Involvement of the central tachykinin NK1 receptor during maintenance of mechanical hypersensitivity induced by diabetes in the rat.
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 -me thyl-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 microg/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]et hyl ]-, 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.
Field
M J
MJ
Department of Biology, Parke-Davis Neuroscience Research Centre, Cambridge University Forvie Site, Cambridge, CB2 2QB, United Kingdom.
McCleary
S
S
Boden
P
P
Suman-Chauhan
N
N
Hughes
J
J
Singh
L
L
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000503:physiopathology*; D004594:Electrophysiology; D005849:Gerbillinae; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000502:physiology; D013373:Substance P
D001572:Benzofurans; C112778:CI 1021; D002219:Carbamates; D064729:Neurokinin-1 Receptor Antagonists; C112777:PD 156982; D018040:Receptors, Neurokinin-1; D013373:Substance P; D005998:Glycine