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?

慢性疼痛是最难忍受和治疗的疾病之一。机制还不清楚。然而，肾上腺素能系统似乎影响许多慢性疼痛综合征。在神经病小鼠中，通过脊髓宽动态范围（WDR）细胞的电生理学记录研究脊髓神经元的肾上腺素能调节，在后爪中具有感受野，将回答以下问题：可能是神经病引起的兴奋性α1肾上腺素能受体的脊髓上调是否可以驱动通常通过主要抑制性α2肾上腺素能受体起作用的下行抑制系统，脊髓神经元回路的促进作用将在细胞外记录单个WDR神经元，并在蓝斑的电和光遗传学刺激之前、期间和之后监测其活性。蓝斑活动在脊髓疼痛刺激的下行抑制中起着关键作用。相比之下，通过冷却记录部位附近的脊髓，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，激活和抑制下行系统的效果将被比较。脊髓阻断α 1-或α 2-肾上腺素受体的鞘内应用特拉唑嗪或阿替美唑分别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，应使用细胞类型和通路特异性分子标记物鉴定α肾上腺素受体所在的背角脊髓细胞。在神经病中，去甲肾上腺素能系统似乎失效，假设是由于脊髓回路中肾上腺素能受体群体的α1/α2比率发生转换。这一假设将在充分研究的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电生理学测试，后者作为复杂区域疼痛综合征的模型，其中肾上腺素能系统经常被发现受到干扰。更好地了解病理机制可能会导致更好的治疗。

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.