title: Evaluation of TSPO PET imaging, a marker of glial activation, to study the neuroimmune footprints of morphine exposure and withdrawal.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Morphine tolerance and withdrawal did not detectably activate microglia and had no impact on [18F]DPA-714 brain kinetics in vivo.
authors.affiliation: 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.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Auvity
authors.affiliation: Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay F-91401, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Goutal
authors.affiliation: Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay F-91401, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Thézé
authors.affiliation: 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.
authors.forename: Catarina
authors.initials: C
authors.lastname: Chaves
authors.affiliation: 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.
authors.forename: Benoît
authors.initials: B
authors.lastname: Hosten
authors.affiliation: Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay F-91401, France.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Kuhnast
authors.affiliation: Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay F-91401, France.
authors.forename: Wadad
authors.initials: W
authors.lastname: Saba
authors.affiliation: Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay F-91401, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Boisgard
authors.affiliation: Imagerie Moléculaire In Vivo, IMIV, CEA, Inserm, CNRS, Univ. Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay F-91401, France.
authors.forename: Irène
authors.initials: I
authors.lastname: Buvat
authors.affiliation: 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.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cisternino
authors.affiliation: 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.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tournier
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011720:Pyrazoles; D011743:Pyrimidines; D051381:Rats
chemical_list: D015415:Biomarkers; C530129:N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo(1,5-a)pyrimidin-3-yl)acetamide; D011720:Pyrazoles; D011743:Pyrimidines; D009020:Morphine
keywords: Addiction; DPA-714; Microglia; Neuroinflammation; Opioid; Tolerance