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Jon-Kar Zubieta, MD, PhD; Terence A. Ketter, MD; Joshua A. Bueller, BA; Yanjun Xu, PhD; Michael R. Kilbourn, PhD; Elizabeth A. Young, MD; Robert A. Koeppe, PhD

Arch Gen Psychiatry. 2003;60:1145-1153.

Background  Human affective responses appear to be regulated by limbic and paralimbic circuits. However, much less is known about the neurochemical systems engaged in this regulation. The µ-opioid neurotransmitter system is distributed in, and thought to regulate the function of, brain regions centrally implicated in affective processing.

Objective  To examine the involvement of µ-opioid neurotransmission in the regulation of affective states in healthy human volunteers.

Design  Measures of µ-opioid receptor availability in vivo were obtained with positron emission tomography and the µ-opioid receptor selective radiotracer [¹¹C]carfentanil during a neutral state and during a sustained sadness state. Subtraction analyses of the binding potential maps were then performed within subjects, between conditions, on a voxel-by-voxel basis.

Setting  Imaging center at a university medical center.

Participants  Fourteen healthy female volunteers.

Intervention  Sustained neutral and sadness states, randomized and counterbalanced in order, elicited by the cued recall of an autobiographical event associated with that emotion.

Main Outcome Measures  Changes in µ-opioid receptor availability and negative and positive affect ratings between conditions. Increases or reductions in the in vivo receptor measure reflect deactivation or activation of neurotransmitter release, respectively.

Results  The sustained sadness condition was associated with a statistically significant deactivation in µ-opioid neurotransmission in the rostral anterior cingulate, ventral pallidum, amygdala, and inferior temporal cortex. This deactivation was reflected by increases in µ-opioid receptor availability in vivo. The deactivation of µ-opioid neurotransmission in the rostral anterior cingulate, ventral pallidum, and amygdala was correlated with the increases in negative affect ratings and the reductions in positive affect ratings during the sustained sadness state.

Conclusions  These data demonstrate dynamic changes in µ-opioid neurotransmission in response to an experimentally induced negative affective state. The direction and localization of these responses confirms the role of the µ-opioid receptor system in the physiological regulation of affective experiences in humans.

From the Department of Psychiatry and Mental Health Research Institute (Drs Zubieta, Xu, and Young and Mr Bueller), and the Department of Radiology, University of Michigan, Ann Arbor (Drs Zubieta, Kilbourn, and Koeppe); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, Calif (Dr Ketter).

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