Daily Intermittent Fasting in Mice Enhances Morphine Induced Anti‐Nociception while Mitigating Multiple Side Effects

Abstract

The opioid epidemic has continued to plague the United States with high levels of abuse and poor quality of life for chronic pain patients requiring continuous use of opioids. Many potential solutions have been proposed to mitigate this epidemic including new medications to reduce the abuse and side effect profiles of opioids; however, new medications are plagued by low efficacy, abuse potential, and toxicities. These limitations suggest that non‐pharmacological interventions could be more efficacious with low side effect profiles. Intermittent fasting (IF) is a time restriction diet which has recently grown in popularity over the past decade in the prevention and mitigation of a variety of pathological states. Numerous animal and human studies have shown the benefits of IF in these disease states, but not in opioid treatment paradigms. We thus subjected male and female CD1 mice to 18‐hour fasting intervals followed by 6‐hour feed periods with standard chow for 1 week. Mice which underwent this diet displayed an enhanced anti‐nociceptive response to systemic morphine both in efficacy and duration using thermal tail flick and post‐operative paw incision pain models. While showing enhanced anti‐nociception, IF mice also demonstrated a reduction in the development of anti‐nociceptive tolerance using the thermal tail flick assay paired with daily systemic morphine treatment. We also found a reduction in the development of opioid induced constipation using both fecal mass and fecal pellet count in IF mice. Seeking a mechanism for our behavioral findings, we performed 35S‐GTPγS assays to assess the functionality of mu opioid receptors within the spinal cord and periaqueductal grey (PAG) tissues from IF mice with and without chronic morphine treatment. The resulting DAMGO concentration‐response curves demonstrated an increased efficacy of mu opioid receptors within the spinal cord in IF mice and an absence of the development of tolerance within the PAG in IF mice, suggesting site‐specific receptor mechanisms for the behavioral effects we observed. These data suggest that a daily IF diet may improve the therapeutic index of acute and chronic opioid therapies for pain patients in the clinic, both in improved analgesia and reduced tolerance and constipation.