PT  - JOURNAL ARTICLE
AU  - Mark J. Field
AU  - M. Isabel Gonzalez
AU  - Ronald J. Tallarida
AU  - Lakhbir Singh
TI  - Gabapentin and the Neurokinin<sub>1</sub> Receptor Antagonist   CI-1021 Act Synergistically in Two Rat Models of  Neuropathic Pain
AID  - 10.1124/jpet.102.033134
DP  - 2002 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 730--735
VI  - 303
IP  - 2
4099  - http://jpet.aspetjournals.org/content/303/2/730.short
4100  - http://jpet.aspetjournals.org/content/303/2/730.full
SO  - J Pharmacol Exp Ther2002 Nov 01; 303
AB  - 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 NK1receptor 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 NK1 receptor antagonists in animal models of neuropathic pain. The American Society for Pharmacology and Experimental Therapeutics