Grant: Project Grant

Opioid medications provide potent pain relief in the short-term, but their long-term use can cause serious adverse effects. A major problem is that chronic opioid users experience debilitating withdrawal symptoms (e.g. tremors, anxiety, depression, insomnia, cardiovascular and gastrointestinal distress) when attempting to stop or reduce their opioid medications. Seeking relief, these individuals continue to use opioid drugs. A misconception is that only illicit opioid use or "opioid addicts" are susceptible to withdrawal. The careful use of prescription opioids can also lead to significant withdrawal symptoms. Optimal therapies for opioid withdrawal are unavailable. Our team recently discovered that immune cells (microglia) residing within the brain and spinal cord play an important role in opioid withdrawal. These immune cells communicate with other cells through specialized channels (pannexin-1), which are like gates that open and close to allow passage of chemical signals. Blocking these channels in the spinal cord alleviates withdrawal without diminishing the pain-relieving benefits of opioid medications. We have new data that pannexin-1 channels gate activity within the locus coeruleus, an area of the brain that communicates with the spinal cord by sending specialized projections containing a chemical (norepinephrine). This proposal addresses exciting new questions about how pannexin-1 channels modulate specific circuitry in the brain and spinal cord that are important for opioid withdrawal. Using advanced cellular imaging, biochemical, and behavioural approaches, experiments will also deconstruct the machinery by which norepinephrine enhances pannexin-1 activity and its impact on microglia signaling. Finally, we will translate our findings into the development of next generation, more potent pannexin-1 targeted drugs for treating opioid withdrawal.