Parent A J, Tétreault P, Roux M, Belleville K, Longpré J-M, Beaudet N, Goffaux P, Sarret P
Dept. of Pharmacology and Physiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke (Qc), Canada.
Dept. of Anesthesiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke (Qc), Canada.
Neuroscience. 2016 Feb 19;315:70-8. doi: 10.1016/j.neuroscience.2015.11.065. Epub 2015 Dec 10.
Clinical evidences suggest that an imbalance between descending inhibition and facilitation drives the development of chronic pain. However, potential mechanisms promoting the establishment of a persistent pain state and the increased pain vulnerability remain unknown. This preclinical study was designed to evaluate temporal changes in descending pain modulation at specific experimental endpoints (12, 28, 90 and 168 days) using a novel double-hit model of chronic/tonic pain (first hit: chronic constriction injury (CCI) model; second hit: tonic formalin pain in the contralateral hindpaw). Basal activity of bulbo-spinal monoaminergic systems was further assessed through liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) screening of cerebrospinal fluid (CSF). We found that CCI-operated rats exhibited a reduced nociceptive response profile, peaking on day 28, when subjected to tonic pain. This behavioral response was accompanied by a rapid increase in basal CSF serotonin and norepinephrine levels 12 days after neuropathy, followed by a return to sham levels on day 28. These molecular and behavioral adaptive changes in descending pain inhibition seemed to slowly fade over time. We therefore suggest that chronic neuropathic pain produces a transient hyperactivation of bulbo-spinal monoaminergic drive when previously primed using a tonic pain paradigm (i.e., formalin test), translating into inhibition of subsequent nociceptive behaviors. Altogether, we propose that early hyperactivation of descending pain inhibitory mechanisms, and its potential ensuing exhaustion, could be part of the temporal neurophysiological chain of events favoring chronic neuropathic pain establishment.
临床证据表明，下行抑制和易化之间的失衡驱动了慢性疼痛的发展。然而，促进持续性疼痛状态建立和疼痛易感性增加的潜在机制仍不清楚。本临床前研究旨在使用一种新型的慢性/紧张性疼痛双打击模型（第一次打击：慢性缩窄性损伤（CCI）模型；第二次打击：对侧后爪的紧张性福尔马林疼痛），评估在特定实验终点（12、28、90和168天）下行疼痛调制的时间变化。通过液相色谱-串联质谱（LC-MS/MS）对脑脊液（CSF）进行筛查，进一步评估延髓-脊髓单胺能系统的基础活性。我们发现，接受CCI手术的大鼠在遭受紧张性疼痛时，伤害性反应曲线降低，在第28天达到峰值。这种行为反应伴随着神经病变后12天脑脊液中血清素和去甲肾上腺素基础水平的快速升高，随后在第28天恢复到假手术水平。下行疼痛抑制中的这些分子和行为适应性变化似乎随着时间的推移而缓慢消退。因此，我们认为，当使用紧张性疼痛范式（即福尔马林试验）预先激发时，慢性神经性疼痛会导致延髓-脊髓单胺能驱动的短暂过度激活，从而转化为对后续伤害性行为的抑制。总之，我们提出，下行疼痛抑制机制的早期过度激活及其可能随之而来的耗竭，可能是有利于慢性神经性疼痛建立的时间性神经生理事件链的一部分。
