Imaging the Neuroimmune Effects of Acute Opioid Administration
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Change in Brain TSPO availability
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- Single (Participant)
盲法说明
Subjects are informed that they will receive a single morphine injection. Subjects are blinded to the morphine dose condition. Investigators and assessors are not blinded to morphine dose condition.
入排标准
- 年龄范围
- 21 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Men and women aged between 21 and 50 years (driver's license or valid state ID).
- •Physically healthy by medical history, physical, neurological, EKG and laboratory examinations (reviewed by the Study Physician).
- •Normal weight, as indicated by a body mass index (BMI) and body weight ≤ 250lbs.
- •Read, comprehend, and write English at a sufficient level to complete study-related materials.
- •Able to provide voluntary and written informed consent.
- •Eligibility and willingness to participate in study procedures, including MRI and PET scanning.
- •Previous medical use of opioids without adverse reactions (≥2 lifetime uses).
- •Medically eligible to receive up to 0.1 mg/kg deltoid intramuscular morphine (based on medical history, medical exams, and not meeting any exclusion criteria below).
- •Medically eligible to receive 10mg of oral metoclopramide based on medical history, medical exams, and current medications.
- •Exclusion criteria:
- •Any DSM-5 Axis I disorder diagnosis based on Structured Clinical Interview for DSM-5 (SCID-5), including meeting criteria for substance dependence.
- •Any current psychotropic medication use, including MAOI use within the past 14 days
- •Recent (past 6 months) medical or non-medical opioid-use.
- •Prior medical use prescription opioids for >14 consecutive days (self-report)
- •Prior non-medical use of any opioid (i.e., recreational opioid use will be excluded).
- •Positive result on a urine drug screen (excluding marijuana).
- •Current or previous chronic pain disorder (>6 months of continuous pain).
- •'Low affinity binding' individuals based on rs6971 polymorphism (<10% of the population).
- •For females, pregnancy (positive urine test).
- •Current use of non-steroidal anti-inflammatory medications or statins.
- •Medical contraindication to receive up to 0.1 mg/kg intramuscular morphine administration as determined by Study Physician. This includes:
- •known hypersensitivity/allergy to morphine;
- •acute or severe bronchial asthma;
- •known or suspected gastrointestinal obstruction, including paralytic ileus;
- •seizure disorder;
- •concomitant use of a benzodiazepine or any other CNS depressant;
- •any other significant medical condition, that in the opinion of the Study Physician and Investigators, could: put the patient at risk because of participation in the study, or influence the results of the study, or cause concern about the patient's ability to successfully complete in the study.
- •Known family history (first-degree relative) of opioid-use disorder or alcohol-use disorder.
- •MRI contraindications, including metal in body (or work in metal/machine shop), pacemaker, claustrophobia, or inability to tolerate MRI scanning.
- •Medical contraindications to metoclopramide, as determined by the Study Physician, including:
- •known hypersensitivity/allergy to metoclopramide;
- •mechanical gastrointestinal obstruction, perforation, or hemorrhage;
- •seizure disorder;
- •history of tardive dyskinesia;
- •or concomitant use of medications/agents likely to increase extrapyramidal reactions.
排除标准
- 未提供
研究组 & 干预措施
High Morphine Dose
Subjects in this experimental arm will receive a single intramuscular morphine dose (non-dominant deltoid muscle; 0.07 mg/kg).
干预措施: High Morphine Dose (Drug)
Low Morphine Dose
Subjects in this experimental arm will receive a single intramuscular morphine dose (non-dominant deltoid muscle; 0.04 mg/kg).
干预措施: Low Morphine Dose (Drug)
结局指标
主要结局
Change in Brain TSPO availability
时间窗: One 120-minute PET [11C]PBR28 scan before and one PET [11C]PBR28 scan 2hr after morphine challenge.
Relative to pre-morphine levels, we will measure the change in brain regional TSPO availability (VT) after morphine. VT will be calculated for brain regions of interest using multi-linear analysis 1 (t\*=30) using the metabolite-corrected arterial input function.
次要结局
- Change in Verbal Memory Performance(This Cogstate task will be administered twice: once before and once ~70 minutes after the morphine challenge.)
- Change in Working Memory (easy)(This Cogstate task will be administered twice: once before and once ~60 minutes after the morphine challenge.)
- Change in Psychomotor Speed(This Cogstate task will be administered twice: once before and once ~45 minutes after the morphine challenge.)
- Change in Visual Attention(This Cogstate task will be administered twice: once before and once ~50 minutes after the morphine challenge.)
- Change in Visual Learning(This Cogstate task will be administered twice: once before and once ~55 minutes after the morphine challenge.)
- Change in Working Memory (hard)(This Cogstate task will be administered twice: once before and once ~65 minutes after the morphine challenge.)
- Change in Verbal Learning Performance(This Cogstate task will be administered twice: once before and once ~40 minutes after the morphine challenge.)
- Change in Venous Epinephrine Concentration(Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.)
- Change in Venous Norepinephrine Concentration(Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.)
- Change in Thermal Pain Sensitivity(The Cold Pressor Task will be administered once before and once ~90-minutes after the morphine challenge.)
- Change in Venous Cytokine/Chemokine Concentration(Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.)
- Change in Venous Cortisol Concentration(Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.)
- Change in Venous Pregnenolone Concentration(Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.)
- Change in Venous Ghrelin Concentration(Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.)
- Change in Thermal Pain Tolerance(The Cold Pressor Task will be administered once before and once ~90-minutes after the morphine challenge.)
- Change in Reward Responsiveness(The Probabilistic Reward Task will be administered once before and once ~260 minutes after morphine.)
- Change in Venous Allopregnanolone Concentration(Plasma samples will be collected 10-minutes before and 60-minutes, 110-minutes, and 250-minutes after the morphine challenge.)
研究者
Eric Woodcock
Associate Research Scientist
Yale University