Impact of opiate-HIV-1 interactions on neurotoxic signaling.
Opiate drug abuse exacerbates the pathogenesis of human immunodeficiency virus-1 (HIV-1) in the central nervous system through direct actions on glia and neurons. Opiate abuse causes widespread disruption of astroglial and microglial function, and significant increases in astroglial-derived proinflammatory cytokines and chemokines, which likely contributes to neuronal dysfunction, death, and HIV encephalitis. Neurons are also directly affected by opiate-HIV-1 interactions. HIV-1 and the viral proteins gp120 and Tat activate multiple caspase-dependent and caspase-independent proapoptotic pathways in neurons involving phosphatidylinositol 3-kinase (PI3 kinase)/Akt, as well as p38, c-Jun N-terminal kinase (JNK) and/or other mitogen-activated protein kinases (MAPKs). Opiates appear to decrease the threshold for HIV-1-mediated neurotoxicity by sending convergent signals that exacerbate proapoptotic events induced by viral and cellular toxic products. The synergistic proinflammatory and neurotoxic effects of opiate drugs on glia and neurons are largely mediated through mu opioid receptors, which are expressed by subpopulations of astroglia, microglia, and neurons. Opiate abuse intrinsically modifies the host response to HIV-1. Identification of how this occurs is providing considerable insight toward understanding the mechanisms underlying HIV-1-associated dementia.
Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, 800 Rose Street, Lexington, KY 40536-0298, USA. khauser@uky.edu
Kurt F
KF
Hauser
Nazira
N
El-Hage
Shreya
S
Buch
Avindra
A
Nath
William R
WR
Tyor
Annadora J
AJ
Bruce-Keller
Pamela E
PE
Knapp
D015526:AIDS Dementia Complex / Q000503:physiopathology* / Q000821:virology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D009294:Narcotics / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects / Q000821:virology; D009474:Neurons / Q000187:drug effects / Q000821:virology; D009293:Opioid-Related Disorders / Q000378:metabolism / Q000503:physiopathology / Q000821:virology
D009294:Narcotics