Effects of placebo administration on immune mechanisms and relationships with central endogenous opioid neurotransmission

Alan Prossin,Alisa Koch,Phillip Campbell,Geoffroy Laumet,Jon-Kar Zubieta,Christian S Stohler,Robert Dantzer

doi:10.1038/s41380-021-01365-x

Abstract

Behavioral conditioning and expectation can have profound impact on animal and human physiology. Placebo, administered under positive expectation in clinical trials, can have potent effects on disease pathology, obscuring active medications. Emerging evidence suggests placebo-responsive neurotransmitter systems (e.g., endogenous opioid) regulate immune function by manipulating inflammatory proteins including IL-18, a potent pro-inflammatory, nociceptive cytokine implicated in pathophysiology of various diseases. Validation that neuroimmune interactions involving brain μ-opioid receptor (MOR) activity and plasma IL-18 underlie placebo analgesic expectation could have widespread clinical applications. Unfortunately, current lack of mechanistic clarity obfuscates clinical translation. To elucidate neuroimmune interactions underlying placebo analgesia, we exposed 37 healthy human volunteers to a standardized pain challenge on each of 2 days within a Positron Emission Tomography (PET) neuroimaging paradigm using the MOR selective radiotracer, 11C-Carfentanil (CFN). Each day volunteers received an intervention (placebo under analgesic expectation or no treatment), completed PET scanning, and rated their pain experience. MOR BPND parametric maps were generated from PET scans using standard methods. Results showed placebo reduced plasma IL-18 during pain (W74 = −3.7, p < 0.001), the extent correlating with reduction in pain scores. Placebo reduction in IL-18 covaried with placebo-induced endogenous opioid release in the left nucleus accumbens (T148 = 3.33; puncorr < 0.001) and left amygdala (T148 = 3.30; puncorr < 0.001). These findings are consistent with a modulating effect of placebo (under analgesic expectation in humans) on a potent nociceptive, pro-inflammatory cytokine (IL-18) and underlying relationships with endogenous opioid activity, a neurotransmitter system critically involved in pain, stress, and mood regulation.

Highlights

Behavioral expectation and conditioning can have profound effects across various medical illnesses including affective disorders [1], irritable bowel syndrome [2], asthma [3], osteoarthritic pain [4], and acute and chronic pain states [5,6,7,8,9,10,11,12]
We previously showed, in healthy humans during a non-painful, control condition, that plasma IL-1β was inversely proportional to μ-opioid receptor (μOR) BPND in the amygdala bilaterally
Sustained pain induced increase in anti-nociceptive IL-1ra covaried with endogenous opioid release in the nucleus accumbens, an effect moderated by pro-nociceptive IL-1β, suggesting strong interactions between central endogenous opioid neurotransmitter mechanisms and inflammatory mechanisms [20]

Summary

Introduction

Behavioral expectation and conditioning can have profound effects across various medical illnesses including affective disorders [1], irritable bowel syndrome [2], asthma [3], osteoarthritic pain [4], and acute and chronic pain states [5,6,7,8,9,10,11,12]. Research highlighting potential disease-modifying effects suggests placebo-responsive neurotransmitter systems can regulate immune function. Mood-induced regulation of IL-18 covaried with μ-opioid receptor (μOR) availability and endogenous opioid release in the nucleus accumbens and amygdala [29,30,31] during neutral (and sustained sad) affective states. These data suggest bidirectional relationships exist between central neurotransmitters modifiable by placebo administration (e.g., endogenous opioid) and stress-reactive innate immune processes.

Methods

Results

Conclusion