Background
Gastrointestinal (GI) dysfunction is a major cause of morbidity in AIDS. HIV-1-induced neuropathogenesis is significantly enhanced by opiate abuse, which increases proinflammatory chemokine/cytokine release, the production of reactive species, glial reactivity, and neuronal injury in the CNS. Despite marked interactions in the gut, little is known about the effects of HIV-1 in combination with opiate use on the enteric nervous system (ENS).
Methods
To explore HIV-opiate interactions in myenteric neurons, effects of Tat ± morphine (0.03 μM, 0.3 μM, 3 μM) were examined in isolated neurons from doxycycline- (DOX-) inducible HIV-1 Tat1-86 transgenic mice or following in vitro Tat 100 nM exposure (> 6 h).
Key Results
Current clamp recordings demonstrated increased neuronal excitability in neurons of inducible Tat(+) mice (Tat+/DOX) compared to control Tat−/DOX. In neurons from Tat+/DOX, but not from Tat−/DOX mice, 0.03 μM morphine significantly reduced neuronal excitability, fast transient and late long-lasting sodium currents. There was a significant leftward shift in V0.5 of inactivation following exposure to 0.03 μM morphine, with a 50% decrease in availability of sodium channels at −100 mV. Similar effects were noted with in vitro Tat exposure in the presence of 0.3 μM morphine. Additionally, GI motility was significantly more sensitive to morphine in Tat(+) mice than Tat(−) mice.
Conclusions & Inferences
Overall, these data suggest that the sensitivity of enteric neurons to morphine is enhanced in the presence of Tat. Opiates and HIV-1 may uniquely interact to exacerbate the deleterious effects of HIV-1-infection and opiate exposure on GI function.