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

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 [18 F]DPA-714 was performed 60h after morphine withdrawal. Kinetic modeling was performed to estimate [18 F]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 [18 F]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 [18 F]DPA-714 brain kinetics in vivo.