Ballard Kimberly A, Pellegrino Trisha C, Alonzo Norma C, Nugent Alexandria L, Bayer Barbara M
Department of Neuroscience, Georgetown University Medical Center, 3900 Reservoir Road, Washington DC 20007, USA.
J Neuroimmune Pharmacol. 2006 Mar;1(1):106-15. doi: 10.1007/s11481-005-9008-9.
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.
长期递增剂量给予吗啡会导致神经适应性变化，从而引发对吗啡许多急性效应的耐受性，如镇痛、下丘脑 - 垂体 - 肾上腺（HPA）轴激活以及免疫细胞活性抑制。有趣的是，使用啮齿动物模型还发现，吗啡耐受性还伴随着束缚应激免疫抑制作用的增强。这些观察结果引发了一种假说，即伴随阿片类药物耐受性的神经元状态改变可能导致这种对应激的免疫敏感性增强。为了使用不同应激源进一步验证这一假说，将Sprague - Dawley大鼠长期用吗啡处理至少8天，然后分别用心理应激（水应激）或全身性应激源[吗啡戒断、脂多糖（10微克/千克腹腔注射刺激）]进行刺激。结果发现，无论采用何种应激类型，与同样处理的生理盐水对照组相比，吗啡耐受动物的丝裂原刺激的血液淋巴细胞反应显著降低。为了确定中枢应激途径的直接激活是否也可能导致免疫敏感性增强，对吗啡耐受动物进行脑室内注射白细胞介素 - 1β（1纳克/微升），这种细胞因子通过中枢机制激活HPA轴。与其他类型的应激相似，与对照组相比，这种直接的中枢刺激在吗啡耐受动物中也表现出更强的免疫抑制作用。总的来说，这些研究表明，吗啡耐受动物对各种应激源对免疫细胞功能的削弱作用更敏感，这种作用可能是由于慢性吗啡暴露期间发生的神经适应性变化所致。
