Opioidergic activation of the descending pain inhibitory system underlies placebo analgesia

Placebo analgesia is caused by inactive treatment, implicating endogenous brain function involvement. However, the neurobiological basis remains unclear. In this study, we found that μ-opioid signals in the medial prefrontal cortex (mPFC) activate the descending pain inhibitory system to initiate pl...

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Published in:Science advances 2025-01, Vol.11 (3), p.eadp8494
Main Authors: Neyama, Hiroyuki, Wu, Yuping, Nakaya, Yuka, Kato, Shigeki, Shimizu, Tomoko, Tahara, Tsuyoshi, Shigeta, Mika, Inoue, Michiko, Miyamichi, Kazunari, Matsushita, Natsuki, Mashimo, Tomoji, Miyasaka, Yoshiki, Dai, Yi, Noguchi, Koichi, Watanabe, Yasuyoshi, Kobayashi, Masayuki, Kobayashi, Kazuto, Cui, Yilong
Format: Article
Language:English
Subjects:
Analgesia - methods
Analgesics, Opioid - pharmacology
Animals
Male
Neuralgia - metabolism
Neurons - metabolism
Neuroscience
Pain - metabolism
Periaqueductal Gray - metabolism
Placebo Effect
Prefrontal Cortex - metabolism
Psychological Science
Rats
Rats, Sprague-Dawley
Receptors, GABA-A - metabolism
Receptors, Opioid, mu - metabolism
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Summary:Placebo analgesia is caused by inactive treatment, implicating endogenous brain function involvement. However, the neurobiological basis remains unclear. In this study, we found that μ-opioid signals in the medial prefrontal cortex (mPFC) activate the descending pain inhibitory system to initiate placebo analgesia in neuropathic pain rats. Chemogenetic manipulation demonstrated that specific activation of μ-opioid receptor-positive (MOR ) neurons in the mPFC or suppression of the mPFC-ventrolateral periaqueductal gray (vlPAG) circuit inhibited placebo analgesia in rats. MOR neurons in the mPFC are monosynaptically connected and directly inhibit layer V pyramidal neurons that project to the vlPAG via GABA receptors. Thus, intrinsic opioid signaling in the mPFC disinhibits excitatory outflow to the vlPAG by suppressing MOR neurons, leading to descending pain inhibitory system activation that initiates placebo analgesia. Our results shed light on the fundamental neurobiological mechanism of the placebo effect that maximizes therapeutic efficacy and reduces adverse drug effects in medical practice.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.adp8494