Morphine-Induced Tolerance Is Reduced by the Consumption of a Ketogenic Diet, but Not a High Fat/High Carbohydrate Diet
Opioid drugs like morphine are used medicinally for pain relief, but also have abuse liability that can lead to opioid use disorder (OUD), which contributes to nearly 70% of drug overdose deaths in the United States. Another rising health concern is the global obesity epidemic, and new evidence suggests that obesity and OUD might converge to impact individuals. For example, high body mass index (BMI) is associated with greater reports of pain among women. Further, opioid overdose risk is increased among individuals diagnosed with obesity, suggesting a potential relationship that might convey enhanced vulnerability among some populations. Given the high rates of obesity and pain-related conditions among women, in this study, 24 female rats (n=8/diet) eating either standard chow (17% kcal from fat), high fat chow (60% kcal from fat), or ketogenic chow (90.5% kcal from fat) were tested with cumulative doses morphine using a warm water tail withdrawal procedure to measure antinociception examined acutely (0.32 – 17.8 mg/kg; IP) and after 19-days of twice daily injections to assess for tolerance (3.2 – 56 mg/kg, IP). After chronic morphine administration, morphine was discontinued, and non-precipitated withdrawal signs were observed in rats for 5 days. Body weight, food consumption, and the adverse effects of morphine (e.g., fecal output, respiratory depression, body temperature) were recorded periodically throughout the study. It was hypothesized that rats eating high fat chow would be more sensitive to morphine-induced antinociception, tolerance following chronic administration, adverse effects of morphine (such as respiratory depression), and withdrawal following discontinuation of morphine, as compared to rats eating a ketogenic or standard chow. However, the antinociceptive effects of morphine tested during acute conditions did not differ among rats eating different diets. When tested during chronic administration, all rats developed tolerance to the antinociceptive effects of morphine; however, this effect was greater among rats eating standard chow and high fat chow, as compared to rats eating ketogenic chow. The adverse effects of morphine (e.g., fecal output, respiration, and body temperature) were not different among rats eating different diets. Finally, observable withdrawal signs following morphine discontinuation was also not different between groups; however, rats eating ketogenic chow experience less withdrawal-related weight loss than other groups. These results demonstrate that while most of the effects of morphine are not altered by dietary intake, tolerance to the pain relieving effects of opioid drugs might not develop as severely for individuals eating a ketogenic diet. This might mean that patients taking opioids chronically for pain management should consider adopting a ketogenic diet to reduce the risk of tolerance, and therefore reduce the need to increase the dose of their pain medication over time.
Beltran, Nina M, "Morphine-Induced Tolerance Is Reduced by the Consumption of a Ketogenic Diet, but Not a High Fat/High Carbohydrate Diet" (2022). ETD Collection for University of Texas, El Paso. AAI30242445.