Supraspinal Modulation of Neuropathic Pain

描述(申请人提供)：大脑对疼痛信号的脊椎传递产生强大的影响。本实验室最近的证据表明，蓝斑(LC)是一个重要的脑干去甲肾上腺素能中枢，它促进了周围神经损伤引起的机械和温度超敏反应。这些发现导致假设，在周围神经损伤的背景下，神经损伤诱导的疼痛的表达(目标1)需要来自LC的下行易化影响，部分是通过增加背角的伤害性处理(目标2)。 目的#1a将验证这样的假设，即用局部麻醉剂(利多卡因)或突触抑制剂(钴)微量注射破坏LC中的突触活动将减少坐骨神经胫骨和腓总支切断后产生的触觉和冷过敏，使腓肠神经保持完整。目的#1b将验证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神经元可以防止或减少损伤诱导的超敏反应的发展的假设。 目的#2将使用类似的策略，结合测量刺激诱发的c-fos在背角的表达来检验破坏LC功能将：(A)阻止或(B)逆转神经损伤引起的脊髓伤害性信息处理的假说。这项为期两年的R21研究试图确定LC是否发挥促进作用，有助于神经病理性疼痛的表达。所获得的结果将为R01应用于进一步研究介导下行易化的脊髓上网络提供基础。对慢性神经性疼痛潜在的脊髓上去甲肾上腺素能机制的进一步了解，可能有助于确定可能通过直接或间接阻断下行易化而起作用的全新的止痛药类别。

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.