Huang Yung-Jen, Lee Kuan H, Murphy Lauren, Garraway Sandra M, Grau James W
Behavioral and Cellular Neuroscience, Department of Psychology, Texas A&M University, College Station, TX 77843, USA.
Center for Pain Research, Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Exp Neurol. 2016 Nov;285(Pt A):82-95. doi: 10.1016/j.expneurol.2016.09.005. Epub 2016 Sep 15.
Noxious input can sensitize pain (nociceptive) circuits within the spinal cord, inducing a lasting increase in spinal cord neural excitability (central sensitization) that is thought to contribute to chronic pain. The development of spinally-mediated central sensitization is regulated by descending fibers and GABAergic interneurons. The current study provides evidence that spinal cord injury (SCI) transforms how GABA affects nociceptive transmission within the spinal cord, recapitulating an earlier developmental state wherein GABA has an excitatory effect. In spinally transected rats, noxious electrical stimulation and inflammation induce enhanced mechanical reactivity (EMR), a behavioral index of nociceptive sensitization. Pretreatment with the GABA receptor antagonist bicuculline blocked these effects. Peripheral application of an irritant (capsaicin) also induced EMR. Both the induction and maintenance of this effect were blocked by bicuculline. Cellular indices of central sensitization [c-fos expression and ERK phosphorylation (pERK)] were also attenuated. In intact (sham operated) rats, bicuculline had the opposite effect. Pretreatment with a GABA agonist (muscimol) attenuated nociceptive sensitization in intact, but not spinally injured, rats. The effect of SCI on GABA function was linked to a reduction in the Cl transporter, KCC2, leading to a reduction in intracellular Cl that would attenuate GABA-mediated inhibition. Pharmacologically blocking the KCC2 channel (with i.t. DIOA) in intact rats mimicked the effect of SCI. Conversely, a pharmacological treatment (bumetanide) that should increase intracellular Cl levels blocked the effect of SCI. The results suggest that GABAergic neurons drive, rather than inhibit, the development of nociceptive sensitization after spinal injury.
伤害性输入可使脊髓内的疼痛（伤害性感受）回路敏感化，导致脊髓神经兴奋性持续增加（中枢敏化），这被认为是慢性疼痛产生的原因之一。脊髓介导的中枢敏化的发展受下行纤维和GABA能中间神经元的调节。目前的研究提供了证据表明脊髓损伤（SCI）改变了GABA对脊髓内伤害性信息传递的影响，重现了早期发育状态，即GABA具有兴奋作用。在脊髓横断的大鼠中，伤害性电刺激和炎症会诱导增强的机械反应性（EMR），这是伤害性感受敏感化的行为指标。用GABA受体拮抗剂荷包牡丹碱预处理可阻断这些效应。外周应用刺激物（辣椒素）也会诱导EMR。这种效应的诱导和维持均被荷包牡丹碱阻断。中枢敏化的细胞指标[c-fos表达和ERK磷酸化（pERK）]也减弱。在完整（假手术）大鼠中，荷包牡丹碱产生相反的作用。用GABA激动剂（蝇蕈醇）预处理可减弱完整大鼠而非脊髓损伤大鼠的伤害性感受敏感化。SCI对GABA功能的影响与Cl转运体KCC2的减少有关，导致细胞内Cl减少，从而减弱GABA介导的抑制作用。在完整大鼠中用药物阻断KCC2通道（经鞘内注射二碘阿替洛尔）可模拟SCI的作用。相反，一种应增加细胞内Cl水平的药物治疗（布美他尼）可阻断SCI的作用。结果表明，GABA能神经元驱动而非抑制脊髓损伤后伤害性感受敏感化的发展。
