Siniscalco Dario, Giordano Catia, Fuccio Carlo, Luongo Livio, Ferraraccio Franca, Rossi Francesca, de Novellis Vito, Roth Kevin A, Maione Sabatino
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Second University of Naples, via S. Maria di Costantinopoli 16, 80138 Napoli, Italy.
Pharmacol Res. 2008 Mar;57(3):223-33. doi: 10.1016/j.phrs.2008.01.007. Epub 2008 Feb 2.
The effect of the non-selective, 1-aminoindan-1,5-dicarboxylic acid (AIDA), and selective (3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl) methanone (JNJ16259685), metabotropic glutamate subtype 1 (mGlu1) receptor antagonists, on rat sciatic nerve chronic constrictive injury (CCI)-induced hyperalgesia, allodynia, spinal dorsal horn apoptosis, and gliosis was examined at 3 and 7 days post-injury. RT-PCR analysis showed increased expression of bax, apoptotic protease-activating factor-1 (apaf-1), nestin, GFAP, and caspase-7 mRNA in the dorsal horn spinal cord by 3 days post-CCI. At 7 days post-CCI, only over-expression of bcl-2, nestin and GFAP mRNA was observed. Administration of AIDA reduced thermal hyperalgesia and mechanical allodynia at 3 and 7 days post-CCI; administration of JNJ16259685 reduced thermal hyperalgesia at 3 and 7 days post-CCI, but not mechanical allodynia. AIDA decreased the mRNA levels of bax, apaf-1, GFAP and caspase-7 genes. JNJ16259685 increased the mRNA levels of bcl-2 and GFAP gene, and decreased APAF-1 and caspases-7 genes. Inhibiting mGlu1 receptors also reduced TUNEL-positive profiles and immunohistochemical reactivity for caspase-7. We report here that despite inhibiting CCI-induced over-expression of pro-apoptotic genes in the spinal cord dorsal horn, the selective mGlu1 receptor antagonist JNJ16259685 exerted only a slight and transient allodynic effect. Moreover, JNJ16259685, but not the non-selective AIDA, increased astrogliosis which may account for its decreased analgesic efficacy. This study provides evidence that the contemporary and partial blockade of group I and likely ionotropic glutamate receptors may be a more suitable therapy than selective blockade of mGlu1 subtype receptors condition to decrease neuropathic pain symptoms.
在大鼠坐骨神经慢性压迫性损伤（CCI）后3天和7天，研究了非选择性的1-氨基茚满-1,5-二羧酸（AIDA）和选择性的（3,4-二氢-2H-吡喃并[2,3-b]喹啉-7-基）-（顺式-4-甲氧基环己基）甲酮（JNJ16259685），即代谢型谷氨酸1（mGlu1）受体拮抗剂，对CCI诱导的痛觉过敏、异常性疼痛、脊髓背角细胞凋亡和胶质增生的影响。逆转录-聚合酶链反应（RT-PCR）分析显示，CCI后3天，脊髓背角中bax、凋亡蛋白酶激活因子-1（apaf-1）、巢蛋白、胶质纤维酸性蛋白（GFAP）和半胱天冬酶-7 mRNA的表达增加。CCI后7天，仅观察到bcl-2、巢蛋白和GFAP mRNA的过表达。给予AIDA可减轻CCI后3天和7天的热痛觉过敏和机械性异常性疼痛；给予JNJ16259685可减轻CCI后3天和7天的热痛觉过敏，但对机械性异常性疼痛无效。AIDA降低了bax、apaf-1、GFAP和半胱天冬酶-7基因的mRNA水平。JNJ16259685增加了bcl-2和GFAP基因的mRNA水平，并降低了APAF-1和半胱天冬酶-7基因的水平。抑制mGlu1受体也减少了TUNEL阳性细胞数量和半胱天冬酶-7的免疫组化反应性。我们在此报告，尽管抑制了CCI诱导的脊髓背角促凋亡基因的过表达，但选择性mGlu1受体拮抗剂JNJ16259685仅产生轻微且短暂的异常性疼痛效应。此外，JNJ16259685而非非选择性的AIDA增加了星形胶质细胞增生，这可能解释了其镇痛效果降低的原因。本研究提供了证据，即与选择性阻断mGlu1亚型受体相比，同时部分阻断I组以及可能的离子型谷氨酸受体可能是减轻神经性疼痛症状更合适的治疗方法。
