Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Department of In Vivo Neurodegeneration, H. Lundbeck A/S, Valby, Denmark.
Eur J Pain. 2018 Feb;22(2):282-294. doi: 10.1002/ejp.1117. Epub 2017 Oct 6.
Following nerve injury, down-regulation of astroglial glutamate transporters (GluTs) with subsequent extracellular glutamate accumulation is a key factor contributing to hyperexcitability within the spinal dorsal horn. Some β-lactam antibiotics can up-regulate GluTs, one of which, ceftriaxone, displays analgesic effects in rodent chronic pain models.
Here, the antinociceptive actions of another β-lactam clavulanic acid, which possesses negligible antibiotic activity, were compared with ceftriaxone in rats with chronic constriction injury (CCI)-induced neuropathic pain. In addition, the protein expression of glutamate transporter-1 (GLT1), its splice variant GLT1b and glutamate-aspartate transporter (GLAST) was measured in the spinal cord of CCI rats. Finally, protein expression of the same GluTs was evaluated in cultured astrocytes obtained from rodents and humans.
Repeated injection of ceftriaxone or clavulanic acid over 10 days alleviated CCI-induced mechanical hypersensitivity, whilst clavulanic acid was additionally able to affect the thermal hypersensitivity. In addition, clavulanic acid up-regulated expression of GLT1b within the spinal cord of CCI rats, whereas ceftriaxone failed to modulate expression of any GluTs in this model. However, both clavulanic acid and ceftriaxone up-regulated GLT1 expression in rat cortical and human spinal astrocyte cultures. Furthermore, clavulanic acid increased expression of GLT1b and GLAST in rat astrocytes in a dose-dependent manner.
Thus, clavulanic acid up-regulates GluTs in cultured rodent- and human astroglia and alleviates CCI-induced hypersensitivity, most likely through up-regulation of GLT1b in spinal dorsal horn.
Chronic dosing of clavulanic acid alleviates neuropathic pain in rats and up-regulates glutamate transporters both in vitro and in vivo. Crucially, a similar up-regulation of glutamate transporters in human spinal astrocytes by clavulanic acid supports the development of novel β-lactam-based analgesics, devoid of antibacterial activity, for the clinical treatment of chronic pain.
神经损伤后，星形胶质细胞谷氨酸转运体（GluTs）的下调导致细胞外谷氨酸积累，这是脊髓背角过度兴奋的一个关键因素。一些β-内酰胺类抗生素可以上调 GluTs，其中一种，头孢曲松，在啮齿类动物慢性疼痛模型中显示出镇痛作用。
在这里，比较了另一种β-内酰胺类克拉维酸（具有微弱抗生素活性）与头孢曲松在慢性缩窄性损伤（CCI）诱导的神经病理性疼痛大鼠中的抗伤害作用。此外，还测量了 CCI 大鼠脊髓中谷氨酸转运体-1（GLT1）、其剪接变体 GLT1b 和谷氨酸-天冬氨酸转运体（GLAST）的蛋白表达。最后，评估了从啮齿动物和人类获得的培养星形胶质细胞中相同 GluTs 的蛋白表达。
重复注射头孢曲松或克拉维酸 10 天可缓解 CCI 引起的机械性痛觉过敏，而克拉维酸还能影响热痛觉过敏。此外，克拉维酸上调了 CCI 大鼠脊髓中 GLT1b 的表达，而头孢曲松在该模型中未能调节任何 GluTs 的表达。然而，克拉维酸和头孢曲松均可上调大鼠皮质和人脊髓星形胶质细胞培养物中的 GLT1 表达。此外，克拉维酸以剂量依赖的方式增加了大鼠星形胶质细胞中 GLT1b 和 GLAST 的表达。
因此，克拉维酸上调了培养的啮齿动物和人星形胶质细胞中的 GluTs，并缓解了 CCI 引起的过敏反应，这很可能是通过脊髓背角中 GLT1b 的上调。
克拉维酸的慢性给药可缓解大鼠的神经病理性疼痛，并在体外和体内均上调谷氨酸转运体。至关重要的是，克拉维酸对人脊髓星形胶质细胞中谷氨酸转运体的类似上调支持了新型无抗菌活性的基于β-内酰胺类的镇痛药的开发，用于慢性疼痛的临床治疗。
