TY - JOUR
T1 - Effects of placebo administration on immune mechanisms and relationships with central endogenous opioid neurotransmission
AU - Prossin, Alan
AU - Koch, Alisa
AU - Campbell, Phillip
AU - Laumet, Geoffroy
AU - Stohler, Christian S.
AU - Dantzer, Robert
AU - Zubieta, Jon Kar
N1 - Funding Information:
Research Support to AP came from the University of Michigan Comprehensive Depression Center Rachel Upjohn Clinical Scholars Award and the National Institutes of Health (K99/R00 DA033454, R61 NS113316). Research support to JKZ came from the National Institutes of Health (R01 DA016423, R01 DA022520) and the Phil F. Jenkins Foundation. Research support to AK came from The Frederick G.L. Huetwell and William D. Robinson Professorship at the University of Michigan, the Veterans Administration Research Service, and the National Institutes of Health (R01 AR48267). Research support to Robert Dantzer came from the National Institutes of Health (R01 CA193522, R01 NS073939) and from a National Institutes of Health Cancer Center Support (CORE) grant (P30 CA016672 to the University of Texas MD Anderson).
Funding Information:
The authors would like to acknowledge the contributions of the late Steven Zalcman, PhD, Department of Psychiatry, University of Medicine and Dentistry of New Jersey, Newark, NJ who provided psychoneuroimmunology guidance and mentoring in the planning stages of the project. Dr. Stacia DeSantis provided statistical guidance during the revision of the manuscript. Additional contributions to this research are mentioned below. Zubieta Lab: Virginia Murphy-Weinberg, Tiffany Love, Heng Wang, Marta Pecina, MBNI staff. Nuclear Medicine: Jill Rothley, Edward McKenna, Andrew Weeden, Paul Kison, Shayna Huber.
Publisher Copyright:
© 2021, The Author(s).
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
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U2 - 10.1038/s41380-021-01365-x
DO - 10.1038/s41380-021-01365-x
M3 - Article
C2 - 34716408
AN - SCOPUS:85118360695
VL - 27
SP - 831
EP - 839
JO - Molecular Psychiatry
JF - Molecular Psychiatry
SN - 1359-4184
IS - 2
ER -