Fig. 3

Neurotoxic effects of HIV-1 Tat and morphine are reversed by loss of glial CCR5. a In C57Bl6/J wild-type co-cultures, Tat is neurotoxic (*p = 0.001 vs control), and co-exposure to morphine enhanced Tat-induced toxicity over a 72-h period (**p < 0.001 vs control, p < 0.05 vs Tat). This interaction was blocked by pretreatment with naloxone, a broad-spectrum opioid receptor antagonist. Naloxone or morphine by themselves had no effect on neuronal survival (n = 4–8). b–d To explore the role of CCR5 in mediating neurotoxic interactions between Tat and morphine, co-cultures in which glia, neurons, or both were deficient in CCR5 were established. b In co-cultures where glia are CCR5-null but neurons are wild-type, exposure to Tat by itself still led to significant neurotoxicity (*p < 0.001 vs control); however, the morphine-enhanced neurotoxicity seen in wild-type cultures was eliminated. In fact, morphine co-treatment entirely abolished Tat toxic effects, restoring neuronal survival to control levels. Pre-treatment with naloxone re-established Tat toxicity, suggesting that actions at the μ-opioid receptor mediate this neuroprotection (n = 4–8). c In co-cultures where neurons are CCR5-null but glia are wild-type, the survival curves are similar to wild-type co-cultures (n = 5). d In co-cultures between CCR5-deficient glia and neurons, the survival curves are similar to co-cultures where only glia were CCR5-deficient (n = 5). Overall, the results from the CCR5-deficient co-cultures suggest an important role for glial CCR5 in the neurotoxic interactions of HIV-1 Tat and opiates that act at the MOR