The Effect of Swim Stress on Morphine Tolerance Development and the Possible Role of Nitric Oxide in this Process

It has been shown that stress and chronic pain could prevent the development of tolerance to morphine analgesia, which appears to be related to the activation of hypothalamus–pitutitary–adrenal (HPA) axis, activation of neuroendocrine systems and changes in neurochemical levels. Moreover, the involvement of nitric oxide (NO) in the development of tolerance to morphine analgesia has been implicated. In the present study, we have tried to investigate the effect of swim stress, as a painless kind of stress, on the development of tolerance to find out whether the inhibition of tolerance is mediated by the direct effect of pain on the pain conduction pathway, or by its stress aspect. Besides, we evaluated the probable interactions between swim stress, nitric oxide level and the development of morphine tolerance. Adult male Wistar rats, weighing 180-220 g, were used in all these experiments. The experimental groups received chronic morphine (20 mg/kg, i.p), swim stress in 20°C water bath (4 min), or a combination of swim stress and chronic morphine (20 mg/kg, i.p), each for 4 days, while the first control group received saline (1 ml/kg, i.p) for 4 days. On the 5^th day, all the experimental and control groups received a single dose of morphine (10 mg/kg i.p). The second control group received saline for 5 days. The intact group received only one single dose of morphine (10 mg/kg, i.p). All the mentioned groups were subjected to tail-flick and formalin tests on the 5^th day. Other experimental groups were subjected to the assay for measuring nitrite as an indicator of NO, using the Griess method. Our results showed that co-administration of swim stress with chronic morphine prevented the development of morphine tolerance and the level of NO increased in the presence of swim stress (p<0001). The combination of morphine and swim stress significantly decreased NO production in comparison with the chronic morphine administered group (p<0.001). These data suggest that the activation of HPA axis and consequently the suppression of (NO) production induced by chronic morphine, lead to the inhibition of morphine tolerance.