Effects of the bradykinin B1 receptor antagonist des-Arg9[Leu8]bradykinin and genetic disruption of the B2 receptor on nociception in rats and mice

Abstract

The contributions of B1 and B2 bradykinin receptors to acute and chronic inflammatory hyperalgesia were examined using the peptide B1 receptor antagonist des-Arg9[Leu8]bradykinin and transgenic Bk2r-/- mice. In normal rats and mice, des-Arg9[Leu8]bradykinin (30 nmol/kg i.v. or s.c.) inhibited carrageenan-induced hyperalgesia and the late phase nociceptive response to formalin. The active dose range was narrow, suggesting partial agonist activity of this peptide. In rats with monoarthritis, des-Arg9[Leu8]bradykinin (up to 30 nmol/kg i.v.) failed to reduce the number of vocalisations elicited by gentle flexion and extension of the inflamed limb; however, hyperalgesia was exacerbated by administration of the B1 receptor agonist des-[Arg9]bradykinin (100 nmol/kg i.v.), consistent with other evidence for local induction of B1 receptors during adjuvant-induced arthritis. The nociceptive response to intraplantar injection of bradykinin (10 nmol) and hyperalgesia induced by carrageenan (0.6 mg) were absent in Bk2r-/- mice, indicating that stimulation of B2 receptors is an essential step in the initiation of some nociceptive and inflammatory reactions. However, the nociceptive response to formalin (2.5% intraplantar), including inhibition of the late phase by des-Arg9[Leu8]bradykinin (0.3 nmol), and induction of thermal hyperalgesia by Freund's adjuvant (0.1%) appeared intact in Bk2r-/- mice. These findings support other evidence for an involvement of B1 receptors in inflammatory hyperalgesia and suggest that B1 receptor antagonists may be clinically useful as anti-inflammatory and analgesic drugs.

Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors

“…The functional status of B1 receptors expressed by resting sensory neurons is at present unclear while functional B2 receptors are expressed (11). However, in one of the behavioral tests used here, the formalin test, in which the B1 receptor is required, mice lacking the B2 receptor do not display hypoal-gesia (3,16). It is possible that B1 receptors located on the nociceptor terminals in the spinal cord or on spinal cord interneurons could mediate the central effects of the receptor.…”

“…Agonists for the B1 receptor are derived from BK and kallidin by carboxypeptidase action, generating des-Arg 9 -BK and des-Arg 10 -kallidin, respectively. Using specific antagonists, the B1 receptor has been implicated in nociception and the accumulation of leukocytes in inflamed tissue (3,5,10). However, despite the detection of mRNA for the B1 receptor in dorsal root ganglia, its role in pain transmission has remained elusive (11).…”

“…The B2 receptor binds the major effector peptide of the kallikrein-kinin system, which is bradykinin (BK) in rodents and kallidin in humans. Deletion of the B2 receptor in mice leads to salt-sensitive hypertension and altered nociception (2)(3)(4). Like the B2 receptor, the B1 receptor is a heptahelical receptor, but unlike B2 receptors, it is not widely expressed in normal tissue but is highly inducible by inflammatory mediators like bacterial lipopolysaccharide (LPS) and cytokines and does not desensitize after agonist binding (5)(6)(7)(8)(9).…”

Overexpression of Kinin B1 Receptors Induces Hypertensive Response to Des-Arg9-bradykinin and Susceptibility to Inflammation

“…The B 2 receptor is constitutively expressed, mediating the actions of intact kinins, bradykinin (BK) in rodents and Lys-BK or kallidin in humans (2). In contrast, the B 1 receptor is expressed at very low levels in normal tissues in most animal species but is induced under the influence of inflammation or exposure of tissues to noxious stimuli, mediating the effects of the carboxypeptidase metabolites of intact kinins, des-Arg 9 -BK (DABK), and des-Arg 10 -kallidin (2). The cellular responses of kinin receptors to agonists are transduced primarily via coupling to either G q protein, which in turn activates phospholipase C to stimulate inositol phosphate production, or the G i protein, acting through phospholipase A 2 to stimulate arachidonic acid pathway (5,6).…”

“…Administration of the B 2 receptor antagonist Hoe-140 blunted the blood pressure-lowering effect of the transgene, whereas intra-arterial bolus injection of BK produced more pronounced blood pressure reduction (7). In contrast, deletion of the B 2 receptor in mice produced an unaltered blood pressure phenotype (8) but led to salt-sensitive hypertension and altered nociception (9,10). Using specific antagonists, the B 1 receptor has been implicated in toxic shock, inflammation, and nociception (11).…”