Molecular targets of opiate drug abuse in neuroAIDS.
Opiate drug abuse, through selective actions at mu-opioid receptors (MOR), exacerbates the pathogenesis of human immunodeficiency virus-1 (HIV-1) in the CNS by disrupting glial homeostasis, increasing inflammation, and decreasing the threshold for pro-apoptotic events in neurons. Neurons are affected directly and indirectly by opiate-HIV interactions. Although most opiates drugs have some affinity for kappa (KOR) and/or delta (DOR) opioid receptors, their neurotoxic effects are largely mediated through MOR. Besides direct actions on the neurons themselves, opiates directly affect MOR-expressing astrocytes and microglia. Because of their broad-reaching actions in glia, opiate abuse causes widespread metabolic derangement, inflammation, and the disruption of neuron-glial relationships, which likely contribute to neuronal dysfunction, death, and HIV encephalitis. In addition to direct actions on neural cells, opioids modulate inflammation and disrupt normal intercellular interactions among immunocytes (macrophages and lymphocytes), which on balance further promote neuronal dysfunction and death. The neural pathways involved in opiate enhancement of HIV-induced inflammation and cell death, appear to involve MOR activation with downstream effects through PI3-kinase/Akt and/or MAPK signaling, which suggests possible targets for therapeutic intervention in neuroAIDS.
Hauser
K F
KF
Department of Anatomy and Neurobiology, University of Kentucky Medical Center, Lexington, KY 40536, USA. khauser@uky.edu
El-Hage
N
N
Buch
S
S
Berger
J R
JR
Tyor
W R
WR
Nath
A
A
Bruce-Keller
A J
AJ
Knapp
P E
PE
D015526:AIDS Dementia Complex / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D006801:Humans; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D009294:Narcotics / Q000494:pharmacology; D009293:Opioid-Related Disorders / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism
D009294:Narcotics