Enhanced immune sensitivity to stress following chronic morphine exposure.

Chronic administration of escalating doses ofmorphine leads to neuroadaptive changes precipitating development of tolerance to many of the acute effects of morphine, such as analgesia, activation of the hypothalamic-pituitary-adrenal (HPA) axis and suppression of immune cell activities. Interestingly, morphine tolerance has also been shown to be accompanied by heightened immunosuppressive effects of restraint stress using a rodent model. These observations have led to the hypothesis that the altered neuronal state accompanying opioid tolerance may contribute to this enhanced immune sensitivity to stress. To further test this hypothesis using different stressors, Sprague-Dawley rats were treated chronically with morphine for at least 8 days and then challenged with either psychological (water stress) or systemic stressors [morphine withdrawal, lipopolysaccharide (10 mug/kg i.p. challenge)]. It was found that, independent of the type of stress employed, morphine-tolerant animals displayed significantly lower mitogen-stimulated blood lymphocyte responses when compared to the responses of similarly treated saline controls. To determine whether direct activation of central stress pathways may also lead to enhanced immune sensitivity, morphine-tolerant animals were centrally injected with IL-1beta (1 ng/mul i.c.v.), a cytokine that activates the HPA axis by central mechanisms. Similar to the other types of stress, this direct central challenge was also found to be more immunosuppressive in morphine-tolerant animals compared to controls. Collectively, these studies demonstrate that morphine-tolerant animals have an enhanced susceptibility to the debilitating effects of a variety of stressors on immune cell function, an effect that is likely due to the neuroadaptive changes that develop during chronic morphine exposure.