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OtherANALGESIA AND DRUGS OF ABUSE

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
Journal of Pharmacology and Experimental Therapeutics June 1998, 285 (3) 1226-1232;
Mark J. Field
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Scott McCleary
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Philip Boden
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Nirmala Suman-Chauhan
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John Hughes
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Lakhbir Singh
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Abstract

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.

Footnotes

  • Send reprint requests to: Dr L. Singh, Department of Biology, Parke-Davis Neuroscience Research Centre, Cambridge University Forvie Site, Robinson Way, Cambridge, CB2 2QB, United Kingdom.

  • Abbreviations:
    PWT
    paw withdrawal threshold
    MED
    minimum effective dose
    NK
    neurokinin
    ACSF
    artificial cerebrospinal fluid
    NSAIDS
    nonsteroidal antiinflammatory drugs
    i.c.v. intracerebroventricular. CI-1021
    carbamic acid, [1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]ethyl]-, 2-benzofuranylmethyl ester, [R-(R*,S*)]
    PD 156982
    glycine, N,N-dimethyl-,2-[[2-[[(2-benzofuranylmethoxy)carbonyl] amino]-3-(1H-indol-3-yl)-2 methyl1oxopropyl]amino]-2 phenylethyl ester, bisulfate, [R-(R*,R*)]
    • Received November 20, 1997.
    • Accepted February 23, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 3
1 Jun 1998
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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
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1226-1232;

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OtherANALGESIA AND DRUGS OF ABUSE

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
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1226-1232;
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