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

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 protein18 kDa (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(10–40 mg/kg) on five days to achieve tolerance and a withdrawal syndromeafter morphinediscontinuation. MicroPET imaging with [ 18 F] DPA-714was performed 60 h after morphinewithdrawal. Kinetic modeling was performed to estimate [ 18 F] DPA-714volume 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 14 days after morphinediscontinuation. Results The baseline binding of [ 18 F] DPA-714to the brain (V T = 0.086 ± 0.009 mL cm −3 ) was not increased by morphineexposure and withdrawal (V T = 0.079 ± 0.010 mL cm −3 ) indicating the absence of TSPO overexpression, even at the regional level. Accordingly, expression of glial markers did not increase after morphinediscontinuation. Conclusions Morphinetolerance and withdrawal did not detectably activate microglia and had no impact on [ 18 F] DPA-714brain kinetics in vivo.