Opioids have been postulated to play an immunomodulatory role in the pathogenesis of HIV-1. Synthetic κ-opioid receptor (KOR) ligands have been found to inhibit HIV-1 expression in acutely infected microglial cell cultures. We recently found that interleukin(IL)-1β and tumor necrosis factor(TNF)-α have antiviral effects in acutely infected mixed glial/neuronal cell cultures. In the present study, we investigated whether selective KOR ligands would exert antiviral effects in acutely infected brain cell cultures. While the KOR ligand trans-3,4-dichloro-N-methyl-N[2-(1-pyrolidinyl)cyclohexyl]benzeneaceamide methanesulfonate (U50,488) alone had little anti-HIV-1 activity, this opioid potentiated in a concentration-dependent manner the antiviral activity of TNF-α, but not of IL-1β. The potentiating effect of U50,488 was detected after a 6-hr pretreatment and peaked at 24 hr. The KOR antagonist nor-binaltorphimine completely blocked the potentiating effect of U50,488, suggesting the involvement of a KOR-mediated mechanism. Antibodies to TNF-α completely blocked the potentiating effect of U50,488, suggesting a critical role for TNF-α. Antibodies to IL-1β blocked the potentiating effect of U50,488, suggesting that IL-1β was released following U50,488 treatment, which might contribute to the potentiating effect of U50,488. These in vitro findings support the notion that synthetic κ-opioids could be considered as potential adjunctive therapeutic agents in HIV-1-related brain disease. Copyright (C) 1998 Elsevier Science, Inc.
Bibliographical noteFunding Information:
The monocytotropic HIV-1SF 162 strain was provided by the National Institutes of Health AIDS Research and Reference Reagent Program (National Institute of Allergy and Infectious Diseases). The selective KOR ligands U50,488 and (5α,7α,8β)-(+)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro[4,5]dec-8-yl)-benzeneacetamide (U69,593) were gifts of the Upjohn Co. Dynorphin A 1-17 was purchased from Peninsula Laboratories, Inc. The κ-selective antagonist nor-BNI was provided by P. S. Portoghese (University of Minnesota). Morphine was obtained from the Pharmacy Department in our institution. Other reagents were purchased from the indicated sources: TNF-α and IL-1β (R&D Systems Inc.); antibodies to microglial cell CD68 antigen and astrocyte glial fibrillary acid protein (Dako); anti-neuron specific enolase antibodies (Polysciences); FBS (HyClone Laboratories); DMEM, uridine, fluorodeoxyuridine, penicillin (100 units/mL), streptomycin, and all other culture reagents (Sigma Chemical Co.).
This work was supported, in part, by U.S. Public Health Service Grants DA09924 and DA04381 from the National Institute on Drug Abuse.
Copyright 2007 Elsevier B.V., All rights reserved.
- Brain cell cultures