Scheich B, Vincze P, Szőke É, Borbély É, Hunyady Á, Szolcsányi J, Dénes Á, Környei Zs, Gaszner B, Helyes Zs
Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Hungary.
János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary.
Eur J Pain. 2017 Sep;21(8):1417-1431. doi: 10.1002/ejp.1043. Epub 2017 Apr 25.
Clinical studies demonstrated peripheral nociceptor deficit in stress-related chronic pain states, such as fibromyalgia. The interactions of stress and nociceptive systems have special relevance in chronic pain, but the underlying mechanisms including the role of specific nociceptor populations remain unknown. We investigated the role of capsaicin-sensitive neurones in chronic stress-related nociceptive changes.
Capsaicin-sensitive neurones were desensitized by the capsaicin analogue resiniferatoxin (RTX) in CD1 mice. The effects of desensitization on chronic restraint stress (CRS)-induced responses were analysed using behavioural tests, chronic neuronal activity assessment in the central nervous system with FosB immunohistochemistry and peripheral cytokine concentration measurements.
Chronic restraint stress induced mechanical and cold hypersensitivity and increased light preference in the light-dark box test. Open-field and tail suspension test activities were not altered. Adrenal weight increased, whereas thymus and body weights decreased in response to CRS. FosB immunopositivity increased in the insular cortex, dorsomedial hypothalamic and dorsal raphe nuclei, but not in the spinal cord dorsal horn after the CRS. CRS did not affect the cytokine concentrations of hindpaw tissues. Surprisingly, RTX pretreatment augmented stress-induced mechanical hyperalgesia, abolished light preference and selectively decreased the CRS-induced neuronal activation in the insular cortex. RTX pretreatment alone increased the basal noxious heat threshold without influencing the CRS-evoked cold hyperalgesia and augmented neuronal activation in the somatosensory cortex and interleukin-1α and RANTES production.
Chronic restraint stress induces hyperalgesia without major anxiety, depression-like behaviour or peripheral inflammatory changes. Increased stress-induced mechanical hypersensitivity in RTX-pretreated mice is presumably mediated by central mechanisms including cortical plastic changes.
These are the first data demonstrating the complex interactions between capsaicin-sensitive neurones and chronic stress and their impact on nociception. Capsaicin-sensitive neurones are protective against stress-induced mechanical hyperalgesia by influencing neuronal plasticity in the brain.
临床研究表明，在与压力相关的慢性疼痛状态（如纤维肌痛）中存在外周伤害感受器功能缺陷。压力与伤害感受系统之间的相互作用在慢性疼痛中具有特殊意义，但包括特定伤害感受器群体作用在内的潜在机制仍不清楚。我们研究了辣椒素敏感神经元在慢性压力相关伤害感受变化中的作用。
在CD1小鼠中，用辣椒素类似物树脂毒素（RTX）使辣椒素敏感神经元脱敏。使用行为测试、通过FosB免疫组织化学评估中枢神经系统的慢性神经元活动以及测量外周细胞因子浓度，分析脱敏对慢性束缚应激（CRS）诱导反应的影响。
慢性束缚应激在明暗箱试验中诱导机械性和冷超敏反应，并增加对光的偏好。旷场试验和悬尾试验活动未改变。CRS导致肾上腺重量增加，而胸腺和体重下降。CRS后，岛叶皮质、背内侧下丘脑和中缝背核中的FosB免疫阳性增加，但脊髓背角中未增加。CRS不影响后爪组织的细胞因子浓度。令人惊讶的是，RTX预处理增强了应激诱导的机械性痛觉过敏，消除了对光的偏好，并选择性降低了CRS诱导的岛叶皮质神经元激活。单独的RTX预处理增加了基础伤害性热阈值，而不影响CRS诱发的冷超敏反应，并增强了体感皮质中的神经元激活以及白细胞介素-1α和RANTES的产生。
慢性束缚应激诱导痛觉过敏，但无明显焦虑、抑郁样行为或外周炎症变化。RTX预处理小鼠中应激诱导的机械性超敏反应增加可能由包括皮质可塑性变化在内的中枢机制介导。
这些是首批证明辣椒素敏感神经元与慢性压力之间复杂相互作用及其对伤害感受影响的数据。辣椒素敏感神经元通过影响大脑中的神经元可塑性来预防应激诱导的机械性痛觉过敏。
