Role of the neurosteroid allopregnanolone on exercise-induced hypoalgesia in aged rats
Introduction: A variety of exercise is known beneficial for pain reduction, this phenomenon is denominated Exercise-Induced Hypoalgesia. Since the exercise is a non-pharmacological intervention with minimum adverse effects and also helps maintaining functional activity, EIH may be more appropriate for the elderly. However, the underlying mechanisms especially for aged individuals remains under-investigated. The neurosteroid allopregnanolone (ALLO) is reported to exert anti-nociceptive effect. Furthermore, the ALLO production in the brain increases with exercise and decreases with aging. In the present study, we examined the age-related change and the potential role of ALLO on experimental EIH in rats.
Material and Methods: All experimental procedures on animals were approved by the Institutional Animal Care and Use Committee of the Kochi Medical School. Adult (2-4 months) and aged (20-25 months) rats were randomly divided into one of three groups; non-exercise control, Low-exercise, and High-exercise group (n=12 in each group). The animals in Low- and High-exercise group were subjected to 3 minutes treadmill workout at 20% and 80% maximum oxygen intake intensity, respectively. Pain sensitivity was evaluated the percentage of withdrawal responses to a train of 30 mechanical stimuli with 60-g von Frey filament on the hind paw before and 5, 10, 15, 20, 25 and 30 minutes after exercise. In another pharmacological experiment, the involvement of ALLO in EIH was tested by Medroxy-progesterone (MDP), an ALLO production inhibitor in aged rats. Furthermore, the levels of ALLO in the brain before and after Low-exercise was measured using gas chromatography in both adult and aged rats (n=6 in each point). Differences between the data sets were evaluated by performing repeated-measure one-way analysis of variance test, followed by Bonferroni post hoc tests. Results with p<0.05 were considered statistically significant.
Results: In Low-exercise groups, EIH was not observed in adult rats. However, in aged animals, the withdrawal response rate in exercise group were significantly decrease at 5 and 10 minutes after exercise compared to control (Figure1). The pre-treatment with MDP almost completely suppressed the Low-exercise induced EIH in aged rats, while it showed no effect in control animals. In control groups, the brain levels of ALLO in aged rats was significantly lower than that in adult rats. Furthermore, the ALLO levels significantly increased after Low-exercise in aged rats, whereas significant changes was not observed in adult animals. On the other hand, in High-exercise groups, the withdrawal response rate decreased at 5 and 10 minutes after exercise in adult rats, whereas the EIH was only at 5 minutes after exercise in aged rats. The High-exercise induced EIH in both adult and aged rats was not influenced by the pre-treatment with MDP.
Conclusion: Our results showed that, unlike with adult rats, EIH could be induced by mild exercise in aged animals. Our fidings further indicated that the increase in the brain ALLO may contribute to the development of Low-exercise induced EIH in aged rats.