The bradykinin <scp>B</scp>1 receptor antagonist <scp>BI</scp>113823 reverses inflammatory hyperalgesia by desensitization of peripheral and spinal neurons

Schuelert, Niklas; Just, Stefan; Corradini, Laura; Kuelzer, Raimund; Bernloehr, Christian; Doods, Henri

doi:10.1002/ejp.573

Cited by 14 publications

(8 citation statements)

References 44 publications

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“…As illustrated in Fig. 1, bradykinin can also provoke stimulation of sensory neurons resulting in chronic hyperalgesia (Schuelert et al, 2015), alter the ion secretion by epithelial cells (Cozens et al,1994) and modulate cell migration and tissue injury (Abraham et al, 2006) (Fig. 1).…”

Section: Synthesis and Physiological Effects Of Bradykininmentioning

confidence: 99%

Bradykinin in asthma: Modulation of airway inflammation and remodelling

Ricciardolo

Folkerts

Folino

et al. 2018

European Journal of Pharmacology

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Bradykinin, a pro-inflammatory molecule, and its related peptides have been studied for their effects on acute reactions in upper and lower airways, where they can be synthesised and metabolized after exposure to different stimuli including allergens and viral infection. Bradykinin B and B receptors are constitutively expressed in the airways on several residential and/or immune cells. Their expression can also be induced by inflammatory mediators, usually associated with eosinophil and neutrophil recruitment, such as IL-4, IL-13, TNF-α, IL-6 and IL-8, via intracellular MAPK and NF-κB signalling. In turn, the latters up-regulate both bradykinin receptors. Bradykinin activates epithelial/endothelial and immune cells, neurons and mesenchymal cells (such as fibroblasts, myofibroblasts and smooth muscle cells), which are implicated in the development of airway chronic inflammation, responsiveness and remodelling (a major feature of severe asthma). This review highlights the role of bradykinin and its receptors in respect to chronic inflammatory response involving eosinophils/neutrophils and to vascular/matrix-related airway remodelling in asthmatic airways. This scenario is especially important for understanding the mechanisms involved in the pathogenesis of eosinophilic and/or neutrophilic asthma and hence their therapeutic approach.

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Section: Synthesis and Physiological Effects Of Bradykininmentioning

confidence: 99%

Bradykinin in asthma: Modulation of airway inflammation and remodelling

Ricciardolo

Folkerts

Folino

et al. 2018

European Journal of Pharmacology

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“…Upon release, bradykinin affects nociceptive afferents through activation of two pharmacologically distinctive receptors designated B2 and B1, respectively [35,36]. An increased B1 receptor gene expression was found in peripheral neural tissue in CFA-induced mechanical hyperalgesia, and the selective bradykinin B1 receptor antagonist BI113823 reduced CFA-induced mechanical hyperalgesia [37]. Activation of bradykinin receptors promoted nociceptor sensitization and hyperalgesia by activating the protein kinase C (PKC) second-messenger system [38].…”

Section: Inflammatory Mediatormentioning

confidence: 99%

Peripheral Sensitization

Wei¹,

Tao²,

Yang³

et al. 2020

Peripheral Nerve Disorders and Treatment

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Peripheral sensitization indicates increased responsiveness and reduced threshold of nociceptive neurons in the periphery to the stimulation, which usually occurs after peripheral tissue injury and inflammation. As an integral part of pain, peripheral sensitization and its mechanisms have received much attention, and numerous types of neurotransmitters and chemicals related to peripheral sensitization were investigated. We developed an animal model of peripheral sensitization, and it provides evidence that some neurotransmitters, such as glutamate and substance P, release from adjacent peripheral nerves contributing to the peripheral sensitization of pathological pain. In this chapter, we reviewed the advances in peripheral sensitization, and it will provide a basis for new targets to attenuate pain of peripheral origin.Several animal models of various pain states have been established to investigate the mechanisms of peripheral sensitization, for example, inflammation pain models, neuropathic pain evoked by disease or damage to peripheral nerves, and post-operative pain models. Animal models of inflammatory pain have used a number of different irritants that are injected into skin, paw, muscle, joint, and visceral organ. Carrageenan, complete Freund's adjuvant (CFA), and capsaicin are commonly used inflammatory irritants to induce hyperalgesia. Common nerve injury models include: (1) ligating or transecting the spinal nerves, such as spinal nerve ligation model (SNL); (2) ligating or lesioning the sciatic nerve, such as chronic constriction injury (CCI); and (3) ligating distal branches (peroneal and tibial) of the sciatic nerve (spared nerve injury) [16].To better understand the mechanisms of transmission between peripheral sensory nerve endings, we have successfully established an electrophysiological animal model in which antidromic electrical stimulation of a sensory nerve excites the adjacent primary afferents from the different spinal segments [17]. In this model, two adjacent cutaneous branches of spinal dorsal rami in the thoracic segments, T9 and T10, were dissociated and transected proximally from the spinal cord in anesthetized rats. Then antidromic electrical stimulation with 0.5 ms pulse duration, 20 Hz frequency, and 1 mA intensity was applied to T9 spinal nerve branch, and the nerve activities of T10 nerve branch were recorded [18]. All recorded afferent neurons from the T10 cutaneous branch were classified as Aβ, Aδ, and C fibers according to the conduction velocity and the receptive properties [19]. The discharges of the isolated Aβ, Aδ, and C fibers of the T10 cutaneous branch were significantly enhanced by antidromic electrical stimulation of the adjacent T9 spinal nerve branch [18]. It is in line with our previous studies that antidromic stimulation of T9 spinal nerve branch can activate and sensitize Aβ, Aδ, and C fibers obtained from the adjacent T10 dorsal cutaneous branch [20][21][22][23]. The activation and sensitization of these fibers not only occur between the peripheral sensory nerve...

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“…[4][5][6][7][8][9] In contrast to the B2 receptormediated relaxation to bradykinin, B1 receptors mediate vasoconstriction in cardiopulmonary vascular beds. 8,10,11 We hypothesized that kinin B1 receptors may play an important role in the pathogenesis of PAH.…”

Section: -6mentioning

confidence: 99%

“…7,9 This study examined the effects of kinin B1 receptor blockade with BI113823 in a well-established experimental model of monocrotaline-induced PAH and vascular remodeling in left pneumonectomized rats.…”

Section: -6mentioning

confidence: 99%

“…[4][5][6] Kinin B1 receptors are involved in diverse pathological processes, including inflammation, smooth muscle contraction, increased vascular permeability, edema, pain, cytokine and chemokine release, cell proliferation, and vascular and myocardial remodeling. [4][5][6][7][8][9] In contrast to the B2 receptormediated relaxation to bradykinin, B1 receptors mediate vasoconstriction in cardiopulmonary vascular beds. 8,10,11 We hypothesized that kinin B1 receptors may play an important role in the pathogenesis of PAH.…”

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confidence: 99%

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Inhibition of Kinin B1 Receptors Attenuates Pulmonary Hypertension and Vascular Remodeling

et al. 2015

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P ulmonary arterial hypertension (PAH) is a progressive disease characterized by persistent increases in pulmonary arterial pressure. This increasing pressure is associated with perivascular inflammation, excessive pulmonary vascular proliferation, remodeling, and vasoconstriction. Ultimately, PAH can cause right heart failure and death.1-3 Despite new treatment options, PAH patients still face high mortality rates. [1][2][3] Therefore, it is necessary to develop additional novel therapeutic approaches that target the various components of this multifactorial disease. [1][2][3] Kinins are proinflammatory peptides that exert a variety of biological actions via stimulation of 2 pharmacologically distinct receptor subtypes, B1 and B2. 4,5 The former are normally weakly expressed, but can be upregulated in the presence of cytokines and endotoxins or during tissue injury, whereas the latter are expressed constitutively. 4,5 One important difference between the 2 subtypes is that the B2 is internalized rapidly and desensitizes, whereas kinin B1 receptor-induced responses are more persistent and suggesting the lack of the internalization of the B1 receptorligand complex.4-6 Thus, kinin B1 receptors represent a novel therapeutic target for chronic inflammatory diseases. 4-6Kinin B1 receptors are involved in diverse pathological processes, including inflammation, smooth muscle contraction, increased vascular permeability, edema, pain, cytokine and chemokine release, cell proliferation, and vascular and myocardial remodeling. [4][5][6][7][8][9] In contrast to the B2 receptormediated relaxation to bradykinin, B1 receptors mediate vasoconstriction in cardiopulmonary vascular beds. 8,10,11 We hypothesized that kinin B1 receptors may play an important role in the pathogenesis of PAH. With this same reasoning, B1 receptor antagonists may have therapeutic potential for treating PAH by reducing inflammation, inhibiting smooth muscle contraction, attenuating vascular and cardiac remodeling, and improving cardiac function.The small molecule BI113823 is a newly developed, orally active, nonpeptide B1 receptor antagonist that exerts a potent anti-inflammatory effect with a favorable cardiovascular profile. 7,9 This study examined the effects of kinin B1 receptor blockade with BI113823 in a well-established experimental model of monocrotaline-induced PAH and vascular remodeling in left pneumonectomized rats. 12Abstract-This study examined whether the kinin B1 receptor is involved in the pathogenesis of pulmonary hypertension, and whether its inhibition could reduce inflammation, pulmonary hypertension, vascular remodeling, and right heart dysfunction. Male Wistar rats underwent left pneumonectomy. Seven days later, the rats were injected subcutaneously with monocrotaline (60 mg/kg). The rats were then randomly assigned to receive treatment with vehicle or with BI113823 (a selective B1 receptor antagonist, 30 mg/kg, twice per day) via oral gavage from the day of monocrotaline injection to day 28. By day 28, BI113823-treated rats had s...

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The bradykinin B1 receptor antagonist BI113823 reverses inflammatory hyperalgesia by desensitization of peripheral and spinal neurons

Cited by 14 publications

References 44 publications

Bradykinin in asthma: Modulation of airway inflammation and remodelling

Bradykinin in asthma: Modulation of airway inflammation and remodelling

Peripheral Sensitization

Inhibition of Kinin B1 Receptors Attenuates Pulmonary Hypertension and Vascular Remodeling

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