Neuroimmune Effects of Opioid Administration

Drug Effect

Neuroimmune System, Morphine, PET Imaging, TSPO

Preclinical research indicates acute opioid administration evokes an immune response in the periphery and brain. Here, we will translate those preclinical findings to healthy human volunteers and quantify the neuroimmune response to a morphine challenge using positron emission tomography (PET) imaging with \[11C\]PBR28.

Subjects will be recruited from the local community via media advertisements, flyers, and word-of-mouth. Interested individuals will undergo a phone screen and in-person medical and psychiatric examination. Up to 20 eligible individuals (see Inclusion/Exclusion criteria) will be invited to participate in this study. In a single day, subjects will complete behavioral and physiological testing, a \[11C\]PBR28 PET scan, and report subjective drug effects before and after a morphine challenge. Subjects will complete either a 'High' or 'Low' morphine dose condition (single-blind): 0.07mg/kg i.m. vs. 0.04mg/kg i.m., respectively. To measure the neuroimmune response to morphine, we will use \[11C\]PBR28 PET imaging (120-minute scans on a High Resolution Research Tomograph with Vicra motion correction). \[11C\]PBR28 binds with high affinity and specificity to the 18kDa translocator protein (TSPO), which is highly expressed in microglia and has been shown to respond to inflammatory challenges. TSPO volumes of distribution (VT), i.e., TSPO availability, will be quantified in brain regions of interest using multilinear analysis-1 (MA-1) with the metabolite-corrected arterial input function. The post-morphine \[11C\]PBR28 PET scan will occur 2-hours after the morphine challenge. Specific Aim 1: To determine whether an acute morphine administration increases brain TSPO availability in healthy volunteers. Hypothesis 1: Relative to pre-morphine levels, morphine will significantly increase TSPO availability across brain regions of interest, consistent with a neuroimmune response. Specific Aim 2: To determine whether morphine evokes a dose-dependent increase in brain TSPO availability in healthy volunteers. Hypothesis 2: Relative to pre-morphine levels, morphine will dose-dependently increase TSPO availability across brain regions of interest. Specific Aim 3: To determine whether morphine administration increases peripheral markers of inflammation, e.g., cytokine/chemokine concentration in plasma. Hypothesis 3: Relative to pre-morphine levels, morphine will increase cytokine/chemokine concentrations in plasma, including IL-1B, IL-2, IL-6, IL-10, TNF-a, IFNy, MCP-1, and GM-CSF, consistent with a peripheral immune response. Exploratory Hypotheses: 1) IL-1B, IL-6, TNF-a, IFNy, MCP-1, and GM-CSF will exhibit morphine dose-dependent increases in plasma. 2) The change in IL-6, TNF-a, IFN-y, and GM-CSF levels will be positively correlated with the change in brain TSPO VT levels. Specific Aim 4: To determine whether morphine administration alters pain sensitivity, pain tolerance, cognitive function, and reward responsiveness. Hypothesis 4: Relative to pre-morphine levels, morphine will enhance pain tolerance and impair verbal learning/memory proficiency and impair reward responsiveness. Morphine will not alter pain sensitivity, visual attention, psychomotor processing speed, or working memory proficiency. Exploratory hypotheses: 1) The change in TSPO availability in thalamus will be positively correlated with the change in pain tolerance. 2) The change in TSPO availability in hippocampus will be inversely correlated with the change in verbal learning/memory proficiency. 3) The change in TSPO availability in caudate, ACC, and OFC will be inversely correlated with the change in reward responsiveness. Specific Aim 5: To determine whether morphine administration alters vital signs. Hypothesis 5: Relative to pre-morphine levels, morphine will dose-dependently reduce systolic and diastolic blood pressure. Relative to pre-morphine levels, morphine will lower heart rate. Specific Aim 6: To measure the subjective response to morphine administration. Hypothesis 6: Relative to pre-morphine levels, morphine will dose-dependently increase subjective ratings of 'high', 'good drug effect', 'nausea', and 'bad drug effect'. Exploratory hypotheses: 1) The change in TSPO availability in caudate, ACC, and OFC will be positively correlated with the change in 'high' and 'good drug effect'. 2) The change in TSPO availability in the insula and thalamus will be positively correlated with the change in 'nausea' and 'bad drug effect'. Specific Aim 7: To determine whether morphine administration alters peripheral stress markers of the autonomic nervous system and HPA-axis. Hypothesis 7: Relative to pre-morphine levels, morphine will dose-dependently increase plasma levels of epinephrine, norepinephrine, and cortisol. Specific Aim 8: To determine whether morphine administration alters peripheral markers of neurosteroids. Hypothesis 8: Relative to pre-morphine levels, morphine will dose-dependently increase plasma levels of allopregnanolone and pregnenolone. Specific Aim 9: To determine whether morphine administration alters peripheral markers of the metabolic hormone ghrelin. Hypothesis 9: Relative to pre-morphine levels, morphine will dose-dependently increase plasma levels of ghrelin.

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