疼痛闸门控制学说已发表50周年，其推测的脊髓闸门回路组成及功能尚未完全阐明。申请人在发表闸门控制回路中痛觉回路构成（J Neurosci. 2003,2005）之后，新近研究发现，脊髓后角前馈抑制回路可发挥“痛觉超敏闸门”作用，神经损伤可开启闸门，使触觉信息传递到痛觉通路产生痛觉超敏（J Clin Invest. 2013），丰富和发展了闸门控制学说。本课题提出“痛觉超敏闸门”开启机制假说：内源性大麻素（eCBs）激活星形胶质细胞或/和抑制性神经元的CB1受体，通过突触外NMDA受体活化诱发AMPA受体内吞，产生抑制回路特异性LTD，参与痛觉超敏形成。本课题拟用双膜片钳技术、形态学、分子生物学和行为学技术，以大鼠和细胞特异性CB1基因敲除小鼠为研究平台，深入探讨eCBs参与“痛觉超敏闸门”抑制性回路LTD机制，及其在痛觉超敏中的作用，为阐明神经病理性痛觉超敏的神经学机制提供结构与功能基础。

Melzak and Wall (Science, 1965) proposed a well-known hypothesis, the gate theory of pain, which is highly influential for 50 years. However, the theory remains a conjecture because of insufficient evidence to substantiate the neural circuitry underlying pain signaling and modulation in the spinal dorsal horn. The applicant have reported the functional organization of nociceptive component in the gate theory related neuronal circuits (Lu et al. J Neurosci. 2003,2005). Our recent study (Lu et al. J Clin Invest. 2013) found that the spinal dorsal horn contains a feed-forward inhibitory circuit that can gate incoming low-threshold Abeta input to nociceptive pathway. This study identified a novel “gate” with definite morphological and functional details in the spinal dorsal horn, in which activation of low-threshold innocuous Abeta fibers in neuropathic pain condition “opens” the gate to elicit mechanical allodynia. Based on our previous findings and preliminary data, we propose herein a new hypothesis on how the “allodynia gate” works: The peripheral nerve injury elevates the content of endocannabinoids (eCBs) in spinal dorsal horn, which activats CB1 receptors on the spinal astrocyte and/or inhibitory neurons. The activated astrocyte releases glutamate and activates NMDA receptors on inhibitory neurons. NMDA receptor activation induces the endocytosis of postsynaptic glutamate AMPA receptors of inhibitory neurons. These molecular cascades ventually mediate the development of the eCB dependent LTD (eCB-LTD) in the feed-forward inhibitory circuit, and then, open the “allodynia gate” contributing to the development of neuropathic pain. The present proposal will utilize paired patch-clamp whole-cell recordings, morphological, molecular biological and behaviour techniques to study the mechanisms of eCB-LTD and its potential role in the development of neuropathic allodynia induced by peripheral nerve injury in SD rat and conditional CB1 KO mice.