title: Acute opioid withdrawal is associated with increased neural activity in reward-processing centers in healthy men: A functional magnetic resonance imaging study.
abstract: BACKGROUND
  Opioid analgesics are frequently prescribed for chronic pain. One expected consequence of long-term opioid use is the development of physical dependence. Although previous resting state functional magnetic resonance imaging (fMRI) studies have demonstrated signal changes in reward-associated areas following morphine administration, the effects of acute withdrawal on the human brain have been less well-investigated. In an earlier study by our laboratory, ondansetron was shown to be effective in preventing symptoms associated with opioid withdrawal. The purpose of this current study was to characterize neural activity associated with acute opioid withdrawal and examine whether these changes are modified by ondansetron.
  
  
  METHODS
  Ten participants were enrolled in this placebo-controlled, randomized, double-blind, crossover study and attended three acute opioid withdrawal sessions. Participants received either placebo or ondansetron (8Ymg IV) before morphine administration (10Ymg/70Ykg IV). Participants then underwent acute naloxone-precipitated withdrawal during a resting state fMRI scan. Objective and subjective opioid withdrawal symptoms were assessed.
  
  
  RESULTS
  Imaging results showed that naloxone-precipitated opioid withdrawal was associated with increased neural activity in several reward processing regions, including the right pregenual cingulate, putamen, and bilateral caudate, and decreased neural activity in networks involved in sensorimotor integration. Ondansetron pretreatment did not have a significant effect on the imaging correlates of opioid withdrawal.
  
  
  CONCLUSIONS
  This study presents a preliminary investigation of the regional changes in neural activity during acute opioid withdrawal. The fMRI acute opioid withdrawal model may serve as a tool for studying opioid dependence and withdrawal in human participants.
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive, Grant Building Room S268C, Stanford, CA 94305, United States. Electronic address: lchu@stanford.edu.
authors.forename: Larry F
authors.initials: LF
authors.lastname: Chu
authors.affiliation: Department of Psychology, University of Alabama at Birmingham, 233 Campbell Hall, 1300 University Boulevard, Birmingham, AL 35294, United States.
authors.forename: Joanne C
authors.initials: JC
authors.lastname: Lin
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive, Grant Building Room S268C, Stanford, CA 94305, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Clemenson
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive, Grant Building Room S268C, Stanford, CA 94305, United States.
authors.forename: Ellen
authors.initials: E
authors.lastname: Encisco
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive, Grant Building Room S268C, Stanford, CA 94305, United States.
authors.forename: John
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive, Grant Building Room S268C, Stanford, CA 94305, United States.
authors.forename: Dan
authors.initials: D
authors.lastname: Hoang
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive, Grant Building Room S268C, Stanford, CA 94305, United States.
authors.forename: Heather
authors.initials: H
authors.lastname: Alva
authors.affiliation: Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive, Grant Building Room S268C, Stanford, CA 94305, United States.
authors.forename: Matthew
authors.initials: M
authors.lastname: Erlendson
authors.affiliation: Veterans Affairs Palo Alto Healthcare System, 3801 Miranda Avenue, Palo Alto, CA 94304, United States.
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
authors.affiliation: Department of Psychology, University of Alabama at Birmingham, 233 Campbell Hall, 1300 University Boulevard, Birmingham, AL 35294, United States.
authors.forename: Jarred W
authors.initials: JW
authors.lastname: Younger
mesh_terms: D000328:Adult; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D059907:Functional Neuroimaging; D064368:Healthy Volunteers; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009020:Morphine / Q000037:antagonists & inhibitors; D009270:Naloxone / Q000009:adverse effects; D009434:Neural Pathways / Q000187:drug effects / Q000503:physiopathology*; D017294:Ondansetron / Q000627:therapeutic use; D012201:Reward; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000503:physiopathology*
chemical_list: D009270:Naloxone; D017294:Ondansetron; D009020:Morphine
keywords: Function magnetic resonance imaging (fMRI); Morphine; Naloxone; Resting state; Withdrawal