Kinin receptors in pain and inflammation

In 1949, Rocha e Silva and collaborators reported the existence of a new relaxing substance, liberated in plasma by the action of the snake venom of Bothrops jararaca or by trypsin, which they called bradykinin (BK) (Rocha e Silva et al., 1949). Ever since, BK and related peptides have been seen to be implicated in multiple physiological processes such as control of blood pressure, contraction and relaxation of smooth muscle, in ̄ammatory responses and induction of nociception and hyperalgesia. Apart from this, it is believed that kinins are also implicated in most pathological states such as asthma, allergy, rheumatoid arthritis, endotoxic shock and pancreatitis (Regoli and BarabeÂ, 1980; Bhoola et al., 1992; Hall and Morton, 1997). Kinins (BK and kallidin) are formed from the high and low molecular weight kininogens, by the action of serine protease kallikreins, both in plasma and peripheral tissues. Once released, these peptides are rapidly degraded by a group of enzymes generically called `kininases' (Bhoola et al., 1992). The major effects of kinins are mediated by the activation of at least two distinct receptors named B1 and B2. These receptors have been investigated in many systems, and both have already been cloned in several mammalian species, with 36% of homology between them (Hess 1997; Marceau and Bachvarov, 1998; Pesquero and Bader, 1998). The B2 receptors are by far the best characterized of the kinin receptors, being constitutively and widely expressed throughout the central and peripheral nervous system, mediating most of physiological effects of kinins (Hall and Morton, 1997). Whereas BK and LysBK present high af®nity for B2 receptors, B1 receptors are preferentially and selectively activated by the active metabolites des-Arg-BK and des-Arg-kallidin. With only a few exceptions, B1 receptors are not expressed in signi®cant levels in normal tissues, but their expression occurs rapidly in certain pathological conditions or by the action of proin ̄ammatory agents such as lipopolysaccharide or cytokines (Marceau et al., 1998). Molecular and biochemical studies have now indicated that both receptors belong to the classic seven transmembrane G-protein coupled receptor family. The kinin actions are mainly bound to the activation phospholipase Cb and to the production of inositol 1,4,5triphosphate, with consequent increase of intracellular calcium concentrations. It has also been extensively reported that kinin actions are associated with the secondary production of other mediators including prostanoids, tachykinins, cytokines, mast cell-derived products and nitric oxide, which reinforces the idea of the importance of kinins in the development and maintenance of in ̄ammatory and nociceptive processes (Marceau and Bachvarov, 1998). In the present review, we attempted to focus on the contribution of kinins during painful and in ̄ammatory events, as well as to highlight the pharmacological actions of the selective B1 and B2 kinin receptor antagonists and their possible clinical applications. Due to the short nature of this review, we will limit our discussion to some very recent papers and classical reviews on kinins describing their actions in nociception and some of the in ̄ammatory states.

Kinins in pain and inflammation

Studies have shown that diterpenes have anti-inflammatory and redox-protective pharmacological activities. The present study aimed to investigate the anti-inflammatory properties of phytol, a diterpene alcohol, in a mouse model of acute inflammation, and phytol effect on leukocyte recruitment, cytokines levels, and oxidative stress. The anti-inflammatory activities of phytol were assessed by measuring paw edema induced by different inflammatory agents (e.g., k-carrageenan, compound 48/80, histamine, serotonin, bradykinin, and prostaglandin E2 [PGE2]), myeloperoxidase (MPO) activity, peritonitis model and cytokine levels. Further, oxidative stress was evaluated by determining glutathione (GSH) levels and malondialdehyde (MDA) concentration. The results showed that phytol (7.5, 25, 50, and 75 mg/kg) significantly reduced carrageenan-induced paw edema, in a dose-dependent manner. In addition, phytol (75 mg/kg) inhibited compound 48/80-, histamine-, serotonin-, bradykinin- and PGE2-induced paw edema. It also inhibited the recruitment of total leukocytes and neutrophils; decreased MPO activity, tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1b) levels, and MDA concentration; and increased GSH levels during carrageenan-induced acute inflammation. These results suggest that phytol attenuates the inflammatory response by inhibiting neutrophil migration that is partly caused by reduction in IL-1b and TNF-a levels and oxidative stress.

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Phytol, a diterpene alcohol, inhibits the inflammatory response by reducing cytokine production and oxidative stress.

Background and Objective

In the classic model of pleurisy there is little evidence about the anti-inflammatory effects of low-level laser therapy (LLLT) as well the dosage characteristics, such as wavelength, total energy, number and pattern of treatment In this study we investigated the potential effects of LLLT on modulating the pro-inflammatory and anti-inflammatory mediators of acute inflammation in a rat pleurisy model



Study Design/Materials and Methods

A sample of 48 female Wistar rats were divided into control and experiential groups An inflammation was induced by carrageenan (02 ml) injected into the pleural cavity At 1, 2, and 3 hours after induction a continuous wave (20 mW) diode laser of the InGaAlP (660 nm) type was used in the four laser groups with different doses and treatment patterns One group received a single dose of 21 J and the other three groups received a total energy of 09, 21, and 42 J Four hours later the exudate volume, total and differential leukocytes, protein concentration, NO, IL-6, IL-10, TNF-α, and MCP-1 were measured from the aspirated liquid



Results

All the treatment patterns and quantity of energy studied show significant reduction of the exudate volume (P<005) Using energy of 09 J only NO, IL-6, MCP-1 and IL-10 are significantly reduced (P<005) On the other hand, higher energies (21 and 42 J) significantly reduce all variables independently of the treatment pattern The neutrophil migration has a straight correlation with the TNF-α (r = 0551) and NO (r = 0549) concentration



Conclusions

LLLT—660 nm induced an anti-inflammatory effect characterized by inhibition of either total or differential leukocyte influx, exudation, total protein, NO, IL-6, MCP-1, IL-10, and TNF-α, in a dose-dependent manner Under these conditions, laser treatment with 21 J was more effective than 09 and 42 J Lesers Surg Med 40:500–508, 2008 © 2008 Wiley-Liss, Inc

Tânia S.F Saleh

Papers

Effects of anti-inflammatory drugs upon nitrate and myeloperoxidase levels in the mouse pleurisy induced by carrageenan.

Pro-inflammatory effects induced by bradykinin in a murine model of pleurisy

Oral anti-inflammatory action of NPC 18884, a novel bradykinin B2 receptor antagonist