Contributions of Specific Peripheral Nociceptor Signaling Pathways to Analgesia

Chronic pain represents a massive socioeconomic burden, impacting the lives of 1 in 5 Americans. Existing therapeutics vary widely in both efficacy and availability. Understanding the mechanisms behind chronic pain, including any sexually dimorphic differences, drives the search for novel, efficacious therapeutics. Interestingly, pain correlates with metabolic stress in peripheral sensory neurons; alleviating this metabolic stress relieves chronic pain conditions. We have thus sought to investigate neuronal metabolism in chronic pain in two ways. Our first study involves disrupting the ability to appropriately respond to metabolic stress by deleting liver kinase B1 (LKB1) from peripheral nociceptive neurons marked by Nav1.8 and exposing animals to a stressor in the form of a 24-hour fast. Whereas females experienced LKB1-mediated hypersensitivity, males experienced an initial genotype-independent period of mechanical hypersensitivity, which was maintained in an LKB1-specific fashion. In females, LKB1 was requisite to generate sufficient mitochondrial activity to counteract the fast; male mitochondria were unaffected by fasting. Interestingly, in a model of paclitaxel induced metabolic stress, males but not females experienced anti-nociception in response to PPAR-alpha signaling. This is concurrent with a downregulation of PPAR-alpha after paclitaxel treatment in the DRG, suggesting males and females utilize different metabolic pathways for anti-nociception. Our final study involved the role of cannabinoid receptor one (CB1R) in Nav1.8-containing neurons. Canonically, CB1R reduces cellular energy expenditure via the Gi/o pathway; it has also been established as effective in reducing both chronic and acute pain, but it is unclear what cell is responsible for this phenomenon. To investigate this, we utilized a novel model where CB1R is only present on Nav1.8-contaning neurons (CB1RNav1.8) and exposed animals to a variety of behavioral experiments. Interestingly, we found males and females responded similarly to CB1R agonism, increasing the desirability of the target for pain relief. CB1RNav1.8 and knockout animals behaved similarly in inflammatory pain experiments, and CB1RNav1.8 and wildtype animals behaved similarly in neuropathic pain experiments. These data suggest CB1R in neurons mediate nociception differently based on the source of insult, and CB1R on immune cells may be more responsible in mediating inflammatory pain. Our data lay the foundation for sex-specific and sex-independent peripheral signaling pathways, continuing to establish peripheral mechanisms for more targeted therapeutics.