Effects of HIV‐1 Tat and morphine on the biophysical properties of sodium channels (653.5)

Abstract

HIV‐infection continues to be a major clinical manifestation in the combination antiretroviral therapy era (cART), that is enhanced in opioid‐drug abusers. The gastrointestinal (GI) mucosa plays a major role in HIV‐infection as HIV is mostly transmitted across mucosal surfaces. The enteric nervous system (ENS) controls several GI processes including motility and secretion which are specifically affected in HIV‐infected patients. Opioids directly affect the ENS, causing severe constipation. Because the virus does not infect neurons, it is suggested that viral toxins, such as Tat, modulate neuronal function in HIV‐1‐infected patients. Tat has been shown to increase neuronal excitability but not much is known about effects of Tat on enteric neurons in combination with drug abuse. Recent experimental studies in our lab have shown that Tat increases enteric neuronal excitability by shifting the voltage‐dependence of activation of sodium channels to more negative potentials. In contrast, morphine alone decreases the availability of sodium channels in enteric neurons reducing excitability. Voltage gated sodium channels (VGSCs) are responsible for the generation and propagation of action potentials in neurons. In order to determine the effects of Tat (100 nM) in combination with morphine (0.3µM, 3µM) on the voltage dependence of steady‐state activation/ inactivation of sodium channels, we used a double‐pulse protocol in which a variable conditioning pulse was applied from −100mV to +50mV in 10mV steps for 50 ms followed by a test pulse. In Tat‐treated neurons, the sensitivity to morphine was significantly enhanced. The V0.5 for steady‐state inactivation was shifted in Tat‐treated neurons at 0.3 uM morphine with 50% decrease in maximal availability at ‐100 mV. Morphine did not alter the steady‐state activation. Taken together, data suggest that Tat increases the sensitivity to morphine in enteric neurons that may exacerbate the deleterious effects of morphine on GI motility.Grant Funding Source: Supported by NIDA R01 DA018633, K02 DA027374, K99 DA033878, DK046367.