In recent years, ketamine, once known primarily as an anesthetic, has emerged as a groundbreaking treatment for depression, offering rapid relief to many patients who have not responded to traditional antidepressants. A study published in Translational Psychiatry has shed light on the underlying mechanisms of ketamine’s fast-acting antidepressant effects, revealing a critical role played by the opioid system in the brain.
Despite its known role in blocking certain receptors in the brain associated with glutamate—a neurotransmitter linked to mood regulation—ketamine’s interaction with the brain’s opioid system has remained less understood. The endogenous opioid system, which includes receptors that naturally occurring peptides like endorphins activate, plays a pivotal role in managing pain, reward, and stress responses. This system’s involvement in mood disorders suggests a potential therapeutic target for depression.
“Ketamine has emerged as an important tool in the treatment of depression. Understanding how it works in the brain is critical both to optimize how we use it, and to lead the way to other new treatments,” explained study author Cheng Jiang, an associate research scientist in the Pittenger Lab at the Yale University School of Medicine.
“In recent years, several studies have suggested that the endogenous opioid system plays a key role in ketamine’s effects. This propelled us to explore how endogenous opioids, especially β-endorphin, contribute to ketamine’s functions. We focused on the prefrontal cortex, a brain region that has previously been shown to have a key role in ketamine’s effects.”
The researchers uncovered several pivotal findings that highlight the essential role of the endogenous opioid system, particularly the β-endorphin pathway in the medial prefrontal cortex (mPFC), in the rapid antidepressant effects of ketamine in rats. Their investigations revealed that the preemptive blockade of opioid receptors through systemic administration of naltrexone significantly nullified the antidepressant-like behaviors typically induced by ketamine.
Specifically, in behavioral tests designed to assess symptoms relevant to depression, ketamine’s beneficial effects were completely abrogated by naltrexone. This was evident in tests measuring the time rats spent immobile (indicating despair), their interest in stimuli associated with pleasure (like sniffing female urine, indicating anhedonia), and their willingness to engage with food in a new environment (reflecting anxiety levels).
Further delving into the mechanisms, the study showed that direct infusion of naltrexone into the mPFC also blocked the antidepressant-like actions of ketamine, underscoring the critical role of opioid receptors in this specific brain region. This localized intervention pinpoints the mPFC as a key site where opioid signaling intersects with ketamine’s antidepressant mechanism.
“We found, in rats, that ketamine activates the endogenous opioid system in the prefrontal cortex, and that disrupting this signaling blocks ketamine’s antidepressant-like effects,” Jiang told PsyPost. “This suggests a model in which ketamine activates endogenous opioid signaling, which then works together with other molecular mechanisms to produce antidepressant effects. If this is true, and if it generalizes to humans, it could help us better target and optimize ketamine’s therapeutic effects and perhaps lead the way to other novel antidepressants in the future.”
Moreover, the researchers found that ketamine treatment led to a significant increase in β-endorphin levels in the mPFC. This peptide, which is a primary endogenous agonist for μ-opioid receptors, showed elevated levels shortly after ketamine administration, suggesting a direct or indirect stimulation of β-endorphin release by ketamine.
The increase in β-endorphin was paralleled by an upsurge in the expression of the Pomc gene in the hypothalamus, which encodes the β-endorphin precursor, indicating a systemic effect of ketamine on the body’s opioid peptide production. However, this elevation was transient, with β-endorphin levels returning to baseline 24 hours post-treatment, pointing to the rapid and yet fleeting nature of ketamine’s action on this system.
Interestingly, when the action of β-endorphin in the mPFC was specifically neutralized using an anti-β-endorphin antibody, the antidepressant-like effects of ketamine were again nullified. This finding not only reinforces the importance of β-endorphin but also indicates that its action within the mPFC is necessary for ketamine’s beneficial behavioral outcomes.
Lastly, at the molecular level, ketamine induced changes in the phosphorylation of proteins associated with synaptic signaling within the mPFC, alterations that were prevented by the blockade of opioid receptors or the neutralization of β-endorphin. This suggests that the opioid system’s activation, particularly through β-endorphin, is critical for the synaptic modifications that underlie ketamine’s rapid antidepressant effects.
Using rats enabled the researchers to maintain a controlled environment. Rats share a significant degree of genetic, biological, and neurological similarity with humans, making them highly relevant for studying complex brain functions and disorders, including depression. But future research will need to confirm these findings in humans.
“Our work was in rats; we don’t know how well it will generalize to humans,” Jiang noted. “And we only used male rats. Sex differences have been observed in response to ketamine. It will be important to examine whether differences between males and females in the endogenous opioid system contribute to these differential responses.”
Looking ahead, Jiang said future research could seek “to determine how ketamine increases the presence of β-endorphin, a naturally produced opioid, in the prefrontal cortex. Given the implication of β-endorphin in the pathophysiology and treatment of depression, this may inform the development of novel treatment strategies for depression.”
The study, “The endogenous opioid system in the medial prefrontal cortex mediates ketamine’s antidepressant-like actions,” was authored by Cheng Jiang, Ralph J. DiLeone, Christopher Pittenger, and Ronald S. Duman.
