Acute acetate administration increases endogenous opioid levels in the human brain: A [11C]carfentanil molecular imaging study

Abhishekh H. Ashok; Jim Myers; Gary Frost; Samuel Turton; Roger N. Gunn; Jan Passchier; Alessandro Colasanti; Tiago Reis Marques; David Nutt; Anne Lingford-Hughes; Oliver D. Howes; Eugenii A. Rabiner

doi:10.1177/0269881120965912

Acute acetate administration increases endogenous opioid levels in the human brain: A [¹¹C]carfentanil molecular imaging study

Abhishekh H. Ashok^*, Jim Myers, Gary Frost, Samuel Turton, Roger N. Gunn, Jan Passchier, Alessandro Colasanti, Tiago Reis Marques, David Nutt, Anne Lingford-Hughes, Oliver D. Howes, Eugenii A. Rabiner

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

Abstract

Introduction: A recent study has shown that acetate administration leads to a fourfold increase in the transcription of proopiomelanocortin (POMC) mRNA in the hypothalamus. POMC is cleaved to peptides, including β-endorphin, an endogenous opioid (EO) agonist that binds preferentially to the µ-opioid receptor (MOR). We hypothesised that an acetate challenge would increase the levels of EO in the human brain. We have previously demonstrated that increased EO release in the human brain can be detected using positron emission tomography (PET) with the selective MOR radioligand [¹¹C]carfentanil. We used this approach to evaluate the effects of an acute acetate challenge on EO levels in the brain of healthy human volunteers. Methods: Seven volunteers each completed a baseline [¹¹C]carfentanil PET scan followed by an administration of sodium acetate before a second [¹¹C]carfentanil PET scan. Dynamic PET data were acquired over 90 minutes, and corrected for attenuation, scatter and subject motion. Regional [¹¹C] carfentanil BP_ND values were then calculated using the simplified reference tissue model (with the occipital grey matter as the reference region). Change in regional EO concentration was evaluated as the change in [¹¹C]carfentanil BP_ND following acetate administration. Results: Following sodium acetate administration, 2.5–6.5% reductions in [¹¹C]carfentanil regional BP_ND were seen, with statistical significance reached in the cerebellum, temporal lobe, orbitofrontal cortex, striatum and thalamus. Conclusions: We have demonstrated that an acute acetate challenge has the potential to increase EO release in the human brain, providing a plausible mechanism of the central effects of acetate on appetite in humans.

Original language	English
Pages (from-to)	606-610
Number of pages	5
Journal	Journal of Psychopharmacology
Volume	35
Issue number	5
DOIs	https://doi.org/10.1177/0269881120965912
Publication status	Published - May 2021

Keywords

Acetate
opioid
PET

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1177/0269881120965912

Cite this

Ashok, A. H., Myers, J., Frost, G., Turton, S., Gunn, R. N., Passchier, J., Colasanti, A., Marques, T. R., Nutt, D., Lingford-Hughes, A., Howes, O. D., & Rabiner, E. A. (2021). Acute acetate administration increases endogenous opioid levels in the human brain: A [¹¹C]carfentanil molecular imaging study. Journal of Psychopharmacology, 35(5), 606-610. https://doi.org/10.1177/0269881120965912

@article{23b09d813b1940c688ddcc82284f8686,

title = "Acute acetate administration increases endogenous opioid levels in the human brain: A [11C]carfentanil molecular imaging study",

abstract = "Introduction: A recent study has shown that acetate administration leads to a fourfold increase in the transcription of proopiomelanocortin (POMC) mRNA in the hypothalamus. POMC is cleaved to peptides, including β-endorphin, an endogenous opioid (EO) agonist that binds preferentially to the µ-opioid receptor (MOR). We hypothesised that an acetate challenge would increase the levels of EO in the human brain. We have previously demonstrated that increased EO release in the human brain can be detected using positron emission tomography (PET) with the selective MOR radioligand [11C]carfentanil. We used this approach to evaluate the effects of an acute acetate challenge on EO levels in the brain of healthy human volunteers. Methods: Seven volunteers each completed a baseline [11C]carfentanil PET scan followed by an administration of sodium acetate before a second [11C]carfentanil PET scan. Dynamic PET data were acquired over 90 minutes, and corrected for attenuation, scatter and subject motion. Regional [11C] carfentanil BPND values were then calculated using the simplified reference tissue model (with the occipital grey matter as the reference region). Change in regional EO concentration was evaluated as the change in [11C]carfentanil BPND following acetate administration. Results: Following sodium acetate administration, 2.5–6.5% reductions in [11C]carfentanil regional BPND were seen, with statistical significance reached in the cerebellum, temporal lobe, orbitofrontal cortex, striatum and thalamus. Conclusions: We have demonstrated that an acute acetate challenge has the potential to increase EO release in the human brain, providing a plausible mechanism of the central effects of acetate on appetite in humans.",

keywords = "Acetate, opioid, PET",

author = "Ashok, {Abhishekh H.} and Jim Myers and Gary Frost and Samuel Turton and Gunn, {Roger N.} and Jan Passchier and Alessandro Colasanti and Marques, {Tiago Reis} and David Nutt and Anne Lingford-Hughes and Howes, {Oliver D.} and Rabiner, {Eugenii A.}",

note = "Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This study was partly funded by grants MC-A656-5QD30 from the Medical Research Council-UK, 666 from the Maudsley Charity 094849/Z/10/Z from the Brain and Behavior Research Foundation, and Wellcome Trust to O.D.H. and King{\textquoteright}s College London scholarship to A.H.A. and support from Invicro. Infrastructure support was provided by the NIHR Imperial Biomedical Research Centre and the NIHR Imperial Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This study was partly funded by grants MC-A656-5QD30 from the Medical Research Council-UK, 666 from the Maudsley Charity 094849/Z/10/Z from the Brain and Behavior Research Foundation, and Wellcome Trust to O.D.H. and King?s College London scholarship to A.H.A. and support from Invicro. Infrastructure support was provided by the NIHR Imperial Biomedical Research Centre and the NIHR Imperial Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Funding Information: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: O.D.H. has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Astra-Zeneca, BMS, Eli Lilly, Janssen, Lundbeck, Lyden-Delta, Servier and Roche. Neither O.D.H. nor his family have been employed by or have holdings/a financial stake in any biomedical company. A.L.-H. has received honoraria paid into her institutional funds for speaking and chairing engagements from Lundbeck, Lundbeck Institute UK and Janssen-Cilag. She has received research support from Lundbeck and has been consulted by but received no monies from Britannia Pharmaceuticals. D.N. has consulted for or received speaker{\textquoteright}s fees or travel or grant support from the following companies with an interest in the treatment of addiction: RB pharmaceuticals, Lundbeck, GSK, Pfizer, D&A Pharma, Nalpharm, Opiant Pharmaceutical and Alkermes. R.G. is a consultant for Abbvie and Cerveau. E.A.R. is a consultant for Opiant Pharmaceutical, AbbVie and Teva, and a shareholder in GSK. Publisher Copyright: {\textcopyright} The Author(s) 2021. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = may,

doi = "10.1177/0269881120965912",

language = "English",

volume = "35",

pages = "606--610",

journal = "Journal of Psychopharmacology",

issn = "0269-8811",

publisher = "SAGE Publications Ltd STM",

number = "5",

}

Ashok, AH, Myers, J, Frost, G, Turton, S, Gunn, RN, Passchier, J, Colasanti, A, Marques, TR, Nutt, D, Lingford-Hughes, A, Howes, OD & Rabiner, EA 2021, 'Acute acetate administration increases endogenous opioid levels in the human brain: A [¹¹C]carfentanil molecular imaging study', Journal of Psychopharmacology, vol. 35, no. 5, pp. 606-610. https://doi.org/10.1177/0269881120965912

TY - JOUR

T1 - Acute acetate administration increases endogenous opioid levels in the human brain

T2 - A [11C]carfentanil molecular imaging study

AU - Ashok, Abhishekh H.

AU - Myers, Jim

AU - Frost, Gary

AU - Turton, Samuel

AU - Gunn, Roger N.

AU - Passchier, Jan

AU - Colasanti, Alessandro

AU - Marques, Tiago Reis

AU - Nutt, David

AU - Lingford-Hughes, Anne

AU - Howes, Oliver D.

AU - Rabiner, Eugenii A.

N1 - Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This study was partly funded by grants MC-A656-5QD30 from the Medical Research Council-UK, 666 from the Maudsley Charity 094849/Z/10/Z from the Brain and Behavior Research Foundation, and Wellcome Trust to O.D.H. and King’s College London scholarship to A.H.A. and support from Invicro. Infrastructure support was provided by the NIHR Imperial Biomedical Research Centre and the NIHR Imperial Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Funding Information: The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This study was partly funded by grants MC-A656-5QD30 from the Medical Research Council-UK, 666 from the Maudsley Charity 094849/Z/10/Z from the Brain and Behavior Research Foundation, and Wellcome Trust to O.D.H. and King?s College London scholarship to A.H.A. and support from Invicro. Infrastructure support was provided by the NIHR Imperial Biomedical Research Centre and the NIHR Imperial Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Funding Information: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: O.D.H. has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Astra-Zeneca, BMS, Eli Lilly, Janssen, Lundbeck, Lyden-Delta, Servier and Roche. Neither O.D.H. nor his family have been employed by or have holdings/a financial stake in any biomedical company. A.L.-H. has received honoraria paid into her institutional funds for speaking and chairing engagements from Lundbeck, Lundbeck Institute UK and Janssen-Cilag. She has received research support from Lundbeck and has been consulted by but received no monies from Britannia Pharmaceuticals. D.N. has consulted for or received speaker’s fees or travel or grant support from the following companies with an interest in the treatment of addiction: RB pharmaceuticals, Lundbeck, GSK, Pfizer, D&A Pharma, Nalpharm, Opiant Pharmaceutical and Alkermes. R.G. is a consultant for Abbvie and Cerveau. E.A.R. is a consultant for Opiant Pharmaceutical, AbbVie and Teva, and a shareholder in GSK. Publisher Copyright: © The Author(s) 2021. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/5

Y1 - 2021/5

N2 - Introduction: A recent study has shown that acetate administration leads to a fourfold increase in the transcription of proopiomelanocortin (POMC) mRNA in the hypothalamus. POMC is cleaved to peptides, including β-endorphin, an endogenous opioid (EO) agonist that binds preferentially to the µ-opioid receptor (MOR). We hypothesised that an acetate challenge would increase the levels of EO in the human brain. We have previously demonstrated that increased EO release in the human brain can be detected using positron emission tomography (PET) with the selective MOR radioligand [11C]carfentanil. We used this approach to evaluate the effects of an acute acetate challenge on EO levels in the brain of healthy human volunteers. Methods: Seven volunteers each completed a baseline [11C]carfentanil PET scan followed by an administration of sodium acetate before a second [11C]carfentanil PET scan. Dynamic PET data were acquired over 90 minutes, and corrected for attenuation, scatter and subject motion. Regional [11C] carfentanil BPND values were then calculated using the simplified reference tissue model (with the occipital grey matter as the reference region). Change in regional EO concentration was evaluated as the change in [11C]carfentanil BPND following acetate administration. Results: Following sodium acetate administration, 2.5–6.5% reductions in [11C]carfentanil regional BPND were seen, with statistical significance reached in the cerebellum, temporal lobe, orbitofrontal cortex, striatum and thalamus. Conclusions: We have demonstrated that an acute acetate challenge has the potential to increase EO release in the human brain, providing a plausible mechanism of the central effects of acetate on appetite in humans.

AB - Introduction: A recent study has shown that acetate administration leads to a fourfold increase in the transcription of proopiomelanocortin (POMC) mRNA in the hypothalamus. POMC is cleaved to peptides, including β-endorphin, an endogenous opioid (EO) agonist that binds preferentially to the µ-opioid receptor (MOR). We hypothesised that an acetate challenge would increase the levels of EO in the human brain. We have previously demonstrated that increased EO release in the human brain can be detected using positron emission tomography (PET) with the selective MOR radioligand [11C]carfentanil. We used this approach to evaluate the effects of an acute acetate challenge on EO levels in the brain of healthy human volunteers. Methods: Seven volunteers each completed a baseline [11C]carfentanil PET scan followed by an administration of sodium acetate before a second [11C]carfentanil PET scan. Dynamic PET data were acquired over 90 minutes, and corrected for attenuation, scatter and subject motion. Regional [11C] carfentanil BPND values were then calculated using the simplified reference tissue model (with the occipital grey matter as the reference region). Change in regional EO concentration was evaluated as the change in [11C]carfentanil BPND following acetate administration. Results: Following sodium acetate administration, 2.5–6.5% reductions in [11C]carfentanil regional BPND were seen, with statistical significance reached in the cerebellum, temporal lobe, orbitofrontal cortex, striatum and thalamus. Conclusions: We have demonstrated that an acute acetate challenge has the potential to increase EO release in the human brain, providing a plausible mechanism of the central effects of acetate on appetite in humans.

KW - Acetate

KW - opioid

KW - PET

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U2 - 10.1177/0269881120965912

DO - 10.1177/0269881120965912

M3 - Article

AN - SCOPUS:85098969132

SN - 0269-8811

VL - 35

SP - 606

EP - 610

JO - Journal of Psychopharmacology

JF - Journal of Psychopharmacology

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ER -