Adrenergic Regulation of Spinal Neurons in Chronic Pain: Does the noradrenergic descending pain control system facilitate pain due to spinal reorganization under chronic pain conditions in mice?

慢性疼痛中脊髓神经元的肾上腺素能调节：去甲肾上腺素能下行疼痛控制系统是否有助于小鼠慢性疼痛条件下因脊柱重组而产生的疼痛？

• 批准号: 439922175
• 负责人: Dr. Silke Hirsch
• 金额: --
• 依托单位: Klinik und Poliklinik für Neurologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/439922175?language=en
• 关键词: Adrenergic; Regulation; Spinal; Neurons; Chronic

Chronic pain is one of the most difficult to endure and to treat conditions. Mechanisms are not well understood. Yet, the adrenergic system seems to influence many chronic pain syndromes. Studying the adrenergic regulation of spinal neurons in neuropathic mice via electrophysiologically recording from spinal wide dynamic range (WDR) cells in vivo with receptive fields in the hind paw shall answer the following question: Can a, presumably neuropathy-induced, spinal upregulation of excitatory α1 adrenergic receptors drive the descending inhibitory system, which usually acts via predominating inhibitory α2 adrenergic receptors, towards facilitation in spinal neuronal circuits? Single WDR neurons will be recorded extracellularly and their activity will be monitored before, during and after electrical and optogenetic stimulation of locus coeruleus. Locus coeruleus activity plays a key role in descending inhibition of painful stimuli in the spinal cord. Comparably, evoked spinal WDR neuronal activity will be recorded before and after inhibition of the descending fibres via cooling of spinal cord proximal to the recording site. Thereby both effects - of activating and of inhibiting the descending system - will be compared. Spinal blockade of alpha1- or alpha2-adrenoceptors by intrathecal application of terazosin or atipamezole respectively will clarify the impact of these receptor subtypes on the spinal neuronal activity. Histological and molecular analyses will be used for receptor quantification in the spinal cord. Additionally, the spinal cells of the dorsal horn α adrenoceptors are located on shall be identified using cell-type and pathway-specific molecular markers. In neuropathy, the noradrenergic system seems to fail, hypothetically due to a switch in the α1/α2 ratio of the adrenergic receptor population in the spinal circuitry. This hypothesis will be tested electrophysiologically and pharmacologically in the well-studied murine neuropathic pain model PNL (partial nerve ligation) and in bone-fractured mice, the latter as a model of complex regional pain syndrome, in which the adrenergic system is often found to be disturbed. A better understanding of the pathological mechanisms may result in a better therapy.

慢性疼痛是最难忍受和治疗的病症之一。机制尚不清楚。然而，肾上腺素能系统似乎影响许多慢性疼痛综合征。通过后爪感受野体内脊髓宽动态范围 (WDR) 细胞的电生理学记录来研究神经病小鼠脊髓神经元的肾上腺素能调节，应回答以下问题：可能是神经病诱导的脊髓兴奋性 α1 肾上腺素能受体的上调能否驱动下行抑制系统，该系统通常通过主导作用发挥作用 抑制性α2肾上腺素能受体，促进脊髓神经元回路？将在细胞外记录单个 WDR 神经元，并在蓝斑电刺激和光遗传学刺激之前、期间和之后监测其活动。蓝斑活动在脊髓疼痛刺激的下降抑制中起着关键作用。相比之下，通过冷却记录位点附近的脊髓，在抑制下行纤维之前和之后记录诱发的脊髓 WDR 神经元活动。因此，将比较激活和抑制下行系统的两种效果。分别通过鞘内应用特拉唑嗪或阿替美唑对 α1 或 α2 肾上腺素受体进行脊髓阻滞，将阐明这些受体亚型对脊髓神经元活动的影响。组织学和分子分析将用于脊髓中的受体定量。此外，应使用细胞类型和途径特异性分子标记来识别背角 α 肾上腺素受体所在的脊髓细胞。在神经病中，去甲肾上腺素能系统似乎出现故障，推测是由于脊髓回路中肾上腺素能受体群的 α1/α2 比例发生变化。这一假设将在经过充分研究的小鼠神经病理性疼痛模型 PNL（部分神经结扎）和骨折小鼠中进行电生理学和药理学测试，后者是复杂区域疼痛综合征的模型，其中肾上腺素能系统经常受到干扰。更好地了解病理机制可能会带来更好的治疗。