Morphine disrupts macrophage functions even during HIV infection

Abstract

HIV‐associated neurocognitive impairment (HIV‐NCI) is a debilitating comorbidity that reduces quality of life in 15–40% of people with HIV (PWH) taking antiretroviral therapy (ART). Opioid use has been shown to increase neurocognitive deficits in PWH. Monocyte‐derived macrophages (MDMs) harbor HIV in the CNS even in PWH on ART. We hypothesized that morphine (MOR), a metabolite of heroin, further dysregulates functional processes in MDMs to increase neuropathogenesis. We found that, in uninfected and HIV‐infected primary human MDMs, MOR activates these cells by increasing phagocytosis and up‐regulating reactive oxygen species. Effects of MOR on phagocytosis were dependent on μ‐opioid receptor activity and were mediated, in part, by inhibited lysosomal degradation of phagocytized substrates. All results persisted when cells were treated with both MOR and a commonly prescribed ART cocktail, suggesting minimal impact of ART during opioid exposure. We then performed mass spectrometry in HIV‐infected MDMs treated with or without MOR to determine proteomic changes that suggest additional mechanisms by which opioids affect macrophage homeostasis. Using downstream pathway analyses, we found that MOR dysregulates ER quality control and extracellular matrix invasion. Our data indicate that MOR enhances inflammatory functions and impacts additional cellular processes in HIV‐infected MDMs to potentially increases neuropathogenesis in PWH using opioids.

Morphine acts in vitro to directly prime nociceptors

“…DRG cultures were prepared from whole DRGs not cleared of non-neuronal cells. While it has been reported that these cells express MOR and can act indirectly to contribute to sensitization of DRG neurons 44 , 45 by an activated of immune response, in vivo 46 – 48 However, we prepared low-density DRG neuronal cultures that were used within 3 days, at which time there is minimal growth of non-neuronal cells and nociceptor neurites. This approach has allowed us to patch nociceptors without neighboring non-neuronal cells within > 100 µm.…”

Altered Membrane Expression and Function of CD11b Play a Role in the Immunosuppressive Effects of Morphine on Macrophages at the Nanomolar Level

“…Clinical studies have found that the use of opioids (e.g., morphine, fentanyl) causes, in addition to some common side effects such as tolerance, addiction, respiratory depression, nausea, and constipation, an immunosuppressive effect that increases the risk of infection [ 1 , 2 ]. It is known that opioid addicts are at increased risk of infection, and the intersection between HIV infection and intravenous drug abuse has been identified [ 3 , 4 ]. In vitro and in vivo experiments, as well as epidemiological and clinical studies on different patient populations, have also shown that opioids such as morphine and fentanyl impair the function of macrophages, natural killer (NK) cells, and T cells, and weaken the intestinal barrier, inducing immunosuppression of the innate and adaptive immune systems, as well as damaging the mucosal barrier [ 5 , 6 , 7 ].…”