Kannampalli Pradeep, Pochiraju Soumya, Bruckert Mitchell, Shaker Reza, Banerjee Banani, Sengupta Jyoti N
Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
Eur J Pharmacol. 2014 Mar 15;727:87-98. doi: 10.1016/j.ejphar.2014.01.026. Epub 2014 Jan 28.
The present study investigates the analgesic effect of minocycline, a semi-synthetic tetracycline antibiotic, in a rat model of inflammation-induced visceral pain. Inflammation was induced in male rats by intracolonic administration of tri-nitrobenzenesulphonic acid (TNBS). Visceral hyperalgesia was assessed by comparing the viscero-motor response (VMR) to graded colorectal distension (CRD) prior and post 7 days after TNBS treatment. Electrophysiology recordings from CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons were performed in naïve and inflamed rats. Colonic inflammation produced visceral hyperalgesia characterized by increase in the VMRs to CRD accompanied with simultaneous activation of microglia in the spinal cord and satellite glial cells (SGCs) in the dorsal root ganglions (DRGs). Selectively inhibiting the glial activation following inflammation by araC (Arabinofuranosyl Cytidine) prevented the development of visceral hyperalgesia. Intrathecal minocycline significantly attenuated the VMR to CRD in inflamed rats, whereas systemic minocycline produced a delayed effect. In electrophysiology experiments, minocycline significantly attenuated the mechanotransduction of CRD-sensitive PNAs and the responses of CRD-sensitive LS spinal neurons in TNBS-treated rats. While the spinal effect of minocycline was observed within 5min of administration, systemic injection of the drug produced a delayed effect (60min) in inflamed rats. Interestingly, minocycline did not exhibit analgesic effect in naïve, non-inflamed rats. The results demonstrate that intrathecal injection of minocycline can effectively attenuate inflammation-induced visceral hyperalgesia. Minocycline might as well act on neuronal targets in the spinal cord of inflamed rats, in addition to the widely reported glial inhibitory action to produce analgesia.
本研究在炎症诱导的内脏痛大鼠模型中，研究了半合成四环素抗生素米诺环素的镇痛作用。通过向雄性大鼠结肠内注射三硝基苯磺酸（TNBS）诱导炎症。通过比较TNBS治疗前和治疗后7天对分级结肠扩张（CRD）的内脏运动反应（VMR）来评估内脏痛觉过敏。在未处理和发炎的大鼠中，对CRD敏感的盆神经传入纤维（PNA）和腰骶（LS）脊髓神经元进行电生理记录。结肠炎症产生内脏痛觉过敏，其特征是对CRD的VMR增加，同时脊髓中的小胶质细胞和背根神经节（DRG）中的卫星胶质细胞（SGC）被激活。用阿糖胞苷（阿拉伯呋喃糖胞苷）选择性抑制炎症后胶质细胞的激活可防止内脏痛觉过敏的发展。鞘内注射米诺环素可显著减轻发炎大鼠对CRD的VMR，而全身注射米诺环素则产生延迟效应。在电生理实验中，米诺环素显著减弱了TNBS处理大鼠中CRD敏感PNA的机械转导和CRD敏感LS脊髓神经元的反应。虽然米诺环素的脊髓效应在给药后5分钟内即可观察到，但在发炎大鼠中全身注射该药物则产生延迟效应（60分钟）。有趣的是，米诺环素在未处理的非发炎大鼠中未表现出镇痛作用。结果表明，鞘内注射米诺环素可有效减轻炎症诱导的内脏痛觉过敏。除了广泛报道的胶质抑制作用外，米诺环素还可能作用于发炎大鼠脊髓中的神经元靶点以产生镇痛作用。
