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Drug Alcohol Depend. 2017 Jan 1;170:43-50. doi: 10.1016/j.drugalcdep.2016.10.037. Epub 2016 Nov 8.

Evaluation of TSPO PET imaging, a marker of glial activation, to study the neuroimmune footprints of morphine exposure and withdrawal.

Author information

1
Variabilité de la Réponse aux Psychotropes, INSERM U1144, Paris F-75006, France; Université Paris Descartes, UMR-S 1144, Paris F-75006, France; Université Paris Diderot, UMR-S 1144, Paris F-75013, France; Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay F-91401, France.
2
Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay F-91401, France.
3
Variabilité de la Réponse aux Psychotropes, INSERM U1144, Paris F-75006, France; Université Paris Descartes, UMR-S 1144, Paris F-75006, France; Université Paris Diderot, UMR-S 1144, Paris F-75013, France; REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
4
Variabilité de la Réponse aux Psychotropes, INSERM U1144, Paris F-75006, France; Université Paris Descartes, UMR-S 1144, Paris F-75006, France; Université Paris Diderot, UMR-S 1144, Paris F-75013, France; Assistance publique hôpitaux de Paris, AP-HP, Paris F-75004, France.
5
Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay F-91401, France. Electronic address: nicolas.tournier@cea.fr.

Abstract

INTRODUCTION:

A growing area of research suggests that neuroimmunity may impact the pharmacology of opioids. Microglia is a key component of the brain immunity. Preclinical and clinical studies have demonstrated that microglial modulators may improve morphine-induced analgesia and prevent the development of tolerance and dependence. Positron emission tomography (PET) using translocator protein 18kDa (TSPO) radioligand is a clinically validated strategy for the non-invasive detection of microglial activation. We hypothesized that TSPO PET imaging may be used to study the neuroimmune component of opioid tolerance and withdrawal.

METHODS:

Healthy rats (n=6 in each group) received either saline or escalating doses of morphine (10-40mg/kg) on five days to achieve tolerance and a withdrawal syndrome after morphine discontinuation. MicroPET imaging with [18F]DPA-714 was performed 60h after morphine withdrawal. Kinetic modeling was performed to estimate [18F]DPA-714 volume of distribution (VT) in several brain regions using dynamic PET images and corresponding metabolite-corrected input functions. Immunohistochemistry (IHC) experiments on striatal brain slices were performed to assess the expression of glial markers (Iba1, GFAP and CD68) during 14days after morphine discontinuation.

RESULTS:

The baseline binding of [18F]DPA-714 to the brain (VT=0.086±0.009mLcm-3) was not increased by morphine exposure and withdrawal (VT=0.079±0.010mLcm-3) indicating the absence of TSPO overexpression, even at the regional level. Accordingly, expression of glial markers did not increase after morphine discontinuation.

CONCLUSIONS:

Morphine tolerance and withdrawal did not detectably activate microglia and had no impact on [18F]DPA-714 brain kinetics in vivo.

KEYWORDS:

Addiction; DPA-714; Microglia; Neuroinflammation; Opioid; Tolerance

[Indexed for MEDLINE]

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