Posted on 14-03-2017

A microglial pannexin-1 mechanism is critical for morphine withdrawal

Morphine is the gold standard medication for pain management due to its potent analgesic properties. Unfortunately, morphine is also associated severe withdrawal symptoms including nausea, chills, and severe headaches. These symptoms often negatively impact a patient’s attempts to stop opiate-based therapies. As a result, there is significant interest in trying to alleviate negative side effects without attenuation of morphine’s analgesic effect. However, the current understanding of the mechanisms underlying withdrawal is limited.

In the present study, a collaboration between scientists in Calgary, Toronto, and Quebec City sought to investigate the molecular underpinnings of morphine withdrawal, implicating microglia (the immune cells of the central nervous system) and the pannexin-1 (Panx1) channel in this process. Using a combination of behavioural and genetic techniques, the authors show that ablation of Panx1 specifically in microglia prevents negative symptoms such as teeth chattering, headshakes, and grooming behaviors after morphine termination in both mice and rats. The authors also found evidence of changes in spinal cord neuronal excitability using electrophysiological recordings during morphine withdrawal. Further investigation of the Panx1 mechanism revealed that there was an increase in P2X7 receptors on microglia during morphine withdrawal, which is known to activate Panx1 channels. This in turn results in the release of ATP from microglia, which the authors show to be critical in the development of spinal cord hyperexcitability and withdrawal symptoms. Administration of Panx1 blockers was effective in reducing behavioral indicators of withdrawal, but did not affect the analgesia associated with morphine treatment.

This study provides new understanding as to the mechanisms underlying withdrawal from morphine. With Panx1 blockers already being used clinically for other conditions such as gout, this opens up the possibility of fast-tracking clinical trials of Panx1 blockers in treatment of opiate withdrawal. This newly elucidated mechanism has immense therapeutic potential for patients attempting to terminate opiate therapy.

Reference: Burma et al. (2017). Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents. Nature Medicine.

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