Regulation of human affective responses by anterior cingulate
and limbic mu-opioid neurotransmission

Zubieta JK, Ketter TA, Bueller JA, Xu Y, Kilbourn MR, Young EA, Koeppe RA.
Department of Psychiatry and Mental Health Research Institute,
University of Michigan, 205 Zina Pitcher Place,
Ann Arbor, MI 48109-0720, USA.
Arch Gen Psychiatry. 2003 Nov;60(11):1145-53.


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 mu-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 mu-opioid neurotransmission in the regulation of affective states in healthy human volunteers. DESIGN: Measures of mu-opioid receptor availability in vivo were obtained with positron emission tomography and the mu-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 mu-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 mu-opioid neurotransmission in the rostral anterior cingulate, ventral pallidum, amygdala, and inferior temporal cortex. This deactivation was reflected by increases in mu-opioid receptor availability in vivo. The deactivation of mu-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 mu-opioid neurotransmission in response to an experimentally induced negative affective state. The direction and localization of these responses confirms the role of the mu-opioid receptor system in the physiological regulation of affective experiences in humans.
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