posted on 2020-05-28, 00:13authored byBelin
G. Teklezgi, Annapurna Pamreddy, Sphamandla Ntshangase, Sipho Mdanda, Sanil D. Singh, Nirmala D. Gopal, Tricia Naicker, Hendrik G. Kruger, Thavendran Govender, Sooraj Baijnath
Overdose
is the main cause of mortality among heroin users. Many
of these overdose-induced deaths can be prevented through the timely
administration of naloxone (NLX), a nonselective mu (μ)-, kappa
(κ)-, and delta (δ)-opioid receptor antagonist. NLX competitively
inhibits opioid-overdose-induced respiratory depression without eliciting
any narcotic effect itself. The aim of this study was to investigate
the antagonistic action of NLX by comparing its distribution to that
of 6-monacetylmorphine (6-MAM), heroin’s major metabolite,
in a rodent model using mass spectrometric imaging (MSI) in combination
with liquid chromatography–tandem mass spectrometry (LC–MS/MS). Male
Sprague–Dawley rats (n = 5) received heroin
(10 mg kg–1) intraperitoneally, NLX (10 mg kg–1) intranasally, and NLX injected intranasally 5 min
after heroin administration. The animals were sacrificed 15 min after
dose and brain tissues were harvested. The MSI image analysis showed
a region-specific distribution of 6-MAM in the brain regions including
the corpus callosum, hippocampal formation, cerebral cortex, corticospinal
tracts, caudate putamen, thalamus, globus pallidus, hypothalamus,
and basal forebrain regions of the brain. The antagonist had a similar
biodistribution throughout the brain in both groups of animals that
received NLX or NLX after heroin administration. The MSI analysis
demonstrated that the intensity of 6-MAM in these brain regions was
reduced following NLX treatment. The decrease in 6-MAM intensity was
caused by its displacement by the antagonist and its binding to these
receptors in these specific brain regions, consequently enhancing
the opioid elimination. These findings will contribute to the evaluation
of other narcotic antagonists that might be considered for use in
the treatment of drug overdose via MSI.