Analgesic effect of oxytocin in alcohol-dependent male and female rats

Introduction

Chronic alcohol exposure in humans and rodents causes tolerance to the analgesic effects of alcohol, and enhances pain sensitivity during alcohol withdrawal (i.e., hyperalgesia). The available literature suggests a bidirectional enhancement between chronic alcohol consumption and chronic pain sensitivity. We previously found that oxytocin administration could reduce alcohol consumption in alcohol-dependent rats, and now hypothesize that oxytocin, through analgesic action in the central nervous system, could ameliorate the hyperalgesia induced by alcohol-dependence. To test this hypothesis, we assessed the ability of central and peripheral oxytocin administration to alter thermal (Hargreaves assay) and mechanical (Von Frey assay) pain sensitivity, in male and female rats, made alcohol dependent through repeated cycles of chronic-intermittent ethanol-vapor exposure (CIEV; compared to air-exposed controls).

Methods

Male and female cohorts of Wistar rats were surgically prepared with an ICV cannula and assigned to two groups matched in terms of initial response in the Hargreaves assay. Rats in the alcohol dependent group were exposed to chronic-intermittent alcohol-vapor, while air-exposed control rats were exposed only to room air and served as the control group. The thermal nociception sensitivity of all rats was monitored via weekly Hargreaves assay to determine alcohol-dependence-induced hyperalgesia in dependent rats. Next, rats were ICV administered oxytocin (0, 0.5, or 5 μg in 2.5 μL saline) prior to Hargreaves testing (Experiment 1) or Von Frey testing (Experiment 2). Finally, rats were IP administered oxytocin (0, 0.1, or 1 mg/kg) prior to Hargreaves testing (Experiment 3) or Von Frey testing (Experiment 4). In a follow-up experiment, female rats were tested to directly compare three methods for applying the Von Frey test.

Results

Male and female alcohol-dependent rats developed hyperalgesia, observed in the Hargreaves assay (Experiment 1 & 3), however, hyperalgesia was not so readily observed when the same rats were tested in the Von Frey assay (Experiments 2 & 4, with the exception of female rats in Experiment 4; follow-up testing indicated that the method of Von Frey test employed is likely important to explain this discrepancy). In both the Hargreaves and Von Frey assays, and in both male and female rats, following central or peripheral administration, oxytocin produced analgesia similarly in both alcohol dependent rats and air-exposed controls.

Conclusion

Together, these data suggest the oxytocin system could be targeted to produce therapeutic action in disease that produce hyperalgesia such as in alcohol dependence. We discuss methodological considerations and future experiments that could further elucidate a role for oxytocin in the overlapping neurobiology of alcohol dependence and chronic pain.