Contributions of the gut microbiome to chronic pain and opioid dependence
Depression is highly prevalent amongst those suffering from chronic pain and opioid addiction. Neuroimmune signaling within the ventral tegmental area contribute to altered dopamine signaling and depression-like behaviours in animal models of these diseases. Emerging evidence have shown that neuroinflammation can be caused by disruptions to commensal bacteria of the gut (the gut microbiota) along a poorly understood gut-brain signaling axis. In this program, we are investigating the influence of chronic pain and/or chronic opioids on the composition of bacterial species that make up the gut microbiome. We ask mechanistic-based questions in order to establish the signaling mechanism by which bacteria in the intestine influence brain function in chronic pain and opioid addiction.
The first results from this program were published last year in the journal Neuropsychopharmacology (read the paper here). You can read more about this work in the recent Nature Medicine news feature and on the Pain Research Forum.
The results from this program will illuminate whether strategies that target gut microbiota are effective therapies for opioid use disorder and/or chronic pain. Strategies to improve gut health may improve treatment outcomes for those suffering from chronic pain or opioid addiction.
Neuroimmune regulation of negative affect in chronic pain
Ventral tegmental area (VTA) microglia contribute to the negative affect (i.e. depression) associated with chronic pain (read the paper here). We hypothesize this microglia-dependent hypo-dopaminergic state underlies the negative affective symptoms, such as depression and anxiety, that are co-morbid with chronic pain (read our recent reviews here). In this program, we are investigating the impact of microglia in other brain regions mediating reward, including the amygdala and prefrontal cortex. Currently, we model a unique form of chronic pain associated with multiple sclerosis. This model engages a robust immune response that contributes to the progressive neurodegeneration leading to impaired motor behaviour and chronic pain. Our research is beginning to investigate the influence of this inflammation on affective and reward circuits contributing to chronic pain.
Sex differences in kappa opioid receptor function in pain and anxiety circuits
The kappa opioid receptor is an attractive drug target for its analgesic properties; however, their dysphoric effects have limited clinical utility. Our group has recently shown that a significant portion of kappa opioid receptor analgesia is due to engagement of dysphoric pathways leading to stress-induced analgesia (read the paper here) . Kappa opioid receptor-mediated analgesia is also notable for the significant sex difference in
analgesia, with females exhibiting less KOR analgesia than males. Sexually dimorphic traits can be due to either the influence of gonadal hormones (testosterone or estrogen) or the complement of genes expressed on the X or Y chromosome. In this project, we are investigating the hormonal and chromosomal contributions to the sex difference in kappa opioid receptor function. We are also exploring how this system changes in chronic pain in male and female animals.
This project is currently funded by a NSERC Discovery Grant.