Date of Award

2025-05-01

Degree Name

Doctor of Philosophy

Department

Psychology

Advisor(s)

Katherine M. Serafine

Abstract

Introduction: Opioid drugs (e.g., morphine) are used medicinally for pain relief but can also lead to opioid use disorder (OUD). These medications are prescribed at a higher rate among individuals with obesity (who might consume high fat diets) than the general population. Further, previous work from our lab and others has demonstrated that eating a high fat diet enhances sensitivity of rats to other addictive substances, including stimulants. However, it is not known if dietary manipulations impact individual sensitivity to the effects of opioids. This dissertation systematically explored the effects of dietary manipulation on sensitivity to the effects of morphine. Aim 1 evaluated behavioral sensitivity to acute and chronic morphine among rats eating different diets and Aim 2 evaluated the effects of dietary manipulations and chronic morphine on metabolic factors, stress, and sex hormones using behavioral and physiological methods. It was hypothesized that eating a high fat/high carbohydrate diet would increase tolerance to morphine's antinociceptive effects and that eating a ketogenic diet would reduce withdrawal severity. It was further hypothesized that food restriction would enhance tolerance and have no effect on withdrawal severity as compared with rats with free access to diets. Finally, we hypothesized that these expected diet-induced differences in opioid tolerance and withdrawal would be mediated by diet-induced alterations in metabolic markers, as well as sex and stress hormones. Methods: Male Sprague-Dawley rats (n=7-8 per dietary group used in both aims) were randomly assigned to either free or restricted access to a low fat chow, a high fat/high carbohydrate chow, or a high fat/low carbohydrate (ketogenic) chow. Rats were injected with saline or doses of morphine (0.32-56 mg/kg, IP) to assess nociception, antinociception, and tolerance over a 6-week period using the warm water tail withdrawal procedure. To assess hyperalgesia, paw biting was measured immediately after warm water tail withdrawal procedures during the bottle brush test. To assess withdrawal following chronic morphine administration, naltrexone (17.8 mg/kg, SC) was administered to precipitate withdrawal, and up to 14 withdrawal signs (i.e., wet dog shake, ptosis, teeth chattering, paw tremors, chromodacryorrhea, lacrimation, and diarrhea) and weight loss were observed. To assess reward, sensitization was measured from morphine-induced locomotor activity (0.32-10 mg/kg, IP). To assess constipation (using a separate group of rats; n=8/group), fecal boli were measured hourly for 6 hours following an injection of saline or morphine (1, 3.2, or 10 mg/kg, IP) in rats with free access to a low fat chow, a high fat/high carbohydrate chow, or a ketogenic chow. To assess affective pain, facial coding of grimace features was measured using the Rat Grimace Scale (RGS), and to assess stress, aggressive and defensive behaviors were measured using the bottle brush test. Testosterone, corticosterone, ketones, and leptin were measured from serum using ELISA kits. Results: There were no dietary group differences in the antinociceptive effects of acute morphine; however, rats with free access to high fat/high carbohydrate chow developed greater tolerance to the antinociceptive effects of morphine as compared to the other dietary groups. In contrast, morphine-induced hyperalgesia was increased among rats with restricted access to high fat/high carbohydrate chow or restricted access to ketogenic chow than rats with free access to low fat chow. Naltrexone precipitated withdrawal in all rats; however, rats with free or restricted access to ketogenic chow displayed fewer withdrawal signs and lost less withdrawal-related body weight than rats with free access to low fat chow. Further, rats with free access to a high fat/high carbohydrate or ketogenic chow regained weight at a faster rate than the other dietary groups. Further, there were no dietary group differences regarding morphine-induced locomotion, and sensitization was observed at only one test. Morphine induced constipation in all groups; however, rats with access to a high fat/high carbohydrate or ketogenic chow produced less feces than rats with access to a low fat chow following injections of saline or morphine. There were no meaningful dietary group differences in aggressive or defensive behaviors, RGS scores, or grooming behavior; however, defensive and RGS scores were greater for all rats during chronic morphine and withdrawal testing as compared to acute morphine testing. Rats with restricted access to chows had smaller concentrations of testosterone than rats with free access; however, corticosterone concentrations were comparable among rats eating different diets. Rats with free access to high fat/high carbohydrate chow or ketogenic chow had significantly greater leptin concentrations than the other dietary groups. Further, rats with free or restricted access to ketogenic chow had significantly greater concentrations of β-hydroxybutyrate than the other dietary groups. Conclusion: These results demonstrate that dietary factors can impact the effects of morphine, including tolerance, hyperalgesia, constipation, and withdrawal severity. Further, these data suggest that eating a high fat/high carbohydrate diet enhances opioid tolerance, whereas a ketogenic diet mitigates the severity of morphine withdrawal. These results have implications for considering nutritional factors when developing personalized pain management strategies to reduce risk factors associated with OUD.

Language

en

Provenance

Received from ProQuest

File Size

114 p.

File Format

application/pdf

Rights Holder

Nina Marie Beltran

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