Ketogenic diets and thermal pain: dissociation of hypoalgesia, elevated ketones, and lowered glucose in rats [post-print]

Ketogenic diets are high-fat, low-carbohydrate formulations effective in treating medicallyrefractory epilepsy, and recently we demonstrated lowered sensitivity to thermal pain in rats fed a ketogenic diet for 3-4 weeks. Regarding anticonvulsant and hypoalgesic mechanisms, theories are divided as to direct effects of increased ketones and/or decreased glucose, metabolic hallmarks of these diets. To address this point, we characterized the time course of ketogenic diet-induced thermal hypoalgesia, ketosis, and lowered glucose in young male rats fed ad libitum on normal chow or ketogenic diets. A strict 6.6:1 (fat:(carbohydrates + protein), by weight), ketogenic diet increased blood ketones and reduced blood glucose by two days of feeding, but thermal hypoalgesia did not appear until 10 days. Thus, ketosis and decreased glucose are not sufficient for hypoalgesia. After feeding a 6.6:1 ketogenic diet for 19 days, decreased thermal pain sensitivity and changes in blood chemistry reversed one day after return to normal chow. Effects on were consistent between two different diet formulations: a more moderate and clinically-relevant ketogenic diet formula (3.0:1) produced hypoalgesia and similar changes in blood chemistry as the 6.6:1 diet, thus increasing translational potential. Furthermore, feeding the 3.0:1 diet throughout an extended protocol (10-11 weeks) revealed that significant hypoalgesia and increased ketones persisted whereas low glucose did not, demonstrating that ketogenic dietinduced hypoalgesia does not depend on reduced glucose. In separate experiments we determined that effects on thermal pain responses were not secondary to motor or cognitive changes. Together, these findings dissociate diet-related changes in nociception from direct actions of elevated ketones or decreased glucose, and suggest mechanisms with a slower onset in this paradigm. Overall, our data indicate that metabolic approaches can relieve pain. M AN US CR IP T AC CE PT ED ACCEPTED MANUSCRIPT 3