Synergistic Effect and Mechanism of Apoptosis Induction by Morphine and the HIV-1gp120V3 Loop in Hippocampal Neurons.

HIV-associated neurocognitive disorders (HAND) are a collective name for neurological disorders associated with HIV-1 infection. The incidence and severity of HAND are increased by concomitant opioid use disorder, such as heroin and morphine abuse. Our previous study showed that the HIV-1 envelope protein gp120 and morphine synergistically induce apoptosis in rat hippocampal neurons. However, the underlying mechanism remains unclear. We hypothesized that morphine and gp120 activated the neuronal apoptosis signaling pathway via their typical membrane receptors. If they shared key signaling molecules, their induction of neuronal apoptosis could be inhibited by blocking these targets. We found that morphine and gp120V3 loop synergistically induced hippocampal neuron apoptosis, mediated by activating the extracellular signal-regulated kinase (ERK) pathway, increasing the intracellular Ca2 + concentration and expression of caspase-, and reducing the mitochondrial membrane potential. The ERK inhibitor PD98509 and the phosphatidylinositol 3-kinase activator IGF-1 blocked this effect. These results indicate that ERK plays a crucial role in the apoptosis of hippocampal neurons in HAND.