Stress and chronic pain have been shown to prevent the development of tolerance to morphine analgesia, which appears to be related to neuroendocrine activity and alternation in neurochemicals. Also the involvement of nitric oxide (NO) has been implicated in tolerance to morphine analgesia. In our pervious study, we showed that co-administration of swim stress (ss) with chronic morphine, prevents the development of morphine tolerance. In this study the probable interactions between swim stress and nitric oxide level on development of morphine tolerance were investigated. Adult male NMRI rats weighing 180-220 g were divided into control and experimental groups (N = 8) that received morphine 20 mg/kg (i.p.) for 4 days, swim stress 4 minutes for 4 days at 20 ?C water and combination of both swim stress and morphine injection for 4 days. Nitric oxide was measured as indicator of NO by Griess methods. Swim stress raised NO level (P<0.001). Combination of morphine injection and swim stress significantly decreased nitric oxide level compared to chronic morphine treated group (P<0.001). These data suggest that at least two parallel systems may be activated during stress: 1. inbibition of morphine tolerance may be mediated by stress via activation of HPA axis as described by other reports in case of pain stress, and HPA axis activation in tolerance prevention, and 2. suppression of nitric oxide synthase (NOS) activity.