PT  - JOURNAL ARTICLE
AU  - Field, Mark J.
AU  - McCleary, Scott
AU  - Boden, Philip
AU  - Suman-Chauhan, Nirmala
AU  - Hughes, John
AU  - Singh, Lakhbir
TI  - Involvement of the Central Tachykinin NK<sub>1</sub> Receptor during Maintenance of Mechanical Hypersensitivity Induced by Diabetes in the Rat
DP  - 1998 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1226--1232
VI  - 285
IP  - 3
4099  - http://jpet.aspetjournals.org/content/285/3/1226.short
4100  - http://jpet.aspetjournals.org/content/285/3/1226.full
SO  - J Pharmacol Exp Ther1998 Jun 01; 285
AB  - Our study examines the role of central and peripheral neurokinin1 (NK1) receptors in diabetes-induced mechanical hypersensitivity. Glycine, N, N-dimethyl-, 2-[[2-[[(2-benzofuranylmethoxy)carbonyl]amino]-3-(1H-indol-3-yl)-2-methyl-1-oxopropyl] amino]-2-phenylethylester, bisulfate, [R-(R*,R*)] (PD 156982) is a selective NK1receptor antagonist with nanomolar affinity for the human (IC50 = 1.4 nM) and guinea pig (IC50 = 9.6 nM) NK1 receptors. However, it has approximately two orders of magnitude lower affinity for the rodent NK1 receptor (IC50 = 820 nM). In electrophysiological studies, PD 156982 inhibited NK1 receptor-mediated responses in the guinea pig locus ceruleus, in a competitive manner, with an equilibrium constant of 13.9 nM. The intracerebroventricular (10-100 μg/animal) but not systemic administration of PD 156982 (1-100 mg/kg, s.c.) blocked the [Sar9,Met(O2)11] substance P-induced gerbil foot tapping response. This indicates that PD 156982 is unable to penetrate into the central nervous system. However, PD 156982 (10-100 mg/kg, s.c.) blocked the mechanical hypersensitivity induced by administration of substance P into the plantar surface of a rat paw. This suggests that PD 156982 can effectively antagonize peripheral NK1 receptors in vivo. The chemically related compound carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]ethyl]-, 2-benzofuranylmethyl ester, [R-(R*,S*)] (CI-1021) is also a selective NK1 receptor antagonist but can penetrate into the central nervous system. PD 156982 (10-100 mg/kg, s.c.) failed to block streptozocin (75 mg/kg, i.p.) induced mechanical hypersensitivity. In contrast, CI-1021 dose-dependently (3-100 mg/kg, s.c.) blocked this hypersensitivity state with a minimum effective dose of 10 mg/kg. At these doses CI-1021 also antagonized mechanical hypersensitivity mediated by central NK1 but not NK2 receptors in the rat. It is suggested that the central NK1 receptor may play an important role in diabetes-induced hypersensitivity. The American Society for Pharmacology and Experimental Therapeutics