Supraspinal Modulation of Neuropathic Pain

描述（由申请人提供）：大脑对疼痛信号的脊柱传输产生强大的影响。本实验室的最新研究表明，蓝斑（LC）是脑干去甲肾上腺素能神经中枢，对周围神经损伤引起的机械和热超敏反应具有促进作用。这些发现导致了这样的假设：在周围神经损伤的情况下，神经损伤诱导的疼痛的表达需要LC的下降易化影响（目标#1），部分原因是增加了背角的伤害性处理（目标#2）。 目的#1a将检验以下假设：通过局部麻醉剂（利多卡因）或突触抑制剂（钴）的微量注射破坏LC中的突触活动，将降低坐骨神经胫骨和腓总神经分支横断后产生的触觉和冷超敏反应，使腓肠神经保持完整。目的#1b将检验以下假设：在假手术或神经损伤前用去甲肾上腺素能神经毒素（DSP-4）不可逆地破坏LC神经元将预防或减少损伤诱导的超敏反应的发生。 目的#2将使用类似的策略结合测量背角中c-fos的刺激诱发表达来测试LC功能的破坏将：（a）预防或（B）逆转神经损伤诱导的脊髓伤害性处理的假设。这项为期两年的R21研究旨在确定LC是否发挥促进神经病理性疼痛表达的易化作用。研究结果将为进一步研究脊髓上神经网络介导下行易化提供基础。对慢性神经病理性疼痛的脊髓上去甲肾上腺素能机制的进一步了解可能有助于确定全新的镇痛药物类别，这些药物可能通过直接或间接阻断下行易化来发挥作用。

DESCRIPTION (provided by applicant): The brain exerts a powerful influence on the spinal transmission of pain signals. Recent evidence from our laboratory suggests that the locus coeruleus (LC), an important brainstem noradrenergic center, facilitates the mechanical and thermal hypersensitivity induced by injury to peripheral nerves. These findings led to the hypothesis that in the setting of peripheral nerve injury, descending facilitatory influences from the LC are required for the expression of nerve injury-induced pain (Aim #1), in part by increasing nociceptive processing at the dorsal horn (Aim #2). AIM #1a will test the hypothesis that disruption of synaptic activity in the LC with the microinjection of either a local anesthetic (lidocaine) or a synaptic inhibitor (cobalt) will decrease the tactile and cold hypersensitivity that develops following transection of the tibial and common peroneal branches of the sciatic nerve, leaving the sural nerve intact. Aim #1b will test the hypothesis that irreversible destruction of LC neurons with a noradrenergic neurotoxin (DSP-4) before sham or nerve injury will prevent or reduce the development of injury-induced hypersensitivity. Aim #2 will use similar strategies in combination with measurement of stimulus-evoked expression of c-fos in the dorsal horn to test the hypotheses that disruption of LC function will: (a) prevent or (b) reverse nerve injury-induced spinal nociceptive processing. This two-year R21 study seeks to firmly establish whether the LC exerts facilitatory influences that contribute to the expression of neuropathic pain. The results achieved will provide the basis for an R01 application to further investigate the supraspinal network mediating descending facilitation. Increased understanding of the supraspinal noradrenergic mechanisms underlying chronic neuropathic pain may help to identify entirely new classes of analgesic drugs that may work by directly or indirectly blocking descending facilitation.