Kinin receptors in pain and inflammation

Abstract

Kinins are among the most potent autacoids involved in inflammatory, vascular and pain processes. These short-lived peptides, including bradykinin, kallidin and T-kinin, are generated during tissue injury and noxious stimulation. However, emerging evidence also suggests that kinins are stored in neuronal elements of the central nervous system (CNS) where they are thought to play a role as neuromediators in various cerebral functions, particularly in the control of nociceptive information. Kinins exert their biological effects through the activation of two transmembrane G-protein-coupled receptors, denoted bradykinin B₁ and B₂. Whereas the B₂ receptor is constitutive and activated by the parent molecules, the B₁ receptor is generally underexpressed in normal tissues and is activated by kinins deprived of the C-terminal Arg (des-Arg⁹-kinins). The induction and increased expression of B₁ receptor occur following tissue injury or after treatment with bacterial endotoxins or cytokines such as interleukin-1β and tumor necrosis factor-α. This review summarizes the most recent data from various animal models which convey support for a role of B₂ receptors in the acute phase of the inflammatory and pain response, and for a role of B₁ receptors in the chronic phase of the response. The B₁ receptor may exert a strategic role in inflammatory diseases with an immune component (diabetes, asthma, rheumatoid arthritis and multiple sclerosis). New information is provided regarding the role of sensory mechanisms subserving spinal hyperalgesia and intrapleural neutrophil migration that occur upon B₁ receptor activation in streptozotocin-treated rats, a model of insulin-dependent diabetes mellitus in which the B₁ receptor seems to be rapidly overexpressed. Although it is widely accepted that the blockade of kinin receptors with specific antagonists could be of benefit in the treatment of somatic and visceral inflammation and pain, recent molecular and functional evidence suggests that the activation of B₁ receptors with an agonist may afford a novel therapeutic approach in the CNS inflammatory demyelinating disorder encountered in multiple sclerosis by reducing immune cell infiltration (T-lymphocytes) into the brain. Hence, the B₁ receptor may exert either a protective or detrimental effect depending on the inflammatory disease. This dual function of the B₁ receptor deserves to be investigated further.

Introduction

Kinins belong to a group of 9–11 amino acid peptides including bradykinin, kallidin, T-kinin and their active metabolites, des-Arg⁹-kinins. Bradykinin and kallidin are generated following the proteolytic cleavage of their respective precursors, high molecular weight kininogen and low molecular weight kininogen, by plasma and tissue serine proteases named kallikreins (for review see Bhoola et al., 1992). T-kinin was identified exclusively in the rat Okamoto and Greenbaum, 1983a, Okamoto and Greenbaum, 1983b. These peptides undergo rapid metabolic degradation by amino-, carboxy- and endopeptidases found in tissues and biological fluids. The most physiologically relevant enzymes are kininase I (carboxypeptidase N), which removes Arg⁹ from kinins to produce the active metabolites des-Arg⁹-kinins, neutral endopeptidase 24.11 (enkephalinase), which cleaves the C-terminal dipeptide Phe⁸–Arg⁹ from bradykinin, and kininase II (also named angiotensin-I-converting enzyme), which acts as dipeptidyl carboxypeptidase to remove the COOH-terminal dipeptide, Phe⁸–Arg⁹. Furthermore, angiotensin-1-converting enzyme cleaves the COOH-terminal dipeptide Ser⁶–Pro⁷ of bradykinin-(1–7) to produce bradykinin-(1–5), which is the final metabolite of bradykinin and des-Arg⁹-bradykinin. Kallidin and T-kinin are also subject to transformation into bradykinin by aminopeptidase activity Kuoppala et al., 2000, Murphey et al., 2000, Campbell, 2000, Couture and Lindsey, 2000.