A great unmet need exists for pain therapies that are non-addictive and/or address pain that remains intractable to treatments available currently. Opiates, the most powerful drugs to treat pain, pose serious side effects and addictive potential; on the other hand, non-steroidal anti- inflammatory drugs (NSAIDs) are often ineffective in some types of pain. There is emerging evidence to suggest that ketogenic diets may alleviate pain. A ketogenic diet is a regimen that is high in fat and low in carbohydrates, like a strict Atkins diet. The carbohydrate restriction decreases glucose metabolism and promotes use of ketone bodies as energy in tissues such as brain and spinal cord, which induces a metabolic shift in those tissues. The ketogenic diet has shown proven clinical efficacy in epilepsy, even drug-refractory epilepsy, for many decades and demonstrated basic research potential for neuroprotection in several types of acute and chronic brain injuries and neurodegenerative conditions. A number of biochemical consequences of ketogenic diets all suggest that a ketogenic diet will be effective in elevating pain thresholds and reducing inflammatory pain. Our recent work shows that a ketogenic diet can reduce inflammation and reduce sensitivity to thermal pain in male rodents. Unfortunately, little work exists on this topic in female people or rodents, who/which have different pain sensitivity and different responses to analgesics than males; in addition, these variables change across the menstrual/estrous cycle. Our central hypothesis is that ketogenic diets will alleviate pain, particularly inflammatory pain, in female rodents in an estrous cycle stage-dependent manner. The present objective is to test the effects of ketogenic diets in acute pain (nocifensive behavior regarding heat;
Specific Aim 1), acute inflammatory pain (nocifensive behavior regarding intraplantar formalin;
Specific Aim 2), and persistent inflammatory pain (tactile allodynia and other behaviors after intraplantar complete Freund?s adjuvant;
Specific Aim 3) while monitoring estrous cycle stage and studying any effects of the ketogenic diet on characteristics of the estrous cycle itself. Testing our hypothesis in well-established animal models is feasible and may yield new therapeutic opportunities for pain relief and a new avenue for developing pain treatments that are both effective and non-addictive.

Public Health Relevance

Pain is common and debilitating, often without adequate treatment options and sometimes involving drugs with addictive potential. Evidence suggests that an established treatment for epileptic seizures ? a low carbohydrate ketogenic diet ? can provide relief in acute pain and inflammatory pain. This proposal will determine the effectiveness of a ketogenic diet in female rodents in well-characterized models of acute and inflammatory pain, identifying variations in pain sensitivity and ketogenic diet effectiveness across the estrous cycle.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
2R15AT008742-03
Application #
9591038
Study Section
Special Emphasis Panel (ZAT1)
Program Officer
Belfer, Inna
Project Start
2015-03-01
Project End
2021-06-30
Budget Start
2018-07-09
Budget End
2021-06-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Trinity College
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
069259950
City
Hartford
State
CT
Country
United States
Zip Code
Elamin, Marwa; Ruskin, David N; Masino, Susan A et al. (2018) Ketogenic Diet Modulates NAD+-Dependent Enzymes and Reduces DNA Damage in Hippocampus. Front Cell Neurosci 12:263
Ruskin, David N; Fortin, Jessica A; Bisnauth, Subrina N et al. (2017) Ketogenic diets improve behaviors associated with autism spectrum disorder in a sex-specific manner in the EL mouse. Physiol Behav 168:138-145
Ruskin, David N; Murphy, Michelle I; Slade, Sierra L et al. (2017) Ketogenic diet improves behaviors in a maternal immune activation model of autism spectrum disorder. PLoS One 12:e0171643
Kawamura, Masahito Jr; Ruskin, David N; Masino, Susan A (2016) Metabolic Therapy for Temporal Lobe Epilepsy in a Dish: Investigating Mechanisms of Ketogenic Diet using Electrophysiological Recordings in Hippocampal Slices. Front Mol Neurosci 9:112
Blaise, J Harry; Ruskin, David N; Koranda, Jessica L et al. (2015) Effects of a ketogenic diet on hippocampal plasticity in freely moving juvenile rats. Physiol Rep 3: