AMP-activated kinase and the endogenous endocannabinoid system might contribute to antinociceptive effects of prolonged moderate caloric restriction in mice

Abstract

BackgroundCaloric restriction is associated with broad therapeutic potential in various diseases and an increase in health and life span. In this study, we assessed the impact of caloric restriction on acute and inflammatory nociception in mice, which were either fed ad libitum or subjected to caloric restriction with 80% of the daily average for two weeks.ResultsThe behavioral tests revealed that inflammatory nociception in the formalin test and in zymosan-induced mechanical hypersensitivity were significantly decreased when mice underwent caloric restriction. As potential mediators of the diet-induced antinociception, we assessed genes typically induced by inflammatory stimuli, AMP-activated kinase, and the endocannabinoid system which have all already been associated with nociceptive responses. Zymosan-induced inflammatory markers such as COX-2, TNFα, IL-1β, and c-fos in the spinal cord were not altered by caloric restriction. In contrast, AMPKα2 knock-out mice showed significant differences in comparison to C57BL/6 mice and their respective wild type littermates by missing the antinociceptive effects after caloric restriction. Endocannabinoid levels of anandamide and 2-arachidonyl glyceroldetermined in serum by LC-MS/MS were not affected by either caloric restriction alone or in combination with zymosan treatment. However, cannabinoid receptor type 1 expression in the spinal cord, which was not altered by caloric restriction in control mice, was significantly increased after caloric restriction in zymosan-induced paw inflammation. Since increased cannabinoid receptor type 1 signaling might influence AMP-activated kinase activity, we analyzed effects of anandamide on AMP-activated kinase in cell culture and observed a significant activation of AMP-activated kinase. Thus, endocannabionoid-induced AMP-activated kinase activation might be involved in antinociceptive effects after caloric restriction.ConclusionOur data suggest that caloric restriction has an impact on inflammatory nociception which might involve AMP-activated kinase activation and an increased activity of the endogenous endocannabinoid system by caloric restriction-induced cannabinoid receptor type 1 upregulation.

Modulation of Endocannabinoids by Caloric Restriction Is Conserved in Mice but Is Not Required for Protection from Acute Kidney Injury

“…Notably, CR consisting of 80% of the daily intake for two weeks did not influence AEA levels of C57Bl6J mice in one previous study [ 38 ]. We assumed this difference to be the result of a more stringent CR protocol (i.e., a longer period of lower calorie intake in the study at hand).…”

“…Interestingly, the literature concerning dietary influences on AEA in humans is much more controversial than in rodents [ 38 ] or C. elegans [ 27 ]. Therefore, we analyzed human serum samples acquired before and after short-term CR in three independent cohorts.…”

Molecular Mechanisms and Pathophysiological Pathways of High-Fat Diets and Caloric Restriction Dietary Patterns on Pain

“…148 In addition to the standard CR regime, 2-week CR with 80% of average daily consumption reduced mechanical hypersensitivity in both the formalin test and the zymosan-induced paw inflammation model. 149 Researchers using transgenic mice found that the effects of CR in attenuating pain perception were related to activation of both AMPK signaling and the endogenous endocannabinoid system. 149 Moreover, a 3-month intermittent fasting diet (IFD) significantly reduced pain responses in mice in thermal and visceral pain models compared to the ad libitum control group.…”

“…149 Researchers using transgenic mice found that the effects of CR in attenuating pain perception were related to activation of both AMPK signaling and the endogenous endocannabinoid system. 149 Moreover, a 3-month intermittent fasting diet (IFD) significantly reduced pain responses in mice in thermal and visceral pain models compared to the ad libitum control group. 150 Expression levels of prodynorphin and κ-opioid receptors were upregulated.…”

Therapeutic opportunities for pain medicines via targeting of specific translation signaling mechanisms

“…AMPK activation in the CNS has also been linked to positive outcomes in chronic pain models with some of the most compelling evidence linking AMPK activation to enhance glutamate clearance via an astrocyte-mediated mechanism (Maixner et al, 2015). Finally, a very recent study has linked AMPK activation to the beneficial effects of exercise on chronic pain (King-Himmelreich et al, 2017). Collectively these studies point to a very positive outlook for the potential of developing potent and specific AMPK activators for the treatment of pain.…”