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.”
The contributing authors for the study were: 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.
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).
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