Vanegas H, Schaible H G
Instituto Venezolano de Investigaciones Científicas (IVIC), Apartado 21827, 1020A, Caracas, Venezuela.
Prog Neurobiol. 2001 Jul;64(4):327-63. doi: 10.1016/s0301-0082(00)00063-0.
The spinal cord is one of the sites where non-steroidal anti-inflammatory drugs (NSAIDs) act to produce analgesia and antinociception. Expression of cyclooxygenase(COX)-1 and COX-2 in the spinal cord and primary afferents suggests that NSAIDs act here by inhibiting the synthesis of prostaglandins (PGs). Basal release of PGD(2), PGE(2), PGF(2alpha) and PGI(2) occurs in the spinal cord and dorsal root ganglia. Prostaglandins then bind to G-protein-coupled receptors located in intrinsic spinal neurons (receptor types DP and EP2) and primary afferent neurons (EP1, EP3, EP4 and IP). Acute and chronic peripheral inflammation, interleukins and spinal cord injury increase the expression of COX-2 and release of PGE(2) and PGI(2). By activating the cAMP and protein kinase A pathway, PGs enhance tetrodotoxin-resistant sodium currents, inhibit voltage-dependent potassium currents and increase voltage-dependent calcium inflow in nociceptive afferents. This decreases firing threshold, increases firing rate and induces release of excitatory amino acids, substance P, calcitonin gene-related peptide (CGRP) and nitric oxide. Conversely, glutamate, substance P and CGRP increase PG release. Prostaglandins also facilitate membrane currents and release of substance P and CGRP induced by low pH, bradykinin and capsaicin. All this should enhance elicitation and synaptic transfer of pain signals in the spinal cord. Direct administration of PGs to the spinal cord causes hyperalgesia and allodynia, and some studies have shown an association between induction of COX-2, increased PG release and enhanced nociception. NSAIDs diminish both basal and enhanced PG release in the spinal cord. Correspondingly, spinal application of NSAIDs generally diminishes neuronal and behavioral responses to acute nociceptive stimulation, and always attenuates behavioral responses to persistent nociception. Spinal application of specific COX-2 inhibitors sometimes diminishes behavioral responses to persistent nociception.
脊髓是非甾体抗炎药（NSAIDs）产生镇痛和抗伤害感受作用的部位之一。脊髓和初级传入神经中环氧合酶（COX）-1和COX-2的表达表明NSAIDs通过抑制前列腺素（PGs）的合成在此处发挥作用。脊髓和背根神经节中存在PGD(2)、PGE(2)、PGF(2α)和PGI(2)的基础释放。然后，前列腺素与位于脊髓固有神经元（DP和EP2受体类型）和初级传入神经元（EP1、EP3、EP4和IP）中的G蛋白偶联受体结合。急性和慢性外周炎症、白细胞介素和脊髓损伤会增加COX-2的表达以及PGE(2)和PGI(2)的释放。通过激活环磷酸腺苷（cAMP）和蛋白激酶A途径，PGs增强了对河豚毒素不敏感的钠电流，抑制电压依赖性钾电流，并增加伤害性传入神经中电压依赖性钙内流。这降低了放电阈值，增加了放电频率，并诱导兴奋性氨基酸、P物质、降钙素基因相关肽（CGRP）和一氧化氮的释放。相反，谷氨酸、P物质和CGRP会增加PG的释放。前列腺素还促进低pH值、缓激肽和辣椒素诱导的膜电流以及P物质和CGRP的释放。所有这些都应增强脊髓中疼痛信号的引发和突触传递。直接将PGs注入脊髓会导致痛觉过敏和异常性疼痛，一些研究表明COX-2的诱导、PG释放增加与伤害感受增强之间存在关联。NSAIDs可减少脊髓中基础和增强的PG释放。相应地，脊髓应用NSAIDs通常会减少对急性伤害性刺激的神经元和行为反应，并且总是会减弱对持续性伤害感受的行为反应。脊髓应用特异性COX-2抑制剂有时会减弱对持续性伤害感受的行为反应。
