Research suggests that understanding how opioids and ?-opioid receptors mediate respiratory depression in the brain is key to preventing respiratory depression.
The investigators confirmed that flupirtine (300 ?M) did reduce the mice’s respiratory rates by 22.2%.6 However, they believe that a specific sub-unit, GIRK2, is a significant driver of much of this drug-induced respiratory depression. The absence of GIRK2 has been found to mute many of the functional GIRK channels found in the brain,7 so when flupirtine was administered to the preBötC of mice lacking the GIRK2 subunit (GIRK2?/?), there was no effect on the respiratory rate.
The next step was to compare the effects of two MOR-agonist, the synthetic opioid peptide [d-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) and fentanyl. A recurring pattern emerged. At baseline, wild-type and GIRK2 mice had similar respiratory rates, but when administered 5 ?M of DAMGO, significantly depressed respiratory rate in wild-type mice compared with GIRK2 mice. Respiratory rate depression by systemic injection of fentanyl was markedly reduced in GIRK2 mice compared with wild-type mice.
According to the lead author of the study Gaspard Montandon, PhD, from the University of Toronto, these findings could influence how researchers approach the prospect of developing therapies to prevent opioid-induced respiratory depression.
“There are several ways that opioids can cause breathing problems, but this is a crucial one [GIRK channels],” said Dr. Montandon in an interview with Practical Pain Management. “Our study is the first to clearly identify a type of potassium channels [GIRK2] contributing to respiratory rate depression by opioid drugs. This is the first time anyone has identified where and how opioids work—and how to shut down their most dangerous effects.”
“This is a very exciting field of research because our current armamentarium of pure opioid agonists come with significant risks for opioid-induced respiratory depression (OIRD),” said Jeffrey Fudin, PharmD, Clinical Pharmacy Specialist in Pain Management and Director, PGY2 Pain & Palliative Care Pharmacy Pain Residency at Samuel Stratton VA Medical Center, in Albany, NY.