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Reported Benefits of Low-Dose Naltrexone Appear to Be Independent of the Endogenous Opioid System Involving Proopiomelanocortin Neurons and β-Endorphin

Naltrexone is an opioid receptor antagonist approved for the treatment of alcohol and opioid use disorders at doses of 50–150 mg/d. Naltrexone has also been prescribed at much lower doses (3–6 mg/d) for the off-label treatment of inflammation and pain. Currently, a compelling mechanistic explanation...

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Autores principales: Metz, Marissa J., Daimon, Caitlin M., Hentges, Shane T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Society for Neuroscience 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211470/
https://www.ncbi.nlm.nih.gov/pubmed/34031099
http://dx.doi.org/10.1523/ENEURO.0087-21.2021
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author Metz, Marissa J.
Daimon, Caitlin M.
Hentges, Shane T.
author_facet Metz, Marissa J.
Daimon, Caitlin M.
Hentges, Shane T.
author_sort Metz, Marissa J.
collection PubMed
description Naltrexone is an opioid receptor antagonist approved for the treatment of alcohol and opioid use disorders at doses of 50–150 mg/d. Naltrexone has also been prescribed at much lower doses (3–6 mg/d) for the off-label treatment of inflammation and pain. Currently, a compelling mechanistic explanation for the reported efficacy of low-dose naltrexone (LDN) is lacking and none of the proposed mechanisms can explain patient reports of improved mood and sense of well-being. Here, we examined the possibility that LDN might alter the activity of the endogenous opioid system involving proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) in male and female mice. Known actions of POMC neurons could account for changes in pain perception and mood. However, using electrophysiologic, imaging and peptide measurement approaches, we found no evidence for such a mechanism. LDN did not change the sensitivity of opioid receptors regulating POMC neurons, the production of the β-endorphin precursor Pomc mRNA, nor the release of β-endorphin into plasma. Spontaneous postsynaptic currents (sPSCs) onto POMC neurons were slightly decreased after LDN treatment and GCaMP fluorescent signal, a proxy for intracellular calcium levels, was slightly increased. However, LDN treatment did not appear to change POMC neuron firing rate, resting membrane potential, nor action potential threshold. Therefore, LDN appears to have only slight effects on POMC neurons that do not translate to changes in intrinsic excitability or baseline electrical activity and mechanisms beyond POMC neurons and altered opioid receptor sensitivity should continue to be explored.
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spelling pubmed-82114702021-06-21 Reported Benefits of Low-Dose Naltrexone Appear to Be Independent of the Endogenous Opioid System Involving Proopiomelanocortin Neurons and β-Endorphin Metz, Marissa J. Daimon, Caitlin M. Hentges, Shane T. eNeuro Research Article: Negative Results Naltrexone is an opioid receptor antagonist approved for the treatment of alcohol and opioid use disorders at doses of 50–150 mg/d. Naltrexone has also been prescribed at much lower doses (3–6 mg/d) for the off-label treatment of inflammation and pain. Currently, a compelling mechanistic explanation for the reported efficacy of low-dose naltrexone (LDN) is lacking and none of the proposed mechanisms can explain patient reports of improved mood and sense of well-being. Here, we examined the possibility that LDN might alter the activity of the endogenous opioid system involving proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) in male and female mice. Known actions of POMC neurons could account for changes in pain perception and mood. However, using electrophysiologic, imaging and peptide measurement approaches, we found no evidence for such a mechanism. LDN did not change the sensitivity of opioid receptors regulating POMC neurons, the production of the β-endorphin precursor Pomc mRNA, nor the release of β-endorphin into plasma. Spontaneous postsynaptic currents (sPSCs) onto POMC neurons were slightly decreased after LDN treatment and GCaMP fluorescent signal, a proxy for intracellular calcium levels, was slightly increased. However, LDN treatment did not appear to change POMC neuron firing rate, resting membrane potential, nor action potential threshold. Therefore, LDN appears to have only slight effects on POMC neurons that do not translate to changes in intrinsic excitability or baseline electrical activity and mechanisms beyond POMC neurons and altered opioid receptor sensitivity should continue to be explored. Society for Neuroscience 2021-06-15 /pmc/articles/PMC8211470/ /pubmed/34031099 http://dx.doi.org/10.1523/ENEURO.0087-21.2021 Text en Copyright © 2021 Metz et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article: Negative Results
Metz, Marissa J.
Daimon, Caitlin M.
Hentges, Shane T.
Reported Benefits of Low-Dose Naltrexone Appear to Be Independent of the Endogenous Opioid System Involving Proopiomelanocortin Neurons and β-Endorphin
title Reported Benefits of Low-Dose Naltrexone Appear to Be Independent of the Endogenous Opioid System Involving Proopiomelanocortin Neurons and β-Endorphin
title_full Reported Benefits of Low-Dose Naltrexone Appear to Be Independent of the Endogenous Opioid System Involving Proopiomelanocortin Neurons and β-Endorphin
title_fullStr Reported Benefits of Low-Dose Naltrexone Appear to Be Independent of the Endogenous Opioid System Involving Proopiomelanocortin Neurons and β-Endorphin
title_full_unstemmed Reported Benefits of Low-Dose Naltrexone Appear to Be Independent of the Endogenous Opioid System Involving Proopiomelanocortin Neurons and β-Endorphin
title_short Reported Benefits of Low-Dose Naltrexone Appear to Be Independent of the Endogenous Opioid System Involving Proopiomelanocortin Neurons and β-Endorphin
title_sort reported benefits of low-dose naltrexone appear to be independent of the endogenous opioid system involving proopiomelanocortin neurons and β-endorphin
topic Research Article: Negative Results
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8211470/
https://www.ncbi.nlm.nih.gov/pubmed/34031099
http://dx.doi.org/10.1523/ENEURO.0087-21.2021
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