Placebo effects mediated by endogenous opioid activity on mu-opioid receptors

Abstract

Reductions in pain ratings when administered a placebo with expected analgesic properties have been described and hypothesized to be mediated by the pain-suppressive endogenous opioid system. Using molecular imaging techniques, we directly examined the activity of the endogenous opioid system on mu-opioid receptors in humans in sustained pain with and without the administration of a placebo. Significant placebo-induced activation of mu-opioid receptor-mediated neurotransmission was observed in both higher-order and sub-cortical brain regions, which included the pregenual and subgenual rostral anterior cingulate, the dorsolateral prefrontal cortex, the insular cortex, and the nucleus accumbens. Regional activations were paralleled by lower ratings of pain intensity, reductions in its sensory and affective qualities, and in the negative emotional state of the volunteers. These data demonstrate that cognitive factors (e.g., expectation of pain relief) are capable of modulating physical and emotional states through the site-specific activation of mu-opioid receptor signaling in the human brain.

Figures

Figure 1.

Effects of pain and placebo on the activation of μ-opioid receptor-mediated neurotransmission. After correction for multiple comparisons, significant μ-opioid system activations during the sustained pain challenge (n = 14) were obtained in the dorsal anterior cingulate [DACing; x,y,z coordinates (in millimeters), 17, 10, 40; cluster size, 715 mm3; z score = 5.54; p < 0.005 after correction for multiple comparisons], medial prefrontal cortex (MPFC; x,y,z, 8, 45, -5; cluster size, 1064 mm3; z score = 3.90;p < 0.001), right (contralateral to pain) insular cortex (Ins; x,y,z, 49, 16, 6; cluster size, 257 mm3; zscore = 4.32; p < 0.005), ventral basal ganglia, bilaterally [nucleus accumbens (NAcc) extending to the ventral pallidum; right, x,y,z, 12, 4, -2, cluster size, 1700 mm3, z score = 9.26, p < 0.0001; left, x,y,z, -19, 9, 4, cluster size, 2177 mm3, z score = 4.32, p < 0.005], medial thalamus (Tha; x,y,z, -3, -15, 7; cluster size, 2283 mm3; z score = 6.49; p < 0.0001), right amygdala (Amy; x,y,z, 25, -2, -21; cluster size, 464 mm3; z score = 6.34; p < 0.0001), left subamygdalar temporal cortex (x,y,z, -28, 10, -38; cluster size, 560 mm3; zscore = 5.36; p < 0.005), and periaqueductal gray (x,y,z, -5, -28, -3; cluster size, 122 mm3; zscore = 3.56; p < 0.05). Significant effects of placebo on the activation of the μ-opioid system (n = 14) were detected in the left dorsolateral prefrontal cortex (DLPFC; x,y,z peak coordinates, -36, 13, 39; cluster size, 1403 mm3; z score = 4.27; p < 0.0001), rostral anterior cingulate (RACing; x,y,z, 14, 49, 13; cluster size, 3193 mm3; z score = 4.18; p < 0.0001), left NAcc (x,y,z, -7, 11, -11; cluster size, 1332 mm3; z score = 4.83; p < 0.0001), and right anterior insula (Ins; x,y,z, 41, 10, -17; cluster size, 844 mm3; z score = 4.15; p < 0.05). The posterior right insula achieved subthreshold levels of significance (x,y,z, 44, -15, 4; cluster size, 732 mm3; z score = 3.81; p < 0.0001 uncorrected for multiple comparisons). z scores of statistical significance are represented by the pseudocolor scale on the right side of the image and are superimposed over an anatomically standardized MRI image in coronal views. The left side of the axial and coronal images corresponds to the right side of the body (contralateral to pain; radiological convention). A map of μ-opioid receptor distribution is shown in the top right corner of the figure in a sagittal view, with binding potential (BP) values (receptor availability in vivo; Bmax/Kd) depicted by the same pseudocolor scale.

Figure 2.

Individual data points for the magnitude of regional μ-opioid system activation in response to the placebo intervention. Individual data points for the change in the binding potential measure (BP; μ-opioid receptor availability in vivo; Bmax/Kd) from the pain condition to the pain plus placebo condition are shown. A threshold of 10% increase in the activation of this neurotransmitter system, evidenced as a reduction in the BP measure during the placebo condition, was used to identify individuals that responded with a robust placebo effect on the activation of this system in each of the regions (dashed line). ACing_Rostral, Rostral (pregenual) region of the anterior cingulate; DLPFC_Left, left dorsolateral prefrontal cortex; Insula_Right, right insular cortex; N.Acc._Left, left nucleus accumbens.

Figure 3.

Relationship between placebo-induced regional μ-opioid system activation and expectation of analgesia. Negative correlation between the expected analgesic effects as rated by the volunteers before the study and the placebo-induced activation of dorsolateral prefrontal cortex (DLPFC) μ-opioid neurotransmission in placebo responders (black circles) and nonresponders (gray circles) are shown. BP, Binding potential.