Trang, TuanBurma, Nicole Elizabeth2018-07-042018-07-042018-06-28Burma, N. E. (2018). Microglial pannexin-1 is a cellular determinant of opioid withdrawal (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/32231http://hdl.handle.net/1880/107009Opioid analgesics are indispensable for treating acute post-operative pain, and a variety of chronic pain conditions. However, an over-reliance on opioids can put individuals at risk of developing severe side effects. For chronic opioid users, stopping or decreasing opioid use is difficult as many individuals experience a severe withdrawal syndrome. Opioid withdrawal is characterized by a host of debilitating signs and symptoms, including somatic and autonomic physical symptoms and an aversive affective component. The adverse effects associated with opioid use have become increasingly linked to the activity of microglia, which are immune cells in the central nervous system. Yet, the cellular mechanisms mediating this microglial response remain poorly understood. This thesis investigates the core cellular mechanisms by which microglial pannexin-1 (Panx1) channels underlie opioid withdrawal and other adverse effects associated with chronic opioid use. My over-arching hypothesis is that microglial Panx1 critically contributes to opioid withdrawal. Here, I show that morphine produces a preferential increase in Panx1 expression and function on microglia, and that genetic ablation of microglial Panx1 is sufficient to attenuate the physical signs and aversive component of morphine withdrawal. I provide novel evidence for direct microglia-neuron signaling in opioid withdrawal, and identify that Panx1-mediated ATP release is a key spinal substrate of physical withdrawal signs. I also demonstrate that morphine analgesia, opioid-induced hyperalgesia, analgesic tolerance, and reward behaviours are notably intact in microglial Panx1-deficient mice. This suggests that the side effects of repeated opioid use may be mechanistically separable, and that microglial Panx1 preferentially underlies the expression of opioid withdrawal. Finally, I show the potent amelioration of opioid withdrawal using the clinically utilized broad-spectrum Panx1 blocker, probenecid, indicating that Panx1 may represent a feasible therapeutic target for combating withdrawal in the clinic. In conclusion, this thesis identifies microglial Panx1 as a novel cellular determinant and unexpected target for combating opioid withdrawal, and as a result, represents a paradigm shift in understanding how opioid withdrawal occurs.engUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.opioidopioid withdrawalMicrogliaPannexin-1panx1P2X7Ropioid-induced hyperalgesiaopioid analgesic tolerancereward behavioursmorphinefentanylpainNeurosciencedoctoral thesis10.11575/PRISM/32231