Erika Harding, Charlie Kwok and Nicole Burma – University of Calgary
Article citation
Kwok CHT*, Harding EK*, Burma NE*, Markovic T, Massaly N, van den Hoogen NJ, Stokes-Heck S, Gambeta E, Komarek K, Yoon HJ, Navis KE, McAllister BB, Canet-Pons J, Fan C, Dalgarno R, Gorobets E, Papatzimas JW, Zhang Z, Kohro Y, Anderson CL, Thompson RJ, Derksen DJ, Morón JA, Zamponi GW, Trang T. Pannexin-1 channel inhibition alleviates opioid withdrawal in rodents by modulating locus coeruleus to spinal cord circuitry. Nat Commun. 2024 Jul 24;15(1):6264. doi: 10.1038/s41467-024-50657-7. PMID: 39048565
Identification of the Pannexin-1 channel in the brain as a target to treat opioid withdrawal symptoms
Opioids remain one of the most effective analgesics, with 10-15% of Canadians receiving opioid prescriptions per year. However, opioids are also highly associated with substance use disorders and overdose related deaths. Last year alone, over 7000 Canadians passed away from opioid overdose related complications. Many people who start with an opioid prescription enter a feedforward cycle of use reinforced by significant withdrawal symptoms. Patients report these symptoms as so aversive they will do anything to avoid them, and current treatments for opioid use disorder have a high degree of relapse. There is a clear need for better treatments of opioid withdrawal.
Research done by Drs. Erika Harding, Charlie Hong Ting Kwok and Nicole Burma in the laboratory of Dr. Tuan Trang at the University of Calgary has identified a channel called Pannexin-1, present in a brain area called the Locus Coeruleus as a potential target to alleviate opioid withdrawal symptoms.
Many opioid withdrawal symptoms are thought to be caused by hyperactive neuron signaling to the spinal cord, of which a brain region called the Locus Coeruleus is a major driver. While studies have shown the Locus Coeruleus is hyperactive during opioid withdrawal, how and why it is hyperactive had remained unclear. The researchers used a combination of behavioural experiments, immunohistochemistry, electrophysiology, and chemogenetics to investigate this question. They found that Pannexin-1 channels present on immune cells called microglia drive changes in Locus Coeruleus neurons to increase their output to the spinal cord, and in turn promote withdrawal symptoms. Genetic ablation or pharmacological inhibition of Locus Coeruleus Pannexin-1 channels was sufficient to reduce both physical and affective components of withdrawal symptoms.
Additionally, the research team synthesized a novel, more selective Pannexin-1 inhibitor, EG-2184. EG-2184 reduced withdrawal behaviours and Locus Coeruleus neuron hyperexcitability. EG-2184 also reduced cue-induced morphine seeking in rats, demonstrating potential applicability to reducing opioid relapse, and consistency across species. This suggests that novel Pannexin-1 inhibiting medications could provide alleviation of opioid withdrawal with better dosages and fewer side effects. Development of these medications has the potential to change the trajectory of opioid use and misuse for millions of people worldwide.
About Drs. Charlie Hong Ting Kwok, Erika Harding and Nicole Burma
This project was spearheaded and organized by its three co-first authors, Dr. Charlie Kwok, Dr. Erika Harding, and Dr. Nicole Burma, under the support and guidance of Dr. Tuan Trang at the University of Calgary Hotchkiss Brain Institute. At the time of this study, Dr. Burma was a PhD candidate in the lab and has since completed her MD and is now a resident physician in Calgary. Drs. Kwok and Harding performed this research as postdoctoral fellows. Dr. Kwok is now a Project Manager at Premier Research and Dr. Harding is a postdoctoral fellow in the labs of Dr. Tuan Trang and Dr. Gerald Zamponi at the University of Calgary.
Source of funding
This project was supported by grants from Canadian Institute of Health Research (CIHR) (PJT-173553; PJ8-169697), Natural Sciences and Engineering Research Council of Canada (NSERC) (RGPIN06289-2019), Vi Riddell Program for Pediatric Pain, and a Campus Alberta Neuroscience Entrepreneurship Grant. Dr. Kwok was supported by a CIHR postdoctoral fellowship, a Louise and Alan Edwards Foundation postdoctoral fellowship, and a Hotchkiss Brain Institute (HBI) postdoctoral fellowship. Dr. Harding was supported by a CIHR postdoctoral fellowship, a Spinal Cord Nerve Injury and Pain (SCNIP) postdoctoral fellowship, and an Eyes High postdoctoral fellowship. Dr. Burma was supported by a CIHR doctoral scholarship, an Alberta Innovates scholarship, and a HBI doctoral scholarship.