Inhibitory Synaptic Transmission, Stress and Drugs of Abuse

描述（由申请人提供）：外周损伤后，触觉发生变化，包括原发性和继发性痛觉过敏和异常性疼痛。GABA能或甘氨酸能抑制的丧失是可引起疼痛感知的这些变化的一种机制。背角中的抑制性神经元在控制伤害性信息通过上行通路流向大脑（在那里它被认为是痛苦的）方面起着关键作用。白细胞介素-1 β（IL-1 β）是一种在脊髓损伤过程中释放的炎性细胞因子，并且已知当引入脊髓时会促进疼痛并引起痛觉过敏。在脊髓切片中使用电生理方法，我们发现IL-1 β上调背角抑制性神经元上的抑制性甘氨酸受体。抑制性神经元的快速抑制有望促进疼痛信号向大脑的传递，从而可能解释IL-1 β如何引起疼痛。我们的初步结果表明，体内炎症增强甘氨酸能突触类似于体外观察到的IL-1 β增强。IL-1 β也在神经性疼痛过程中释放，在这里，我们建议测试是否甘氨酸能神经传递的抑制性中间神经元在疼痛通路中上调神经性疼痛模型。我们的工作可能为治疗目前难以有效治疗的持续性疼痛提供新的药物靶点。

DESCRIPTION (provided by applicant): Following peripheral injury, changes in tactile perception develop, including primary and secondary hyperalgesia and allodynia. A loss of GABAergic or glycinergic inhibition is one mechanism that can cause these changes in pain perception. Inhibitory neurons in the dorsal horn play a key role in controlling the flow of nociceptive information through ascending pathways to the brain where it is perceived as painful. Interleukin-1beta (IL-1beta) is an inflammatory cytokine released in the spinal cord during injury and is known to promote pain and cause hyperalgesia when introduced into the spinal cord. Using electrophysiological methods in spinal cord slices, we have found that IL-1beta upregulates inhibitory glycine receptors on inhibitory neurons in the dorsal horn. The rapid inhibition of inhibitory neurons is expected to promote the transmission of pain signals to the brain, and thus may explain how IL-1beta causes pain. Our preliminary results indicate that inflammation in vivo potentiates glycinergic synapses similarly to IL-1beta potentiation observed in vitro. IL-1beta is also released during neuropathic pain, and here we propose to test whether glycinergic neurotransmission on inhibitory interneurons in the pain pathway is upregulated in a model of neuropathic pain. Our work could suggest novel drug targets for the treatment of persistent pain conditions that are currently difficult to treat effectively.