The University of Arizona School of Medicine, Department of Pharmacology, 1501 N Campbell Ave., Tucson, AZ 85724, USA University of Helsinki, Department of Biosciences and Neuroscience Center, PO Box 65, Helsinki FIN-00014, Finland.
Pain. 2010 Feb;148(2):302-308. doi: 10.1016/j.pain.2009.11.015. Epub 2009 Dec 14.
Treatment of neuropathic pain is a major clinical challenge that has been met with minimal success. After peripheral nerve injury, a decrease in the expression of the K-Cl cotransporter KCC2, a major neuronal Cl(-) extruder, leads to pathologic alterations in GABA(A) and glycine receptor function in the spinal cord. The down-regulation of KCC2 is expected to cause a reduction in Cl(-) extrusion capacity in dorsal horn neurons, which, together with the depolarizing efflux of HCO(3)(-) anions via GABA(A) channels, would result in a decrease in the efficacy of GABA(A)-mediated inhibition. Carbonic anhydrases (CA) facilitate intracellular HCO(3)(-) generation and hence, we hypothesized that inhibition of CAs would enhance the efficacy of GABAergic inhibition in the context of neuropathic pain. Despite the decrease in KCC2 expression, spinal administration of benzodiazepines has been shown to be anti-allodynic in neuropathic conditions. Thus, we also hypothesized that spinal inhibition of CAs might enhance the anti-allodynic effects of spinally administered benzodiazepines. Here, we show that inhibition of spinal CA activity with acetazolamide (ACT) reduces neuropathic allodynia. Moreover, we demonstrate that spinal co-administration of ACT and midazolam (MZL) act synergistically to reduce neuropathic allodynia after peripheral nerve injury. These findings indicate that the combined use of CA inhibitors and benzodiazepines may be effective in the clinical management of neuropathic pain in humans.
治疗神经性疼痛是一项重大的临床挑战，目前仅取得了有限的成功。在外周神经损伤后，K-Cl 共转运蛋白 KCC2 的表达减少，作为主要的神经元氯离子外排器，导致脊髓中 GABA(A)和甘氨酸受体功能的病理性改变。KCC2 的下调预计会导致背角神经元氯离子外排能力降低，加上 GABA(A)通道中 HCO(3)(-)阴离子的去极化外流，会导致 GABA(A)介导的抑制作用降低。碳酸酐酶（CA）促进细胞内 HCO(3)(-)的产生，因此，我们假设抑制 CA 会增强神经性疼痛情况下 GABA 能抑制的效果。尽管 KCC2 的表达减少，但苯二氮䓬类药物在神经性疾病中的脊髓给药已被证明具有抗痛觉过敏作用。因此，我们还假设脊髓 CA 的抑制可能会增强脊髓给予苯二氮䓬类药物的抗痛觉过敏作用。在这里，我们表明，用乙酰唑胺（ACT）抑制脊髓 CA 活性可减轻神经性痛觉过敏。此外，我们证明脊髓给予 ACT 和咪达唑仑（MZL）联合给药可在外周神经损伤后协同减轻神经性痛觉过敏。这些发现表明，CA 抑制剂和苯二氮䓬类药物的联合使用可能在人类神经性疼痛的临床管理中有效。
