Placebo effects on human μ-opioid activity during pain

doi:10.1073/pnas.0702413104

Placebo effects on human μ-opioid activity during pain

*Department of Psychology, Columbia University, 1190 Amsterdam Avenue, New York, NY 10027; and
Departments of ^§Radiology and
^‡Psychiatry and Molecular and Behavioral Neuroscience Institute, University of Michigan, 205 Zina Pitcher Place, Ann Arbor, MI 48109-0720

Communicated by Edward E. Smith, Columbia University, New York, NY, March 15, 2007 (received for review October 26, 2006)

Abstract

Placebo-induced expectancies have been shown to decrease pain in a manner reversible by opioid antagonists, but little is known about the central brain mechanisms of opioid release during placebo treatment. This study examined placebo effects in pain by using positron-emission tomography with [¹¹C]carfentanil, which measures regional μ-opioid receptor availability in vivo. Noxious thermal stimulation was applied at the same temperature for placebo and control conditions. Placebo treatment affected endogenous opioid activity in a number of predicted μ-opioid receptor-rich regions that play central roles in pain and affect, including periaqueductal gray and nearby dorsal raphe and nucleus cuneiformis, amygdala, orbitofrontal cortex, insula, rostral anterior cingulate, and lateral prefrontal cortex. These regions appeared to be subdivided into two sets, one showing placebo-induced opioid activation specific to noxious heat and the other showing placebo-induced opioid reduction during warm stimulation in anticipation of pain. These findings suggest that a mechanism of placebo analgesia is the potentiation of endogenous opioid responses to noxious stimuli. Opioid activity in many of these regions was correlated with placebo effects in reported pain. Connectivity analyses on individual differences in endogenous opioid system activity revealed that placebo treatment increased functional connectivity between the periaqueductal gray and rostral anterior cingulate, as hypothesized a priori, and also increased connectivity among a number of limbic and prefrontal regions, suggesting increased functional integration of opioid responses. Overall, the results suggest that endogenous opioid release in core affective brain regions is an integral part of the mechanism whereby expectancies regulate affective and nociceptive circuits.

Footnotes

^†To whom correspondence should be addressed. E-mail: tor{at}psych.columbia.edu
Author contributions: T.D.W. and J.-K.Z. designed research; T.D.W. and D.J.S. performed research; T.D.W. and J.-K.Z. contributed new reagents/analytic tools; T.D.W. and D.J.S. analyzed data; and T.D.W., D.J.S., and J.-K.Z. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0702413104/DC1.
Abbreviations:

aINS,

anterior insula;

BP,

binding potential;

CH,

control with painful heat;

CW,

control with nonpainful warmth;

DLPFC,

dorsolateral PFC;

DRN,

dorsal raphe nucleus;

DVR,

distribution volume ratio;

fMRI,

functional MRI;

lOFC,

lateral OFC;

mOFC,

medial OFC;

NAC,

nucleus accumbens;

NCF,

nucleus cuneiformis;

OFC,

orbitofrontal cortex;

PAG,

periaqueductal gray;

PET,

positron-emission tomography;

PFC,

prefrontal cortex;

PH,

placebo with painful heat;

pgACC,

pregenual anterior cingulate;

PW,

placebo with nonpainful warmth;

rACC,

rostral anterior cingulate;

ROI,

region of interest;

SVC,

small volume corrected.
Freely available online through the PNAS open access option.