Opioids Recruit the Immune System to Cause Withdrawal Symptoms

According to a study, heroin causes T cells to breach the blood-brain barrier and wreak havoc on the brain, suggesting new strategies for preventing withdrawal.

Researchers have identified a previously unidentified immune system mechanism that leads to unstable and faulty connections among brain cells as one way that opioid use appears to cause withdrawal symptoms.

Despite the immune system’s long-standing association with opioid withdrawal, the new research, which was published January 19 in Cell, is the first to establish a connection between the immune system’s interactions with the brain’s blood-brain barrier and withdrawal, according to immunopathogenesis researcher Luis Montaner, a professor at the Wistar Institute in Philadelphia who was not involved in the study. The study, according to Montaner, provides researchers with “a roadmap for new clinical interventions to be tested” to prevent withdrawal and assist those recovering from opioid addiction or dependence wean off the drug safely while avoiding relapse. This is true even though some of the findings still need to be replicated and verified.

Toby Eisenstein, an immunologist and substance abuse researcher at Temple University who was not involved in the study, said that it “represents a major advance in the emerging field of neural-immune interactions and the role of immune cells and mediators in modulating neural processes during opioid exposure.” “The document is undoubtedly a huge step forward,” I firmly believe. Because opioids and the immune cells found in the new study have long been recognized to have immunosuppressive properties, Eisenstein says she was captivated by the paper’s assertion that withdrawal symptoms are related to an inflammatory immune response. Eisenstein talked about this in a 2019 review article on the effects of morphine on the immune system. 

Moving on to a mouse model, the researchers discovered that administering heroin to mice increased the number of fragile-like Tregs and, consequently, the level of IFN- expression in the blood. IFN- was found to be more prominent in the nucleus accumbens, a part of the brain that regulates goal-directed behaviors and reward pathways, according to the analysis of samples taken from the heroin-treated mice. This finding has implications for understanding and treating addiction.

The heightened IFN- in that area, according to the study’s authors, suggests that the fragile-appearing Treg cells were successful in crossing the blood-brain barrier, the physical barrier that shields the brain from viruses (and many drugs) flowing via the body’s blood vessels. The study connected the vulnerability to breaches in the blood-brain barrier brought on by nucleus accumbens neurons’ production of C-C motif chemokine ligand 2 (Ccl2), which was aided by opioid exposure and enhances Treg trafficking into the brain. Eisenstein found that particularly intriguing: “The fact that the chemokine expression was coming from within the brain hints that brain cells have a larger role in the immune response than previously assumed.” Chemokines are responsible for trafficking immune cell subsets that express the receptor for the particular chemokine.

According to Eisenstein, “I believe the publication is significantly advancing the entire neuroimmune research and perhaps our understanding of what immune mediators and cells are doing in the brain.”

The researchers came to the conclusion that the mice developed withdrawal symptoms because the fragile-appearing Treg cells (and specifically the IFN- they released) were altering the nucleus accumbens and decreasing synaptic connections among neurons. However, staining showed that other cytokines and inflammatory agents remained at the same levels. In conclusion, the research shows that opioid stimulation “boosts the entry of fragile-like Tregs into the [central nervous system] and subsequently leads to structural and behavioral changes.”