ReviewKinin receptors in pain and inflammation
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.
Section snippets
Bradykinin receptors and signalling pathways
Kinins exert their biological effects through the activation of two receptors, denoted as bradykinin B1 and bradykinin B2 receptors on the basis of their distinct pharmacology Regoli and Barabé, 1980, Marceau et al., 1998. Kinins are the endogenous agonists of the prevailing B2 receptor, while des-Arg9-bradykinin and des-Arg10-kallidin are the preferential agonists for the B1 receptor. Present evidence suggests that kallikreins and some other proteases activate human B2 receptor directly,
Regulation of bradykinin receptors
In pathological conditions, the inducible B1 receptor that mediates the inflammatory actions of kinins might be activated by the endogenous biologically active kininase I metabolite (des-Arg9-bradykinin), which is increased at sites of inflammation Raymond et al., 1995, Décarie et al., 1996b. Indeed, evidence from human lung fibroblasts (IMR-90) suggests upregulation of B1 receptors by its own agonist, involving activation of protein kinase C and NF-κB through pertussis and cholera
Bradykinin receptors in pain and inflammation
Results obtained with animal models suggest that B2 receptors are involved in the acute phase of the inflammatory and pain response, whereas B1 receptors participate in the chronic phase of the response Dray and Perkins, 1993, Dray, 1997. This is likely to occur because B2 receptor function is controlled by short-term mechanisms involving fast ligand dissociation, receptor desensitization and internalization, and on long-term stimulation, downregulation Munoz and Leeb-Lundberg, 1992, Munoz et
Central kinins in pain process
Compelling evidence suggests that kinins may act as modulatory transmitters via the activation of B2 receptors in the physiological control of spinal and supraspinal nociceptive neurotransmission. All components of the kallikrein–kinin system have been identified in the brain and spinal cord, including kinin precursors (kininogens), kinin-releasing enzymes (kallikreins), kinins, bradykinin B2 receptor and kinin-degrading enzymes (for a review see Couture and Lindsey, 2000). When administered
Bradykinin receptors in inflammation and leukocyte trafficking
Whereas the B2 receptor is involved in most of the cardinal signs of acute inflammation, including increased vascular permeability, venoconstriction, arterial dilatation and pain through the activation of sensory nerve terminals, this receptor has a limited role in the cellular component of the inflammatory response involving leukocyte recruitment within the microcirculation (McLean et al., 2000a). The pro-inflammatory effects of B1 receptors include promotion of blood-borne leukocyte
Bradykinin B1 receptor on T-lymphocytes
Bradykinin B1 receptor immunoreactivity was observed on vascular endothelial and perivascular inflammatory cells in brain samples taken at autopsy from multiple sclerosis patients (Prat et al., 2000). In addition, the expression of this receptor was upregulated on T lymphocytes (CD3+ cells) derived from peripheral blood of multiple sclerosis patients; it was correlated with the clinical activity of the disease and was virtually absent in healthy control subjects and patients with other
Bradykinin receptors in edema and vascular permeability
The production of edema and vascular permeability is mainly mediated through the constitutive B2 receptor in several models of acute visceral and cutaneous inflammation such as pancreatitis and cystitis or whether it occurs in response to treatment with carrageenan or collagenase Burch and DeHass, 1990, Damas and Remacle-Volon, 1992, Wirth et al., 1992, Décarie et al., 1996b, Griesbacher and Legat, 1997, Griesbacher and Legat, 2000. However, both B1 and B2 receptors appear to be involved in the
Putative role of kinins in diabetes-induced pain and inflammation
Experimental evidence suggests that diabetes is another stimulus that can upregulate B1 receptors. Current evidence indicates that insulin-dependent diabetes mellitus is due to an autoimmune response associated with overproduction of cytokines, including interleukin-1β and tumor necrosis factor-α, that leads to the destruction of pancreatic islet β-cells Hussain et al., 1996, Rabinovitch and Suarez-Pinzon, 1998, Rabinovitch, 1998. Hyperglycemia and the resulting oxidative stress can also
Conclusion
Molecular and pharmacological evidence supports a role for B2 receptors in the acute phase of the inflammatory and pain response, whereas B1 receptors most likely intervene in the chronic phase of inflammatory and pain processes. Recent anatomical and functional studies suggest that the B1 receptor is induced on sensory fibres through the cytokine network to cause neurogenic inflammation, hyperalgesia and leukocyte infiltration. Because of its multicellular location and mode of persistent
Acknowledgements
This work was supported by grants from the Canadian Institutes of Health Research (MOP-14379), the Canadian Diabetes Association and the Heart and Stroke Foundation of Canada.
References (179)
- et al.
Calcitonin gene-related peptides modulate the acute inflammatory response induced by interleukin-1 in the mouse
Eur. J. Pharmacol.
(1994) - et al.
B1 receptors as a new inflammatory target. Could this B the 1?
Trends Pharmacol. Sci.
(1999) - et al.
Nonpeptide antagonists for kinin receptors
Regul. Pept.
(1999) - et al.
Stable expression of the human kinin B1 receptor in chinese hamster ovary cells
J. Biol. Chem.
(1997) - et al.
Structure and genomic organization of the human B1 receptor gene for kinins (BDKRB1)
Genomics
(1996) - et al.
Inflammatory hyperalgesia induced by zymosan in the plantar tissue of the rat: effect of kinin receptor antagonists
Immunopharmacology
(2000) - et al.
Tachykinin and kinin receptor antagonists: therapeutic perspectives in allergic airway disease
Trends Pharmacol. Sci.
(1996) - et al.
Targeted disruption of a B2 bradykinin receptor gene in mice eliminates bradykinin action in smooth muscle and neurons
J. Biol. Chem.
(1995) - et al.
Nociception and inflammatory hyperalgesia in B2 bradykinin receptor knockout mice
Immunopharmacology
(1996) - et al.
Kinins in pain and inflammation
Pain
(2000)
Kinin B2 and B1 receptor-mediated vasoactive effects in rabbit synovium
Peptides
Modulation of kinin B1- but not B2-receptors mediated rat paw edema by IL-1β and TNFα
Peptides
Changes in paw oedema triggered via bradykinin B1 and B2 receptors in streptozotocin-diabetic rats
Eur. J. Pharmacol.
The spinal and peripheral roles of bradykinin and prostaglandins in nociceptive processing in the rat
Eur. J. Pharmacol.
Brain kallikrein–kinin system: from receptors to neuronal pathways and physiological functions
Influence of a long-acting bradykinin antagonist, Hoe 140, on some acute inflammatory reactions in the rat
Eur. J. Pharmacol.
Development of digoxigenin-labeled peptide: application to chemiluminoenzyme immunoassay of bradykinin in inflamed tissues
Peptides
Effects of captopril and icatibant on bradykinin (BK) and des[Arg9]BK in carrageenan-induced edema
Peptides
Bradykinin and inflammatory pain
Trends Neurosci.
Kinins and pain
Spatio-temporal pattern of induction of bradykinin receptors and inflammation in rat dorsal root ganglia after unilateral nerve ligation
Pain
Comparison of the responses of B1 and B2 kinin receptors to agonist stimulation
Immunopharmacology
The role of sensorial neuropeptides in the edematogenic responses mediated by B1 agonist des-Arg9-BK in rats pre-treated with LPS
Regul. Pept.
Susceptibility to infection and altered hematopoiesis in mice deficient in both P- and E-selectins
Cell
Sensory neuropeptide release by bradykinin: mechanisms and pathophysiological implications
Regul. Pept.
Increased blood concentration of des-Arg9-bradykinin in experimental allergic-encephalomyelitis
J. Neurol. Sci.
Possible role of nitric oxide in the antinociceptive action of intraventricular bradykinin in mice
Eur. J. Pharmacol.
Effects of substance P on functionally identified units in cat spinal cord
Brain Res.
The modulatory effects of bradykinin B1 and B2 receptor antagonists upon viscero-visceral hyper-reflexia in a rat model of visceral hyperalgesia
Pain
Blood cell dynamics in P-selectin-deficient mice
Blood
Inflammation modulates the contribution of receptor-subtypes of bradykinin-induced hyperalgesia in the rat
Neuroscience
Intrathecal bradykinin acts presynaptically on spinal noradrenergic terminals to produce antinociception in the rat
Eur. J. Pharmacol.
Increased mRNA expression of the B1 and B2 bradykinin receptors and antinociceptive effects of their antagonists in an animal model of neuropathic pain
Pain
Cardiovascular responses elicited by intrathecal kinins in the conscious rat
Eur. J. Pharmacol.
Localization of bradykinin-like immunoreactivity in the rat spinal cord: effects of capsaicin, melittin, dorsal rhizotomy and peripheral axotomy
Neuroscience
Quantitative autoradiographic localization of [125I-Tyr8]bradykinin receptor binding sites in the rat spinal cord: effects of neonatal capsaicin, noradrenergic deafferentation, dorsal rhizotomy and peripheral axotomy
Neuroscience
Basal and stimulated release of substance P from dissociated cultures of vagal sensory neurons
Brain Res.
Involvement of bradykinin B1 receptors in the polymorphonuclear leukocyte accumulation induced by IL-1β in vivo in the mouse
J. Immunol.
Impaired IL-1β-induced neutrophil accumulation in tachykinin NK1 receptor knockout mice
Br. J. Pharmacol.
Effect of bradykinin and prostaglandins on the release of calcitonin gene-related peptide-like immunoreactivity from the rat spinal cord in vitro
Br. J. Pharmacol.
Altered neutrophil homeostasis in kinin B1 receptor-deficient mice
Biol. Chem.
Suppressive effect of distinct bradykinin B2 receptor antagonist on allergen-evoked exudation and leukocyte infiltration in sensitized rats
Br. J. Pharmacol.
Angiotensin-converting enzyme inhibitor ramiprilat interferes with the sequestration of the B2 kinin receptor within the plasma membrane of native endothelial cells
Circulation
Antinociceptive activity of the bradykinin antagonist Hoe 140 in rat and mouse
Br. J. Pharmacol.
Bioregulation of kinins: kallikreins, kininogens, and kininases
Pharmacol. Rev.
Kallikrein and kinin receptor expression in inflammation and cancer
Biol. Chem.
Involvement of endogenous kinins in the pathogenesis of peptidoglycan-induced arthritis in the Lewis rat
Arthritis Rheum.
Kinins and kinin receptors: importance for the activation of leukocytes
J. Leukocyte Biol.
A bradykinin antagonist inhibits carrageenan edema in rats
Naunyn-Schmiedeberg's Arch. Pharmacol.
Second messengers involved in the mechanism of action of bradykinin in sensory neurones in culture
J. Neurosci.
Cited by (396)
An overview of kinin mediated events in cancer progression and therapeutic applications
2022, Biochimica et Biophysica Acta - Reviews on CancerAntinociceptive and anti-inflammatory activities of butein in different nociceptive and inflammatory mice models
2021, Saudi Journal of Biological SciencesBradykinin actions in the central nervous system: Historical overview and psychiatric implications
2024, Acta NeuropsychiatricaKinin-kallikrein system: New perspectives in heart failure
2024, Heart Failure Reviews