Rivat Cyril, Laboureyras Emilie, Laulin Jean-Paul, Le Roy Chloé, Richebé Philippe, Simonnet Guy
Laboratoire Homéostasie-Allostasie-Pathologie, Université Victor Ségalen Bordeaux 2, Bordeaux 33076, France.
Neuropsychopharmacology. 2007 Oct;32(10):2217-28. doi: 10.1038/sj.npp.1301340. Epub 2007 Feb 14.
It is well admitted that stress induces analgesia (SIA) via endogenous opioid release. However, there is evidence that stressful events play a role in the pathogenesis of pain, but little is known about mechanisms underlying such pain vulnerability. Previous studies reported that a single opioid exposure activates NMDA-dependent pronociceptive systems leading to long-term pain vulnerability after analgesia. Here, we studied whether prior inflammatory pain or/and opioid experiences may favour the development of pain vulnerability after non-nociceptive environmental stress (NNES). Nociceptive threshold (NT) changes were evaluated by paw pressure vocalization test. By contrast to discrete SIA observed in naive rats, 1 h stress induced hyperalgesia (SIH) for several hours (15-65% NT decrease) in pain and opioid experienced rats. Repetition of NNES induced an 18- to 22-fold SIH enhancement (3-4 days), whereas SIA decreased. SIH was still observed 4 months after pain and opioid experiences. This phenomenon is referred to as latent pain sensitization. Furthermore, a fentanyl ultra-low dose (ULD, 50 ng/kg) administration, mimicking SIA in naive rats, induced hyperalgesia (65% NT decrease, 4 h), not analgesia, in pain and opioid-experienced rats. This indicates that low levels of opioids induce opposite effects, that is analgesia vs hyperalgesia dependent on prior life events. In pain and opioid-experienced rats, NMDA receptor antagonists, ketamine or BN2572, completely prevented hyperalgesia when injected just before NNES or fentanyl ULD. This latent pain sensitization model may be important for studying the transition from acute to chronic pain and individual differences in pain vulnerability associated with prior life events.
人们普遍认为，应激通过内源性阿片类物质释放诱导镇痛（SIA）。然而，有证据表明应激事件在疼痛的发病机制中起作用，但对于这种疼痛易感性的潜在机制知之甚少。先前的研究报道，单次阿片类物质暴露会激活NMDA依赖性促痛系统，导致镇痛后出现长期疼痛易感性。在此，我们研究了先前的炎性疼痛或/和阿片类物质经历是否可能有利于非伤害性环境应激（NNES）后疼痛易感性的发展。通过爪部压力发声试验评估伤害性阈值（NT）变化。与未接触过的大鼠中观察到的离散性SIA相反，1小时的应激在经历过疼痛和阿片类物质的大鼠中诱导了数小时的痛觉过敏（SIH）（NT降低15 - 65%）。NNES的重复诱导了SIH增强18至22倍（3 - 4天），而SIA则降低。在经历疼痛和阿片类物质4个月后仍观察到SIH。这种现象被称为潜伏性疼痛敏化。此外，在未接触过的大鼠中模拟SIA的芬太尼超低剂量（ULD，50 ng/kg）给药，在经历过疼痛和阿片类物质的大鼠中诱导了痛觉过敏（NT降低65%，持续4小时），而非镇痛作用。这表明低水平的阿片类物质会产生相反的作用，即镇痛与痛觉过敏取决于先前的生活事件。在经历过疼痛和阿片类物质的大鼠中，NMDA受体拮抗剂氯胺酮或BN2572在NNES或芬太尼ULD之前注射时，可完全预防痛觉过敏。这种潜伏性疼痛敏化模型对于研究从急性疼痛到慢性疼痛的转变以及与先前生活事件相关的疼痛易感性个体差异可能很重要。
