Fluorescent images of a key brain circuit involved in placebo pain relief in mice. Pain-regulating neurons located in the ventrolateral periaqueductal gray (vlPAG) are labeled in green, with their cell bodies visible as green spots and their wire-like axons extending to the brainstem to suppress pain.
Image Credit: Janie Chang-Weinberg
Scientific Frontline: Extended "At a Glance" Summary: The Neurobiology of Placebo Pain Relief
The Core Concept: Placebo pain relief is a phenomenon where the brain generates its own painkilling response—specifically through the release of endogenous opioid neuropeptides—without the administration of active pharmaceutical treatments. It is an expectancy-driven process that empowers the brain to produce broad-spectrum pain reduction on demand.
Key Distinction/Mechanism: Unlike traditional opioid painkillers (like morphine) that flood the system and carry a high risk of addiction and off-target side effects, placebo pain relief relies on precise, native neural circuits linking the cortex to the brainstem and spinal cord. The mechanism centers on the activation of endogenous opioid signaling within a specific brain region known as the ventrolateral periaqueductal gray (vlPAG).
Major Frameworks/Components:
- Reverse Translation Method: An experimental framework where human placebo conditioning protocols are adapted for murine models, bridging the gap between human clinical data and foundational neurobiology.
- Ventrolateral Periaqueductal Gray (vlPAG): The anatomical hub in the brain identified as the critical site for pain signaling and the release of native opioids during placebo trials.
- Endogenous Opioid Neuropeptides: Naturally occurring endorphins that act as the brain's internal painkillers.
- Photoactivatable Naloxone (PhNX): An innovative light-activated drug technology used to precisely control and block opioid receptors in real-time, verifying that internal opioid signaling is the primary driver of placebo relief.
Branch of Science: Neurobiology, Neuroscience, and Pharmacology.
Future Application: Clinical settings may eventually utilize targeted placebo conditioning to help patients build preemptive resilience to pain. This training could be applied before anticipated procedures (such as surgery) or as a generalized buffer against unanticipated injuries, effectively allowing patients to substitute addictive drugs with behavioral and neurological training.
Why It Matters: Understanding and manipulating the brain circuitry behind the placebo effect offers a viable, opioid-free strategy for broad-spectrum pain management. By training the brain to deploy its own targeted painkillers, medical professionals could significantly reduce the reliance on highly addictive prescription opioids, offering safer treatment pathways for acute and chronic pain.
Researchers demonstrate that placebo pain relief generalizes across different types of pain, offering hope for opioid-free pain management strategies
Placebo effects, in which patients experience relief without therapeutic treatment, increasingly have been considered as potentially powerful clinical treatments for ailments such as depression and pain. Yet the neurological mechanisms underlying such processes are not fully understood. Now, a multi-institutional team led by the University of California San Diego’s Matthew Banghart, an associate professor in the School of Biological Sciences, has pinpointed the brain circuitry responsible for placebo pain relief. Their findings, reported in the journal Neuron, describe brain regions that support placebo effects and identify sites where endogenous opioid neuropeptides (commonly referred to as endorphins) provide signals that are critical for placebo pain relief.
The study is the first to establish placebo mechanisms using a “reverse translation” method, in which a placebo protocol that works in humans was directly adapted to mice. Importantly, working with labs at the University of Pennsylvania and UC Irvine, they detected activity in mouse brain areas that correspond to those previously implicated in human studies. By precisely mapping neural pathways and manipulating brain activity in mice, the researchers uncovered essential roles for neural circuits linking the cortex to the brainstem and spinal cord during placebo pain relief.
“We took a placebo protocol from humans and worked it out in mice, and used that to deconstruct the underlying mechanisms,” said Banghart, a faculty member in the Department of Neurobiology. “We went much further than previous studies and pinpointed a site at which endogenous opioid peptides are critical, which previously had not been done.”
Notably, they discovered that training mice to exhibit a placebo effect with one type of pain produces marked relief of several different types of pain, including pain caused by injury.
“This finding has direct implications for how placebo training in humans might be used to produce resilience to future pain that results from injury, whether anticipated — such as an upcoming surgery — or unanticipated pain, such as a broken bone from a fall,” said Banghart.
The results of the research also offer hope of using such “expectancy-driven” placebo effects as a substitute for painkillers that can cause addiction. It’s possible, Banghart says, that patients in clinical settings could be trained to build preemtive resilience to pain using placebo conditioning.
To illuminate the role of naturally occurring opioid peptides in specific areas of the brain, the researchers implemented two emerging technologies. First, using novel sensors developed with colleagues at UC Davis and the Max Planck Florida Institute for Neuroscience, they detected opioid peptide signaling during placebo trials in a region called the ventrolateral periaqueductal gray (vlPAG), which is well-known as a hub for pain signaling.
To establish that these native opioid peptides actually drive pain relief, similar to opioid painkillers such as morphine, the researchers employed a light-activated drug developed in Banghart’s lab called PhNX, for photoactivatable naloxone. Naloxone, also known as Narcan, is the medicine used to reverse opioid overdoses by blocking opioid receptors. Using light, they were able to precisely control the site and timing of opioid signaling interference. Using PhNX, the scienists found that both morphine-induced pain relief and placebo pain relief rely on opioid signaling in the vlPAG brain region.
Co-first author Janie Chang-Weinberg, a PhD student in the Biological Sciences Graduate Program, states: “We essentially trained a mouse brain to create its own broad-spectrum painkillers on demand, precisely where they are needed to treat pain, without the off-target effects of opioid-based painkillers.”
“These results increase the translational relevance of rodent placebo models to clinical contexts, in which patients’ prior experiences with drugs and treatment settings can generalize to broader expectations of improvement,” the researchers conclude in their paper.
Future studies based on the new results will dig more deeply into how placebo learning unfolds in the brain. A primary goal of future studies will be to evaluate different placebo training strategies in mice with hopes of developing protocols that readily translate to produce placebo pain resilience in the general population, especially people living with chronic pain.
“This is something that can be very powerful,” said Banghart. “We should be tapping into it intentionally in order to reduce pain and suffering.”
Funding: The research was funded by the Rita Allen Foundation, the Esther A. & Joseph Klingenstein Fund & Simons Foundation, the Brain & Behavior Research Foundation (R00DA034648, RF1NS126073, U01NS113295 including a BRAIN Initiative Diversity Supplement, U01NS120820, UM1MH136462, DP2GM140923, R01DA056581, R01DA056599, K99DA060979, and T32GM133351).
Published in journal: Neuron
Title: Top-down control of the descending pain modulatory system drives multimodal placebo analgesia
Authors: Giulia Livrizzi, Janie Chang-Weinberg, Desiree A. Johnson, Susan T. Lubejko, Jingzhu Liao, Blake A. Kimmey, Chunyang Dong, Yuan Li, Kevin T. Beier, Gregory Corder, Lin Tian, and Matthew R. Banghart
Source/Credit: University of California San Diego | Mario Aguilera
Reference Number: ns041626_01