The Role of Peripheral Opioid Receptors in Triggering Heroin-induced Brain Hypoxia

Featured Paper of the Month – June 2020.

One of the deadliest effects of opioids, such as heroin, is respiratory depression followed by
brain hypoxia. While it is known that opioid receptors are densely expressed in both the brain
and periphery, it is widely accepted that the hypoxic effects of opioids result solely from their
direct action in the CNS. To examine the role of peripheral opioid receptors in triggering brain
hypoxia, we used oxygen sensors in freely moving rats to examine how naloxone-HCl and
naloxone-methiodide affect brain oxygen responses induced by intravenous heroin at low,
human-relevant doses. In these experiments we found that naloxone-HCl, an opioid antagonist
used to reverse opioid overdoses, eliminated brain oxygen decreases induced by heroin. We
also found that naloxone-methiodide, an opioid antagonist that cannot travel to the brain,
likewise decreased heroin-induced brain oxygen drops. The decreases in oxygen depression
induced by naloxone-methiodide were attributed to the blockage of peripheral opioid
receptors. Therefore, peripheral opioid receptors seem to play a role in triggering brain
hypoxia.

Publication Information

Perekopskiy, David; Afzal, Anum; Jackson, Shelley N; Muller, Ludovic; Woods, Amina S; Kiyatkin, Eugene A

The Role of Peripheral Opioid Receptors in Triggering Heroin-induced Brain Hypoxia. Journal Article

In: Sci Rep, vol. 10, no. 1, pp. 833, 2020, ISSN: 2045-2322 (Electronic); 2045-2322 (Linking).

Abstract | Links

@article{Perekopskiy:2020ys,

title = {The Role of Peripheral Opioid Receptors in Triggering Heroin-induced Brain Hypoxia.},

author = {David Perekopskiy and Anum Afzal and Shelley N Jackson and Ludovic Muller and Amina S Woods and Eugene A Kiyatkin},

url = {https://pubmed.ncbi.nlm.nih.gov/31964994/},

doi = {10.1038/s41598-020-57768-3},

issn = {2045-2322 (Electronic); 2045-2322 (Linking)},

year  = {2020},

date = {2020-01-21},

urldate = {2020-01-21},

journal = {Sci Rep},

volume = {10},

number = {1},

pages = {833},

address = {Behavioral Neuroscience Branch, National Institute on Drug Abuse - Intramural Research Program, National Institutes of Health, DHHS, 333 Cassell Drive, Baltimore, MD, 21224, USA.},

abstract = {While it is known that opioid receptors (ORs) are densely expressed in both the brain and periphery, it is widely accepted that hypoxic effects of opioids result solely from their direct action in the CNS. To examine the role of peripheral ORs in triggering brain hypoxia, we used oxygen sensors in freely moving rats to examine how naloxone-HCl and naloxone-methiodide, the latter which is commonly believed to be peripherally restricted, affect brain oxygen responses induced by intravenous heroin at low, human-relevant doses. Similar to naloxone-HCl, naloxone-methiodide at a relatively low dose (2 mg/kg) fully blocked heroin-induced decreases in brain oxygen levels. As measured by mass spectrometry, naloxone-methiodide was found to be ~40-fold less permeable than naloxone-HCl across the blood-brain barrier, thus acting as a selective blocker of peripheral ORs. Despite this selectivity, a low but detectable amount of naloxone was found in brain tissue after naloxone-methiodide administration, potentially influencing our results. Therefore, we examined the effects of naloxone-methiodide at a very low dose (0.2 mg/kg; at which naloxone was undetectable in brain tissue) and found that this drug still powerfully attenuates heroin-induced brain oxygen responses. These data demonstrate the role of peripheral ORs in triggering heroin-induced respiratory depression and subsequent brain hypoxia.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}