Patients diagnosed with obesity are prescribed opioid medications at a higher rate than the general population; however, it is not known if eating a high fat diet might impact individual sensitivity to these medications. To explore the hypothesis that eating a high fat diet increases sensitivity of rats to the effects of morphine, 24 female Sprague-Dawley rats (n = 8/diet) ate either a standard (low fat) laboratory chow (17% kcal from fat), a high fat/low carbohydrate (ketogenic) chow (90.5% kcal from fat), or a traditional high fat/high carbohydrate chow (60% kcal from fat). Morphine-induced antinociception was assessed using a warm water tail withdrawal procedure, during which latency (in seconds) for rats to remove their tail from warm water baths was recorded following saline or morphine (0.32–56 mg/kg, i.p.) injections. Morphine was administered acutely and chronically (involving 18 days of twice-daily injections, increasing in 1/4 log dose increments every 3 days: 3.2–56 mg/kg, i.p., to induce dependence and assess tolerance). The adverse effects of morphine (i.e., tolerance, withdrawal, and changes in body temperature) were assessed throughout the study. Acute morphine induced comparable antinociception in rats eating different diets, and all rats developed tolerance following chronic morphine exposure. Observable withdrawal signs and body temperature were also comparable among rats eating different diets; however, withdrawal-induced weight loss was less severe for rats eating ketogenic chow. These results suggest that dietary manipulation might modulate the severity of withdrawal-related weight loss in ways that could be relevant for patients.

Eating a high fat/low carbohydrate (ketogenic) or a traditional high fat/high carbohydrate diet did not impact the pain-relieving or adverse effects of opioids (i.e., tolerance or withdrawal) in female rats. However, eating a ketogenic diet may have beneficial effects on opioid withdrawal-related weight loss. Individuals diagnosed with obesity taking opioids for pain-related conditions might therefore consider adopting a ketogenic diet when opioid administration is discontinued to potentially mitigate withdrawal-related weight loss.

This work was supported in part by grants from National Institutes of Health National Institute of General Medical Sciences [Grants RL5GM118969, TL4GM118971, and UL1GM118970 (to M.K.E. and J.C.) and R16 GM149426-01]; National Institutes of Health National Institute on Drug Abuse [Grant R25DA033613] (to K.M.S., A.P.S., and A.N.P.); and National Institute on Drug Abuse Research Centers in Minority Institutions [Grant 3U54MD007592-29S4] (to K.M.S.).

No author has an actual or perceived conflict of interest with the contents of this article.

dx.doi.org/10.1124/jpet.124.002188.