Opioids, such as morphine and fentanyl, are powerful drugs used to manage a variety of pain conditions. However, chronic opioid use can result in the development of physical dependence. When individuals stop opioid use, they may suffer from a debilitating withdrawal syndrome.
Despite an individual’s intention to quit, without proper management of the withdrawal symptoms, success is incredibly difficult to achieve. Finding routes to alleviate the severity or mitigate withdrawal is of utmost importance to improve the chances for rehabilitation and eventually sobriety. Unfortunately, the spectrum of withdrawal symptoms is extensive and as such, difficult to remediate.
For a group of Canadian researchers, including Dr. Tuan Trang from the University of Calgary, another approach is needed to ensure those who wish to quit can accomplish their goal successfully. For these researchers, the answer can only be found after the mechanism behind the symptoms is elucidated. Now, it seems, they have found a path forward.
Last month, the team revealed some progress in their mission. The results, published in the journal, Nature Medicine, discovered how withdrawal occurs at the molecular level in the nervous system. Using a rodent model, they were able to find both a mechanism behind the symptoms and a possible target for therapy.
The experiments recapitulated a withdrawal syndrome similar to what is experienced in humans. The animals first were given several doses of morphine over the course of five days. At this point, they were physically dependent on morphine. The team then injected the animals with a drug known to cause symptoms of withdrawal, known as naloxone.
When withdrawal was confirmed, the team examined the animals at the molecular level for any differences in the nervous system. They then compared their data with controls not suffering from withdrawal. The results revealed a change had occurred in the nature of a particular group of cells known as microglia.
Microglia are immune cells in the brain and spinal cord, and they are necessary to help fight off infections and other chemical threats. They normally survey their environment, and when trouble shows up, they become ‘activated’ in preparation for a fight. The body in turn, responds by becoming more active as it begins to deal with the impending combat.
In the opioid dependent rodents, the team found increased microglial ‘activation’ as compared to the controls. For the authors, this provided clues that the microglia were preparing for battle and could be contributing to opioid withdrawal. When they targeted these cells, they effectively decreased the symptoms of withdrawal.
Confirming microglial activation was only the first step. The team wanted to find the molecule on these cells causing all the trouble. Eventually, one protein known as pannexin-1 became an excellent suspect due to a higher presence in morphine dependent animals.
Pannexin-1, or Panx1 is a protein that is involved in numerous bodily functions. It helps to control blood pressure, taste sensation, and the development of inflammation. Although there have been no previous reports suggesting an involvement in opioid withdrawal, its wide spectrum suggests there may be a possible role.
The first stage of proof required blocking Panx1 to see if the animals would display fewer withdrawal signs. They did. Next was an attempt to show a lack of this protein protected animals from severe withdrawal symptoms. This too also worked. Finally, they needed to prove this effect was similar in both male and female animals, and found that there was no difference. They had their target.
Despite all this progress, there was still one missing piece of the puzzle. The team still needed to find a possible treatment option. Serendipitously, there are existing clinicially utilized drugs that can block Panx1, including probenecid, which is used to treat gout and mefloquine, an anti-malaria therapeutic. When they administered these drugs, the results were dramatic. Rodents given either morphine or fentanyl show significantly less withdrawal signs when either probenecid or mefloquine was used.
The authors point out that these results provide important mechanistic insights and a potential therapeutic target; however, further studies must be conducted before they can translate these findings into the clinic. Considering the strong reliance on opioids to treat a wide variety of pain conditions, the impact of these findings could be immense for improving the clinical utility of opioids. The next steps are to test proof-of-concept in a pilot clinical study, and if all goes well, we may one day have another therapeutic approach to help individuals stop their opioid use.
Original research article:
Burma NE, Bonin RP, Leduc-Pessah H, Baimel C, Cairncross ZF, Mousseau M, Shankara JV, Stemkowski PL, Baimoukhametova D, Bains JS, Antle MC, Zamponi GW, Cahill CM, Borgland SL, De Koninck Y, Trang T. Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents. Nat Med. 2017 Jan 30. doi: 10.1038/nm.4281.