Ketogenic Diets and Thermal Pain: Dissociation of Hypoalgesia, Elevated Ketones, and Lowered Glucose in Rats

Abstract

Ketogenic diets are high-fat, low-carbohydrate formulations effective in treating medically-refractory 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 diet-induced 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.

Ketogenic Diets and Pain

“…This outcome was in clear contrast to rats, where the same diet produces these effects reliably. 22, 23 Other mouse strains might produce different results with the hotplate test. Similarly, other tests of thermal pain might be useful to explore diet-induced changes 25 and could further illuminate species differences.…”

“…2A). 23 Therefore, simply raising blood ketones and lowering blood glucose is not sufficient to produce hypoalgesia. This result seems to rule out a mechanism involving, for instance, direct acute effects of ketones on molecular targets underlying thermal pain sensitivity.…”

“…In addition we used rats, an animal model with positive results regarding ketogenic diets and pain. 22, 23 Finally, in this study we tested two ketogenic diets of differing strength.…”

Dietary Influence on Pain via the Immune System

“…Subsequent work by Ruskin and colleagues has found that various ketogenic diet formulations resulted in less sensitivity in hot plate tests between 49 and 51°C. 165,166 These authors also noted a reduction in CFA-induced edema in the paw, though allodynia was never measured. 165 However, ketogenic diets were shown to have no effect on neuropathic pain induced by sciatic nerve constriction or paclitaxel injection.…”

Laboratory environmental factors and pain behavior: the relevance of unknown unknowns to reproducibility and translation

“…Failure to provide bedding material for a rat to make a nest for her pups can lead to hyperalgesia in those pups when they become adults 55,56 , and the handling of young animals (for example, related to injections, and involving the stress of maternal separation) can cause long-term alterations in pain sensitivity 41,[57][58][59][60][61][62][63] . A growing literature also documents the effect of diet on pain sensitivity [64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80] . In one case, differences in the soy content of rat chow turned out to be wholly responsible for a failure to replicate in Baltimore the findings of studies originally performed in Jerusalem 65 .…”