Vol. 285, Issue 3, 1226-1232, June 1998

Involvement of the Central Tachykinin NK₁ Receptor during Maintenance of Mechanical Hypersensitivity Induced by Diabetes in the Rat

Mark J. Field, Scott McCleary, Philip Boden, Nirmala Suman-Chauhan, John Hughes and Lakhbir Singh

Department of Biology, Parke-Davis Neuroscience Research Centre, Cambridge University Forvie Site, Cambridge, CB2 2QB, United Kingdom

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 NK₁ receptor 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.