The scourge of opioid dependency persists in large part because opioid withdrawal is so painful and debilitating—and unyielding. When withdrawal symptoms take hold, there is little that can ameliorate them. Few medications exist that offer any help. Yet an existing antigout medication, report University of Calgary scientists, is effective in reducing the severity of withdrawal symptoms in opioid-dependent rodents.
The drug, which targets an immune cell pathway called pannexin-1 (Panx1), was identified in a study that investigated the poorly understood cellular mechanisms of opioid withdrawal. Previous studies focused on neurons. The new study, however, looked at microglia, a type of immune cell located throughout the brain and spinal cord
Details of the study appeared January 30 in the journal Nature Medicine, in an article entitled, “Blocking Microglial Pannexin-1 Channels Alleviates Morphine Withdrawal in Rodents.” This article describes how the University of Calgary scientists, led by Tuan Trang, Ph.D., identified the Panx1 channel as a therapeutic target in opiate withdrawal.
“We show that withdrawal from morphine induces long-term synaptic facilitation in lamina I and II neurons within the rodent spinal dorsal horn, a principal site of action for opiate analgesia,” wrote the article’s authors. “Genetic ablation of Panx1 in microglia abolished the spinal synaptic facilitation and ameliorated the sequelae of morphine withdrawal.”
The discovery represents a key shift in understanding how withdrawal occurs and it opens the door to treatments that could have tremendous therapeutic potential.
Once the scientists identified the mechanism, the researchers were able to test an existing drug—in this case an antigout medication called probenecid that is known to have nonselective Panx1 blocking effects. The drug is relatively inexpensive and has few side-effects. Importantly, the researchers were also able to demonstrate that the drug did not affect the opioid's ability to relieve pain.
“We show that Panx1 activation drives ATP [adenosine triphosphate] release from microglia during morphine withdrawal and that degrading endogenous spinal ATP by administering apyrase produces a reduction in withdrawal behaviors,” detailed the authors. “Conversely, we found that pharmacological inhibition of ATP breakdown exacerbates withdrawal. Treatment with a Panx1-blocking peptide (10panx) or the clinically used broad-spectrum Panx1 blockers, mefloquine or probenecid, suppressed ATP release and reduced withdrawal severity.”
With such encouraging preclinical results, the researchers quickly started looking at how to translate this discovery to humans. They are already moving forward with Lori Montgomery, M.D., and Chris Spanswick, M.D., at the Calgary Pain Clinic to design a clinical trial.
“We now need to look to see if this works with patients as well as ensure safety,” said Dr. Spanswick, medical leader of the Calgary Pain Program. “We are at the very early stages of organizing clinical research. It will be some time before this research gets off the ground and we look forward to continuing collaboration with the HBI on this and other areas of research.”
“Opioids are the pharmacological cornerstone for treating chronic pain in a large variety of diseases,” noted Dr. Trang. “Understanding why opioid withdrawal occurs and how to alleviate it, is of critical importance in improving pain therapy and may have implications for substance abuse in opioid addicts. The potential impact is immense.”
The study led by Dr. Trang effectively alleviated withdrawal symptoms in rodents, which could have important implications for patients that may wish to decrease or stop their use of these medications. According to the Centers for Disease Control, 91 Americans die every day from an opioid overdose, whether from prescription opioids or heroin.
