Received for publication November 10, 2005.
Revised March 21, 2006.
Accepted for publication March 23, 2006.

Antinociceptive Pharmacology of LF22-0542, A Novel Non-Peptidic Bradykinin B1 Receptor Antagonist

Abstract

The antinociceptive pharmacology LF22-0542, a novel, non-peptidic B1 antagonist, was characterized. LF22-0542 showed high affinity for human and mouse B1 receptors with virtually no affinity for the human B2 receptor; a selectivity index of at least 4,000 times was obtained when profiling LF22-0542 throughout binding or cell biology assays on 64 other GPCRs, 10 ion channels and 7 enzymes. LF22-0542 was a competitive B1 receptor antagonist. LF22-0542 elicited significant antinociceptive actions in the mouse acetic-acid-induced writhing assay, as well as in the second phase of formalin-induced nociception in mice and in both the first and second phase of the formalin response in rats. LF22-0542 was active after s.c. but not p.o. administration. In B1 receptor KO mice, acetic-acid and formalin responses were significantly reduced and LF22-0542 had no additional effects in these animals. LF22-0542 alleviated thermal hypersensitivity in both acute (carrageenan) and persistent inflammatory (CFA) pain models in rats. LF22-0542 produced full reversal of experimental neuropathic thermal hypersensitivity but was inactive in reversing nerve-injury induced tactile hypersensitivity in rats. In agreement with this observation, B1 KO mice subjected to peripheral nerve injury did not show thermal hypersensitivity but developed nerve injury-induced tactile hypersensitivity normally. The data demonstrate antihyperalgesic actions of a selective systemically administered B1 receptor antagonist and suggest utility of this class of agents for the treatment of inflammatory pain states and for some aspects of neuropathic pain.

Key words: B1 receptor, Bradykinin, Knock out mice, formalin, inflammation, nerve injury

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