstrated an exaggerated anxiolytic response to EtOH in these assays. CONCLUSIONS: These data suggest that beta-E moderates the response to stressful stimuli and supports the hypothesis that this peptide influences the behavioral effects of EtOH.
Subject(s)
Anxiety/chemically induced , Behavior, Animal/drug effects , Ethanol/toxicity , beta-Endorphin/metabolism , Animals , Anxiety/physiopathology , Darkness , Dose-Response Relationship, Drug , Ethanol/administration & dosage , Female , Heterozygote , Injections, Intraperitoneal , Light , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , beta-Endorphin/geneticsABSTRACT
NMDA (N-methyl-d-aspartate) antagonists are known to enhance the analgesic effects of opioids. However, virtually, all studies of this phenomenon have been done using male subjects. Here, the noncompetitive NMDA receptor antagonist dextromethorphan (DEX) was tested over a range of doses (10-200 microg intracerebroventricularly [i.c.v.]) in male and female Swiss Webster mice in combination with 5 mg/kg intraperitoneal (i.p.) morphine. Males exhibited enhanced morphine analgesia following either 100 or 200 microg DEX, but there was no evidence of DEX-mediated potentiation in females at any dose. Instead, DEX attenuated morphine analgesia in females. We also evaluated the effect of 100 microg i.c.v. DEX with different doses of morphine (1, 5 and 10 mg/kg). Again, DEX significantly enhanced morphine analgesia in male mice and attenuated it in females. Next, ovariectomized (OVX) female mice were compared to males following 5 mg/kg i.p. morphine and 100 microg i.c.v. DEX. Male and OVX females exhibited equivalent maximal levels of analgesia following administration of DEX. Morphine analgesia was not enhanced by DEX in sham-treated females and OVX mice with estradiol treatment (5 microg i.p. once daily for 7 days) also did not show DEX enhancement. These experiments demonstrate that the ability of NMDA receptor antagonists to potentiate morphine analgesia is modulated by an estrogen-sensitive mechanism and suggest that sex differences may play a critical role toward a more general understanding of the potentiation of opioid-induced analgesia through NMDA receptor antagonists.
