Abstracts

Rationale: Ketogenic diets are high-fat, low-carbohydrate formulations proven highly effective in treating epilepsy, and recently we demonstrated lowered sensitivity to thermal pain in juvenile and adult rats fed a ketogenic diet for 3 weeks (Ruskin et al., 2009). Regarding anticonvulsant and hypoalgesic mechanisms, theories are divided as to direct effects of increased ketones and/or mild hypoglycemia, metabolic hallmarks of these diets. To address this point, we characterized the time course of ketogenic diet-induced hypoalgesia, ketosis, and hypoglycemia. Methods: Recently-weaned rats were fed ad libitum either a normal (control) or ketogenic diet either a highly restrictive formulation (6.8:1 ratio of fat:(protein+carbohydrate)) or a more clinically-relevant formulation (3.1:1). At multiple time points on the diets (up to 70 days), blood chemistry was quantified (levels of the ketone body beta-hydroxybutyrate and glucose) and behavioral sensitivity to thermal pain was assessed. Blood chemistry and behavior were also quantified after reverting to a normal diet for 24 hours. Results: Ketogenic diets increased blood ketones and decreased blood glucose similarly and significantly within 2 days. In daily tests within 6 days of 6.8:1 ketogenic diet feeding there was no difference in the behavioral response to thermal pain as assessed by hotplate testing, whereas 7 or 14 days of 6.8:1 diet administration increased latencies to nocifensive behavior significantly. Thus, we found a hypoalgesic effect, similar to what we have observed previously, which was delayed compared to ketosis and hypoglycemia. All ketogenic diet-induced changes in blood chemistry and behavioral responses reversed within a day after return to control diet. Feeding a 3.1:1 ketogenic diet for either 14 or 70 days also produced significant hypoalgesia, but at 70 days hypoglycemia was no longer present, showing that hypoalgesia does not depend on hypoglycemia. Conclusions: These findings demonstrate a consistent hypoalgesic effect of ketogenic diets, dissociate changes in nociception from direct actions of elevated ketones or reduced glucose, and suggest mechanisms with a slower onset in this paradigm. Overall, our data indicate that metabolic approaches, like a ketogenic diet, can relieve pain.