Khasar Sachia G, Burkham Jennifer, Dina Olayinka A, Brown Adrienne S, Bogen Oliver, Alessandri-Haber Nicole, Green Paul G, Reichling David B, Levine Jon D
Department of Oral and Maxillofacial Surgery, University of California, San Francisco, California 94143-0440, USA.
J Neurosci. 2008 May 28;28(22):5721-30. doi: 10.1523/JNEUROSCI.0256-08.2008.
Stress dramatically exacerbates pain in diseases such as fibromyalgia and rheumatoid arthritis, but the underlying mechanisms are unknown. We tested the hypothesis that stress causes generalized hyperalgesia by enhancing pronociceptive effects of immune mediators. Rats exposed to nonhabituating sound stress exhibited no change in mechanical nociceptive threshold, but showed a marked increase in hyperalgesia evoked by local injections of prostaglandin E(2) or epinephrine. This enhancement, which developed more than a week after exposure to stress, required concerted action of glucocorticoids and catecholamines at receptors located in the periphery on sensory afferents. The altered response to pronociceptive mediators involved a switch in coupling of their receptors from predominantly stimulatory to inhibitory G-proteins (G(s) to G(i)), and for prostaglandin E(2), emergence of novel dependence on protein kinase C epsilon. Thus, an important mechanism in generalized pain syndromes may be stress-induced coactivation of the hypothalamo-pituitary-adrenal and sympathoadrenal axes, causing a long-lasting alteration in intracellular signaling pathways, enabling normally innocuous levels of immune mediators to produce chronic hyperalgesia.
压力会显著加剧纤维肌痛和类风湿性关节炎等疾病中的疼痛，但潜在机制尚不清楚。我们检验了这样一种假说，即压力通过增强免疫介质的促痛觉作用导致全身性痛觉过敏。暴露于非习惯性声音压力下的大鼠机械性伤害性感受阈值没有变化，但局部注射前列腺素E2或肾上腺素诱发的痛觉过敏显著增加。这种增强在暴露于压力一周多后出现，需要糖皮质激素和儿茶酚胺在感觉传入神经外周的受体上协同作用。对促痛觉介质的反应改变涉及它们的受体从主要与刺激性G蛋白偶联（G(s)）转变为抑制性G蛋白偶联（G(i)），对于前列腺素E2而言，还出现了对蛋白激酶Cε的新依赖性。因此，全身性疼痛综合征的一个重要机制可能是压力诱导下丘脑-垂体-肾上腺轴和交感肾上腺轴的共同激活，导致细胞内信号通路的长期改变，使正常无害水平的免疫介质产生慢性痛觉过敏。
