The Role of Opioid Receptors in Immune System Function

Abstract

Research on the effects of opioids on immune responses was stimulated in the 1980s by the intersection of use of intravenous heroin and HIV infection, to determine if opioids were enhancing HIV progression. The majority of experiments administering opioid alkaloids (morphine and heroin) in vivo, or adding these drugs to cell cultures in vitro, showed that they were immunosuppressive. Immunosuppression was reported as downregulation: of Natural Killer cell activity; of responses of T and B cells to mitogens; of antibody formation in vivo and in vitro; of depression of phagocytic and microbicidal activity of neutrophils and macrophages; of cytokine and chemokine production by macrophages, microglia, and astrocytes; by sensitization to various infections using animal models; and by enhanced replication of HIV in vitro. The specificity of the receptor involved in the immunosuppression was shown to be the mu opioid receptor (MOR) by using pharmacological antagonists and mice genetically deficient in MOR. Beginning with a paper published in 2005, evidence was presented that morphine is immunestimulating via binding to MD2, a molecule associated with Toll-like Receptor 4 (TLR4), the receptor for bacterial lipopolysaccharide (LPS). This concept was pursued to implicate inflammation as a mechanism for the psychoactive effects of the opioid. This review considers the validity of this hypothesis and concludes that it is hard to sustain. The experiments demonstrating immunosuppression were carried out in vivo in rodent strains with normal levels of TLR4, or involved use of cells taken from animals that were wildtype for expression of TLR4. Since engagement of TLR4 is universally accepted to result in immune activation by up-regulation of NF-κB, if morphine were binding to TLR4, it would be predicted that opioids would have been found to be pro-inflammatory, which they were not. Further, morphine is immunosuppressive in mice with a defective TLR4 receptor. Morphine and morphine withdrawal have been shown to permit leakage of Gram-negative bacteria and LPS from the intestinal lumen. LPS is the major ligand for TLR4. It is proposed that an occult variable in experiments where morphine is being proposed to activate TLR4 is actually underlying sepsis induced by the opioid.

The Impact of Substance Use Disorder on COVID-19 Outcomes

“…When hypertension, COPD, ischemic heart disease, and cerebrovascular disease-possible mediators between substance use disorder and COVID-19 adverse outcomes-were added to the matching algorithm, the increased risks for hospitalization and ventilator use persisted, but the mortality risk was attenuated. Overall, our findings are consistent with a broad literature that has reported adverse effects of substance use disorder on the respiratory, cardiovascular, and immune systems (1)(2)(3)9). The attenuation of risks, particularly mortality, in the final model-after matching on respiratory and cardiovascular diseases-suggests that the increased risks experienced by patients with a substance use disorder may be driven, at least in part, by drug-related respiratory and cardiovascular disease (1-3, 9-13).…”

“…For example, opioids exert various suppressive effects on both the innate and adaptive immune systems, especially among those who have long used substances ($90 days in a year). Largely by binding to the mu receptor and modulating various downstream cellular signaling pathways, opioids impair the recruitment and function of virtually all immune cells, such as macrophages, NK cells, granulocytes, and B and T lymphocytes (3). Methamphetamines are also reported to increase immune dysregulation, particularly in the lungs (15).…”

“…Likewise, substance use disorders have long been linked with immunosuppression. There is ample evidence that opioids, alcohol, methamphetamines, smoking, and vaping all have strong immunosuppressive effects, resulting in greater susceptibility to infection, more severe and longer lasting illnesses, and lower levels of protective antibodies in the blood (3,4). In addition, some substance use disorders, such as tobacco (smoking), cocaine, and alcohol use disorders, are associated with adverse cardiovascular effects, including hypertension, ischemia, venous thromboembolism, and brain hemorrhage (5,6).…”

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

“…Though still controversial, there is growing evidence that opioids can also induce a neuroinflammatory response via direct activation of TLR4 (toll-like receptor 4), a transmembrane receptor which activates NFκB signaling and inflammatory cascades(127). Alternatively, independent of opioid action, TLR4 may elicit an inflammatory response during opioid withdrawal(128).…”

Transcriptomic Analysis Reveals Receptor Subclass–Specific Immune Regulation of CD8+ T Cells by Opioids

“…Immune cells respond to environmental and extracellular cues via surface receptors. Opioid receptors (ORs) are G proteincoupled receptors stimulated by endogenous opioid peptides and narcotic analgesic drugs, which display immune regulatory activity (4,5).…”