Sexually Dimorphic Effects of Nociceptor LKB1 on Mitochondrial Metabolism and Mechanical Allodynia After Fasting

Abstract

BackgroundPain induces metabolic stress in pain sensing neurons (nociceptors); alleviating this stress represents an avenue for treating pain. Liver kinase B1 (LKB1) is involved in maintaining energy homeostasis and is a key mediator of the cellular response to metabolic stress. If cellular energy modulation and pain relief is LKB1‐dependent, then its removal could lead to metabolic imbalance and innocuous stimuli becoming painful (allodynia).HypothesisIn a novel mouse transgenic model where LKB1 is removed from Nav1.8+ nociceptors (Nav1.8LKB1‐), we predict nociceptors will have reduced abilities to cope with metabolic stress, leading to energy imbalance and subsequent allodynia.MethodsAfter baselining for mechanical allodynia, animals were fasted for 24hr to induce metabolic stress. A subset of animals had their primary dorsal root ganglia nociceptors cultured for 6 hours for the Seahorse MitoStress assay. The remainder of animals were tested for mechanical allodynia once a day for 5 days after food was returned.ResultsAs expected, a 24hr fast induced mechanical allodynia in a genotype dependent manner, with Nav1.8LKB1‐ animals responding to the fast in a sexually dimorphic manner. While fasting initially caused allodynia in males of both genotypes, Nav1.8LKB1‐ animals took longer to recover. However, in females, only Nav1.8LKB1‐animals exhibited allodynia after fasting. A sexually dimorphic and genotype dependent effect was also seen in neuronal mitochondrial function. In control females, fasting increased neuronal oxidative metabolism, suggesting the LKB1 pathway is necessary to mitigate fasting‐induced energy depletion. Neither fasting nor genotype changed neuronal mitochondrial function in males, suggesting an alternate mechanism was responsible for their initial allodynia.ConclusionsAlthough Nav1.8LKB1‐ animals of both sexes developed genotype‐dependent allodynia in response to a metabolic stressor (24hr fast), only females exhibited a difference in mitochondrial function in response to this fast. These data support existing literature that suggests neuronal processes are responsible for the development of allodynia in females but not males and suggests that these differences are metabolic in nature. However, additional studies are needed to determine how other sex‐ and cell‐specific metabolic processes can contribute to pain development. This includes how the metabolism of immune cells, such as microglia and macrophages, which have been shown contribute to pain in males but not females, can be affected in an LKB1‐dependent manner to reduce a painful phenotype. Acknowledgements: We would like to thank Luz Barron and Han Jeong for their contributions.