Alonzo Norma C, Bayer Barbara M
Department of Neuroscience, Georgetown University, 3970 Reservoir Road NW, Box 54624, NRB EG12, Washington, DC 20057-54624, USA.
J Pharmacol Exp Ther. 2003 Nov;307(2):793-800. doi: 10.1124/jpet.103.053264. Epub 2003 Sep 9.
It has been shown that morphine-tolerant animals have an altered immunological sensitivity to stress. Although the glutamatergic system has been implicated in the neuroadaptive process underlying this tolerant state, its potential role in development of the altered immunological sensitivity consequent to chronic morphine treatment is not known. To determine this, a morphine-tolerant state was induced by 10-day administration of an escalating dose of morphine from 10 to 40 mg/kg (s.c., b.i.d.), and lymphocyte proliferative response to a T-cell mitogen was measured. Morphine challenge (10 mg/kg s.c.) after days of treatment was gradually less immunosuppressive, and this tolerance progression was delayed by concurrent administration of the N-methyl-D-aspartate (NMDA) receptor antagonist (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) (0.1 mg/kg s.c.) with chronic morphine. The effect was independent of glucocorticoid level changes and was not a result of an acute interaction of the drugs or the prolonged presence of the antagonist alone. Subsequent to chronic treatment, animals were subjected to opioid withdrawal and water stress. Both stressors induced 50% immunosuppression in morphine-tolerant animals compared with saline-treated controls. Increased immunological sensitivity to these stressors was attenuated when MK-801 was administered with chronic morphine as demonstrated by an accelerated recovery rate and lack of immunosuppression from opioid withdrawal and water stress, respectively. Together, these findings provide the first evidence that the neuroadapted state of the immune response after chronic morphine can be modified by NMDA receptor antagonism, as illustrated by a temporal deceleration of the development of immunological tolerance during chronic treatment that is associated with an attenuation of the immunological vulnerability of morphine-tolerant animals to stress.
已表明吗啡耐受动物对应激的免疫敏感性发生了改变。尽管谷氨酸能系统参与了这种耐受状态下的神经适应性过程，但其在慢性吗啡治疗后导致的免疫敏感性改变的发展中所起的潜在作用尚不清楚。为了确定这一点，通过连续10天皮下注射剂量从10至40mg/kg递增的吗啡（每天两次）诱导出吗啡耐受状态，并测量淋巴细胞对T细胞有丝分裂原的增殖反应。治疗数天后进行吗啡激发（皮下注射10mg/kg），其免疫抑制作用逐渐减弱，同时给予N-甲基-D-天冬氨酸（NMDA）受体拮抗剂马来酸（-）-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺（MK-801）（皮下注射0.1mg/kg）与慢性吗啡合用可延迟这种耐受进展。该作用与糖皮质激素水平变化无关，也不是药物急性相互作用或仅拮抗剂长期存在的结果。慢性治疗后，对动物进行阿片类药物戒断和水应激处理。与盐水处理的对照相比，两种应激源在吗啡耐受动物中均诱导出50%的免疫抑制。当MK-801与慢性吗啡合用时，对这些应激源的免疫敏感性增加减弱，分别表现为恢复速度加快以及阿片类药物戒断和水应激未出现免疫抑制。总之，这些发现提供了首个证据，即慢性吗啡后免疫反应的神经适应状态可通过NMDA受体拮抗作用进行调节，如慢性治疗期间免疫耐受发展的时间延迟所示，这与吗啡耐受动物对应激的免疫易损性减弱相关。
