Neuroimmune Effects of Opioid Administration
Condition: Drug Effect
Study type: Interventional
Phase: Phase 1

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): High Morphine Dose; Low Morphine Dose
Intervention type(s): Drug; Drug
Intervention description(s): Subjects will receive an intramuscular morphine injection (0.07mg/kg) in the non-dominant deltoid muscle. Metoclopramide (10mg; oral) will be administered PRN to reduce nausea.; Subjects will receive an intramuscular morphine injection (0.04mg/kg) in the non-dominant deltoid muscle. Metoclopramide (10mg; oral) will be administered PRN to reduce nausea.
Other intervention name(s): High Dose; Low Dose
Intervention MeSH terms: Morphine
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Subjects will receive a single intramuscular morphine dose: 'High' (0.07mg/kg i.m.) vs. 'Low' (0.04mg/kg i.m.)
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Neuroimmune System; Morphine; PET Imaging; TSPO