Placebo effects on human mu-opioid activity during pain

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 [(11)C]carfentanil, which measures regional mu-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 mu-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.

Fig. 1.

Study hypotheses and procedures. (A) Mechanisms by which placebo may affect opioid binding. See text for details. +, positive effect; −, inhibitory effect. (B) Study procedures.

Fig. 2.

ROIs showing significant pain-specific opioid activation, [(CH − PH) − (CW − PW)]. ROI extent is shown in green, and significant voxels in or contiguous with ROIs are shown in red/yellow (positive effects) or lavender/blue (negative effects). Amy, amygdala; aOFC, anterior OFC; lOFC, lateral OFC/inferior frontal border; mOFC, medial OFC; thal, thalamus.

Fig. 3.

Placebo effects in heat vs. anticipation. (A) Regions showing placebo-induced opioid increases during heat (CH > PH). Color coding is as in Fig. 1. (B) Bar graphs showing placebo-induced opioid activity in warm (black bars) and heat (gray bars) averaged across regions (x axis). R, right; L, left. Other labels are as in Fig. 2. (C) Regions showing placebo-induced anticipatory opioid decreases (PW > CW). (D) Bar graphs for effects in C. Amy, amygdala; aOFC, anterior OFC; Cau, caudate; IFJ, inferior frontal junction; lOFC, lateral OFC/inferior frontal border; mOFC, medial OFC; thal, thalamus

Fig. 4.

Connectivity analysis of opioid binding potential. (A) 3D rendering of connectivity among regions that show placebo opioid responses. (B) Nonmetric multidimensional scaling (NMDS) connectivity graph of the regions in A. See text for explanation. L, left; R, right; amy, amygdala; aofc, anterior OFC; cau, caudate; ifj, inferior frontal junction; lofc, lateral OFC/inferior frontal border; mofc, medial OFC; thal, thalamus.

Fig. 5.

Placebo-modulated connectivity between PAG and rACC.