(664): Oxidative stress and sensitivity to pain and opioids in rats

Abstract

Oxidative stress plays an important role in aging and development of neurodegeneration. Aberrant pain associated with oxidative stress-induced neurodegenerative disorders is inadequately managed because the neurodegeneration-related changes in sensitivity to pain and opioids are poorly understood. The knowledge about effects of oxidative stress on the opioid system is very limited. We have demonstrated significant decrease in opioid receptor function in neuronal cell cultures exposed to oxidative stress. The goal of this project was to study the relationship between oxidative damage and sensitivity to pain and opioids in rats. Three age groups (3-6, 9-12, and 21-24 months) of male Fisher 344 rats were tested for pain threshold and responses to three doses of morphine or fentanyl using the hot plate method. Various brain regions were used to measure oxidative stress markers and opioid receptors protein levels. The baseline sensitivity to thermal nociceptive stimulus increased significantly with age. There was a significant age-dependent and dose-dependent decrease in the antinociceptive effects of morphine and fentanyl. Levels of oxidative stress markers were the highest in brain regions from the oldest group of rats. There was a significant negative correlation between morphine antinociception and protein oxidation in cortex, striatum, and midbrain (r = 0.73, 0.87, and 0.77, respectively), and lipid peroxidation in cerebral cortex and striatum (r = 0.73 and 0.71, respectively). The mu opioid receptor protein level in cerebral cortex was significantly lower in the oldest rats. The results from this research show that (1) at the advanced age, the sensitivity to pain is significantly increased and the antonociceptive effect of opioids significantly decreased, (2) oxidative stress is negatively correlated with the opioid-induced antinocoception, and (3) age-related changes in pain and analgesia may be due to oxidative stress-induced reduction in opioid receptors protein level. Supported by NIH-NIA AG022550. Oxidative stress plays an important role in aging and development of neurodegeneration. Aberrant pain associated with oxidative stress-induced neurodegenerative disorders is inadequately managed because the neurodegeneration-related changes in sensitivity to pain and opioids are poorly understood. The knowledge about effects of oxidative stress on the opioid system is very limited. We have demonstrated significant decrease in opioid receptor function in neuronal cell cultures exposed to oxidative stress. The goal of this project was to study the relationship between oxidative damage and sensitivity to pain and opioids in rats. Three age groups (3-6, 9-12, and 21-24 months) of male Fisher 344 rats were tested for pain threshold and responses to three doses of morphine or fentanyl using the hot plate method. Various brain regions were used to measure oxidative stress markers and opioid receptors protein levels. The baseline sensitivity to thermal nociceptive stimulus increased significantly with age. There was a significant age-dependent and dose-dependent decrease in the antinociceptive effects of morphine and fentanyl. Levels of oxidative stress markers were the highest in brain regions from the oldest group of rats. There was a significant negative correlation between morphine antinociception and protein oxidation in cortex, striatum, and midbrain (r = 0.73, 0.87, and 0.77, respectively), and lipid peroxidation in cerebral cortex and striatum (r = 0.73 and 0.71, respectively). The mu opioid receptor protein level in cerebral cortex was significantly lower in the oldest rats. The results from this research show that (1) at the advanced age, the sensitivity to pain is significantly increased and the antonociceptive effect of opioids significantly decreased, (2) oxidative stress is negatively correlated with the opioid-induced antinocoception, and (3) age-related changes in pain and analgesia may be due to oxidative stress-induced reduction in opioid receptors protein level. Supported by NIH-NIA AG022550.