Field Mark J, Gonzalez M Isabel, Tallarida Ronald J, Singh Lakhbir
Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA.
J Pharmacol Exp Ther. 2002 Nov;303(2):730-5. doi: 10.1124/jpet.102.033134.
The present study examines the effect of combinations of gabapentin (Neurontin) and a selective neurokinin (NK)(1) receptor antagonist, 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]ethyl]-2-benzofuranylmethyl ester (CI-1021), in two models of neuropathic pain. Dose responses to both gabapentin and CI-1021 were performed against static allodynia induced in the streptozocin and chronic constriction injury (CCI) models. Theoretical additive lines were calculated from these data. Dose responses to various fixed dose ratios of a gabapentin/CI-1021 combination were then examined in both models. In the streptozocin model, administration of gabapentin/CI-1021 combinations at fixed dose ratios of 1:1 and 60:1 resulted in an additive effect with dose response similar to the theoretical additive line. However, a synergistic interaction was seen after fixed dose ratios of 10:1, 20:1, and 40:1 with static allodynia completely blocked and the dose responses shifted approximately 8-, 30-, and 10-fold leftward, respectively, from the theoretical additive values. In the CCI model, after fixed dose ratios of 5:1 and 20:1, combinations of gabapentin and CI-1021 produced an additive response. At the fixed dose ratio of 10:1 static allodynia was completely blocked with an approximate 10-fold leftward shift of the dose response from the theoretical additive value, indicating synergy. The combination of gabapentin with a structurally unrelated NK(1) receptor antagonist, (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), also produced synergy, at a fixed dose ratio of 20:1. This ratio completely blocked streptozocin-induced static allodynia and was approximately shifted leftward 5-fold from the theoretical additive value. These data suggest a synergistic interaction between gabapentin and NK(1) receptor antagonists in animal models of neuropathic pain.
本研究在两种神经性疼痛模型中考察了加巴喷丁（Neurontin）与选择性神经激肽（NK）（1）受体拮抗剂1-(1H-吲哚-3-基甲基)-1-甲基-2-氧代-2-[(1-苯乙基)氨基]乙基]-2-苯并呋喃基甲酯（CI-1021）联合使用的效果。针对链脲佐菌素和慢性缩窄性损伤（CCI）模型中诱导的静态痛觉过敏，分别进行了加巴喷丁和CI-1021的剂量反应实验。根据这些数据计算出理论相加线。然后在两种模型中考察了加巴喷丁/CI-1021不同固定剂量比的剂量反应。在链脲佐菌素模型中，以1:1和60:1的固定剂量比给予加巴喷丁/CI-1021联合用药产生相加效应，剂量反应与理论相加线相似。然而，在10:1、20:1和40:1的固定剂量比下观察到协同相互作用，静态痛觉过敏完全被阻断，剂量反应分别从理论相加值向左移动约8倍、30倍和10倍。在CCI模型中，在5:1和20:1的固定剂量比下，加巴喷丁和CI-1021联合用药产生相加反应。在10:1的固定剂量比下，静态痛觉过敏完全被阻断，剂量反应从理论相加值向左移动约10倍，表明存在协同作用。加巴喷丁与结构不相关的NK（1）受体拮抗剂(2S,3S)-3-(2-甲氧基苄基氨基)-2-苯基哌啶（CP-99,994）联合使用，在20:1的固定剂量比下也产生协同作用。该比例完全阻断了链脲佐菌素诱导的静态痛觉过敏，并且从理论相加值向左移动了约5倍。这些数据表明在神经性疼痛动物模型中加巴喷丁与NK（1）受体拮抗剂之间存在协同相互作用。
