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 (V_T) 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 (V_T=0.086±0.009mLcm^-3) was not increased by morphine exposure and withdrawal (V_T=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.