Placebo Effects Mediated by Endogenous Opioid Activity on μ-Opioid Receptors

TLDR

Placebo reduces pain ratings by engaging the endogenous opioid system. The study used PET imaging to directly assess μ‑opioid receptor activity in humans experiencing sustained pain with and without placebo. Using PET imaging of μ‑opioid receptors, the authors compared receptor activity in sustained pain with and without placebo. Placebo produced significant μ‑opioid receptor activation in pregenual and subgenual rostral anterior cingulate, dorsolateral prefrontal cortex, insular cortex, and nucleus accumbens, which correlated with reduced pain intensity, sensory and affective qualities, and negative emotions, demonstrating that expectation of relief modulates physical and emotional states via site‑specific μ‑opioid signaling.

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 μ-opioid receptors in humans in sustained pain with and without the administration of a placebo. Significant placebo-induced activation of μ-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 μ-opioid receptor signaling in the human brain.