Kinin B1 receptors contributes to acute pain following minor surgery in humans
© Hamza et al; licensee BioMed Central Ltd. 2010
Received: 9 September 2009
Accepted: 13 February 2010
Published: 13 February 2010
Kinins play an important role in regulation of pain and hyperalgesia after tissue injury and inflammation by activating two types of G-protein-coupled receptors, the kinin B1 and B2 receptors. It is generally accepted that the B2 receptor is constitutively expressed, whereas the B1 receptor is induced in response to inflammation. However, little is known about the regulatory effects of kinin receptors on the onset of acute inflammation and inflammatory pain in humans. The present study investigated the changes in gene expression of kinin receptors and the levels of their endogenous ligands at an early time point following tissue injury and their relation to clinical pain, as well as the effect of COX-inhibition on their expression levels.
Tissue injury resulted in a significant up-regulation in the gene expression of B1 and B2 receptors at 3 hours post-surgery, the onset of acute inflammatory pain. Interestingly, the up-regulation in the gene expression of B1 and B2 receptors was positively correlated to pain intensity only after ketorolac treatment, signifying an interaction between prostaglandins and kinins in the inflammatory pain process. Further, the gene expression of both B1 and B2 receptors were correlated. Following tissue injury, B1 ligands des-Arg9-BK and des-Arg10-KD were significantly lower at the third hour compared to the first 2 hours in both the placebo and the ketorolac treatment groups but did not differ significantly between groups. Tissue injury also resulted in the down-regulation of TRPV1 gene expression at 3 hours post-surgery with no significant effect by ketorolac treatment. Interestingly, the change in gene expression of TRPV1 was correlated to the change in gene expression of B1 receptor but not B2 receptor.
These results provide evidence at the transcriptional level in a clinical model of tissue injury that up-regulation of kinin receptors are involved in the development of the early phase of inflammation and inflammatory pain. The up-regulation of B1 receptors may contribute to acute inflammatory pain through TRPV1 activation.
Tissue injury results in the liberation of various pain and inflammatory mediators; we have reported earlier in the oral surgery model of acute inflammatory pain the production or up-regulation of a number of prostanoids, cytokines and chemokines [1–4] following tissue injury. Hargreaves and colleagues have also shown an increase in bradykinin (BK) concentration following third molar tooth extraction . Further, they showed that the NSAID flurbiprofen prevented this increase in BK levels.
Bradykinin-related peptides, collectively known as kinins, are proinflammatory mediators that mediate vascular responses and pain following tissue injury. Kinins bind to two types of G protein-coupled receptors, the B1 and B2 receptors, both of which have been cloned [6, 7]. B1 receptors are activated by the endogenous kinins lacking the carboxy-terminal Arg residue, namely des-Arg9-BK and Lys-des-Arg9-BK, also known as des-Arg10-KD. B2 receptors are activated by the full sequence of the endogenous kinins BK, and Lys-BK, also known as kallidin (KD) . B2 receptors are constitutively expressed but undergo extensive desensitization by their agonists. They are widely distributed and mediate most of the biological actions of BK. On the other hand, B1 receptors are induced during the inflammatory processes or at least strongly regulated, except in the spinal cord, where they are constitutively expressed in both rat and man . Further, B1 receptors are only subjected to limited desensitization, which make them a better target for analgesics [10, 11]. In experimental studies, the expression of B1 receptors has been reported to occur in response to the B1 ligand Lys-des-Arg9-BK  and inflammatory cytokines such as IL-1β and TNF-α [13–15]. Regulation of B1 expression by B2 receptor through activation of NFκB and MAP kinases has also been observed [12, 15]. However, to our knowledge this has not been shown in man.
Kinin receptors are expressed in neuronal tissues, are upregulated in response to painful stimuli and their antagonists produce an antinociceptive effect in different pain models [16, 17]. Furthermore, B1 receptor knockout mice are refractory to chemical and thermal nociceptive stimuli . Transient receptor potential vanilloid 1 (TRPV1) is suggested to mediate ionic mechanisms coupling BK receptors to the excitation and sensitization of nociceptors .
The interaction between prostaglandins (PG) and BK in the process of inflammatory pain is well established [20, 21] as BK induces prostaglandin release in various tissues [20, 22, 23]. It is suggested that BK-induced sensitization is in part secondary to prostaglandin synthesis, since NSAIDs inhibit BK-mediated sensitization of heat responses, while prostaglandin E2/I2 reverse this inhibition [24, 25].
The aim of the present study was to investigate the role of kinin receptors in acute inflammatory pain in humans by assessing the gene expression of B1 and B2 receptors following oral surgery and its correlation to self-reported pain intensity, as well as to evaluate the levels of their immunoreactive ligands at the site of tissue injury using the microdialysis technique. The interaction between the kinin system and COX-PG pathway was also studied.
1. Effect of tissue injury and ketorolac treatment on BK and des-Arg9-BK
HPLC analysis performed on microdialysate samples collected at the site of tissue injury from both placebo and ketorolac treatment groups, showed that kinins detected by chemiluminescent enzyme immunoassays were mainly detected at the retention time corresponding to the reference peptides des-Arg9-BK (18.6 min), BK (24.1 min), des-Arg10-KD (24.7 min) and KD (29.8 min).
2. Effect of tissue injury and ketorolac treatment on BDKRB1 and BDKRB2 gene expression at the site of tissue injury
Gene expression of kinin receptors, TRPV1 and NFκB:
B 1 receptor
17.4 ± 3.6
16.2 ± 3.6
2.5 ± 0.9
(p < 0.0001)
18.6 ± 3.4
17.4 ± 3.5
2.4 ± 0.8
(p < 0.0001)
B 2 receptor
14.8 ± 3.0
13.8 ± 2.9
2.0 ± 0.6
(p < 0.0001)
15.6 ± 2.7
14.7 ± 2.7
1.9 ± 0.5
(p < 0.0001)
17.3 ± 0.6
17.0 ± 0.4
1.3 ± 1.2
(p = 0.027)
17.3 ± 0.5
17.0 ± 0.7
1.4 ± 0.8
(p = 0.042)
18.8 ± 2.9
19.8 ± 2.7
-2.2 ± 0.9
(p < 0.0001)
19.5 ± 2.7
20.7 ± 2.9
-2.6 ± 1.1
(p < 0.0001)
3. Correlation between pain intensity and the gene expression of BK receptors
The contribution of kinins to pain is well established. Further, the correlation between BK and KD and change in pain intensity was recently reported in man . We assessed here whether the gene expression of kinin receptors was also correlated to pain intensity.
The correlation between the sum of pain intensity scores as measured by VAS and the up-regulation of gene expression of BDKRB1 and BDKRB2 following tissue injury was examined using Pearson's correlation coefficients (Fig. 2 b-e). Both BDKRB1 (r = 0.68; p = 0.005; n = 15) and BDKRB2 (r = 0.58; p = 0.02; n = 15) were positively correlated to pain intensity in the ketorolac treatment group. On the other hand, BDKRB1 (r = 0.22; p = 0.425; n = 15) and BDKRB2 (r = 0.50; p = 0.058; n = 15) did not significantly correlate to pain intensity in the placebo treatment group.
4. Effect of tissue injury and ketorolac treatment on TRPV1 and NFκB gene expression at the site of tissue injury
To investigate the mechanism of B1 receptor up-regulation and the contribution of TRPV1 receptor to the algesic mechanisms of both kinin receptors, we further evaluated the gene expression of both TRPV1 and NFκB in the same biopsies and examined the correlation among the changes in their gene expression levels.
NFκB was slightly, though significantly, up-regulated following tissue injury in both the placebo treated group (1.3-fold, p = 0.027; paired t-test; n = 15) and the ketorolac treatment group (1.4-fold, p = 0.042; paired t-test; n = 13; Table 1). There was no significant difference between the two treatment groups (p = 0.56; unpaired t-test).
On the other hand, TRPV1 was significantly down regulated following tissue injury in both the placebo treated group (2.2-fold, p < 0.0001; paired t-test; n = 15) and the ketorolac treatment group (2.6-fold, p < 0.0001; paired t-test; n = 15). However, there was no significant difference between the two treatment groups (p = 0.33; unpaired t-test).
5. Correlation between the gene expression of BDKRB1, BDKRB2, TRPV1 and NFκB
Kinin levels are very difficult to measure accurately in biological samples, particularly in blood, due to the presence of metabolic enzymes that have the capacity to synthesize or metabolize kinins in vitro. Further, kinins act locally close to their site of formation before they are rapidly hydrolyzed . The microdialysis technique overcomes these difficulties by collecting the kinins at the site of inflammation and excluding the large molecular weight enzymes that may change kinin levels.
In the present study, and in accordance with previous studies [5, 26], we show an elevation in the tissue levels of BK and KD following tissue injury. While the chemiluminoenzyme immunoassay does not distinguish between the two peptides, the use of immuno-HPLC approach showed clearly that both peptides were present in the microdialysis samples. Since microdialysis sampling in this study started at the completion of third molar extraction (approximately 30 minutes duration), and the intervals of sampling was relatively long (1 hour) to allow for sufficient volume of each sample, the rise of immunoreactive peptide concentration was not detected, but rather the fall of its concentration 3 hours following surgery was detected. This is expected since the concentration of both kinins are rapidly elevated within 15 min following injury .
Further, we show for the first time in an in-vivo human study, a similar pattern for B1 receptor ligands (des-Arg9-BK, des-Arg10-KD), being elevated following tissue injury before their levels decrease at the latter time points. The immuno-HPLC approach provides evidence for the presence of des-Arg10-KD, which is the most potent known human B1 receptor agonist . Most of the earlier studies of acute inflammatory pain focused on BK and KD due to the impression that the B1 receptors are only expressed in chronic inflammation . However, we show here that the B1 receptor is up-regulated as early as 3 hours following tissue injury in humans. Further, pre-surgery biopsies showed expression of both B1 and B2 mRNA before any tissue injury. This early expression of B1 receptor  or even its constitutive expression  has been shown earlier in some experimental studies. The importance of B1 receptor lies in the role that it plays in maintaining inflammation in chronic pain states, in contrast to the B2 receptor that is quickly desensitized. Several mechanisms have been suggested to induce B1 receptor up-regulation in response to inflammation. First, it may be cross up-regulated by activation of B2 receptors . The correlation we show here between the gene expression of B2 and B1 receptor supports this mechanism in the present clinical model of tissue injury. Second, our earlier study showed marked up-regulation of IL-1β  and TNF-α  following surgery, and TNF-α was densely expressed on infiltrated inflammatory cells, particularly, on macrophages. Given both TNF-α and IL-1β are known to upregulate B1 receptor both in-vitro  and in-vivo , we hypothesize that the up-regulation of both IL-1β and TNF-α may contribute to the up-regulation of B1 shown in this study. Finally, our recent study demonstrates that an inflammatory cascade mediated by IL-6, IL-8, CCL2, CXCL1 and CXCL2 contributes to the development of acute inflammation and inflammatory pain . This cascade may also contribute to the B1 receptor up-regulation since neutrophil influx has been suggested to contribute to the up-regulation of B1 receptors .
The activation of the transcription factor NFκB is a critical step in up-regulation of B1 receptors that are induced not only by IL-1β and TNF-α [15, 33], but also by its own agonists  or by activation of B2 receptors . The small change in NFκB gene expression suggests that this may be mediated primarily at the protein level (i.e. the activation of NFκB) and the role of NFκB gene expression is relatively small at the early stage of this clinical model of tissue injury. However, to confirm the role of activation of NFκB in this model further analysis at the protein level is warranted. Due to the limited size of the biopsy, we were unable to conduct the study at both the protein and the gene expression levels.
Kinin receptors are known to be expressed in different tissues besides primary sensory neurons. Immunohistochemical studies showed immunoreactivity for both B1 and B2 receptors in epithelial cells, submucosal glands, fibroblast, vascular smooth muscle, vascular endothelial cells, and macrophages of human nasal turbinates . Further, B1 and B2 receptor genes are expressed in gingival fibroblasts . Inflammatory cells such as mast cells also, shows expression of B1 and B2 receptor . Thus, cellular localization of B1 and B2 receptor in the present study could be gingival fibroblasts, epithelial cells in oral mucosa or the inflammatory cellular infiltrate. However, since we did not carry out immunohistochemical studies, we cannot be certain of the cell types of the kinin receptors in oral mucosa, as qRT-PCR cannot distinguish the cellular origin of mRNA expressed.
In gingival fibroblasts, BK up-regulates IL-1β and TNFα-stimulated IL-6  and IL-8  production. Several other studies showed an induction of IL-6, IL-8 and CCL2 via activation of B1 or B2 receptors in a variety of cells [41–47]. Protein kinase C (PKC) signaling pathway seems to be responsible for BK induced IL-8 production in gingival fibroblasts , and PI-PLC and NF-κB signaling pathways are thought to be responsible for BK increased IL-6 production, in synovial fibroblasts . As mentioned earlier, we have recently shown a correlation between the gene expression of IL-6, IL-8 and CCL2 and pain intensity, in the oral surgery model . Therefore, it is possible that kinins besides activating B1 and B2 receptors on sensory nerve terminals, also activate B1 and B2 receptors on gingival fibroblasts or inflammatory cells inducing the expression of these cytokines, which contributes to the development of inflammatory pain.
TRPV1, a non-selective cation channel expressed in a group of sensory neurons , is considered an important target of BK signaling pathways to activate sensory neurons . However, several other tissues express TRPV1 in humans, including keratinocytes , mast cells , synovial cells  and dental pulp fibroblasts . Activation of the TRPV1 results in an increased release of IL-8 and PGE2 by epidermal keratinocytes , IL-6  and IL-8  by human bronchial epithelial cells and IL-6 by dental pulp fibroblast . Engler et al. showed an increased gene and protein expression of IL-6 in cultured synovial fibroblasts from osteoarthritis (OA) and rheumatoid arthritis (RA) patients in response to the TRPV1 agonist capsaicin, suggesting a possible non-neuronal role for TRPV1 in OA and RA pain . Therefore, it is possible that TRPV1 represent a target of BK signaling pathways both to induce cytokines by non-neuronal cells and to activate sensory neurons. It is suggested that B2 receptor via PKC signaling pathway activates TRPV1 in neuronal cells . The activation of TRPV1 by B1 receptors was also suggested earlier [56, 57]. This would pose a plausible explanation to the correlation between the change in gene expression of both receptors even with the up-regulation of B1 and down-regulation of TRPV1.
In the present study, we did not see a correlation between B2 receptor and TRPV1 gene expression. The absence of significant correlation between B2 and TRPV1 gene expression could possibly reflect the dissociation between gene expression levels and the functionality of B2 receptors due to the constitutive nature of B2 receptors and their rapid desensitization. It could also be due to the contribution of other TRP receptors to the signaling mechanism of B2 receptors. Recently, using TRPV1-KO mice, TRPV1-independent mechanisms were shown to contribute to BK-evoked pain responses , which might include TRPA1 and other ion channels . The down-regulation of TRPV1 in response to tissue injury is however, an unexpected finding, given its pronociceptive role . Yet, the same finding was seen following spinal cord injury in rat , where TRPV-1 receptor gene expression levels were decreased at the level of spinal cord injury but increased at rostral spinal cord areas. The up-regulation of TRPV1 is frequently reported at the spinal level following neuropathic pain models [61, 62]). It is possible that TRPV1 would play different roles in the periphery or at the spinal level.
In conclusion, we propose here that B1 receptor is upregulated early following tissue injury in man, possibly in response to kinin activation, and cytokines and chemokines secretion. B1 receptor activation contributes to the development of acute inflammatory pain possibly via the activation of TRPV1.
Subjects, timeline of clinical procedures and biopsy collection
Demographic data of participants:
22.3 ± 3.5
19.2 ± 2.9
19 ± 3.6
18.8 ± 2.6
7.1 ± 2.1
7.1 ± 1.0
7.5 ± 0.9
7.2 ± 0.9
For 29 patients, following satisfactory local anesthesia, two mandibular third molars were extracted and a surgical difficulty score was assigned for each tooth as follows: a score of (2) for soft tissue impactions, (3) for partial bony impactions and (4) for full bony impactions. After extraction, a microdialysis probe (CMA/20 Microdialysis Probe; CMA/Microdialysis, North Chelmsford, MA) was placed bilaterally along the buccal aspect of the mandible, beneath the mucogingival flap elevated for the surgical procedure. The probe fiber consists of a 10-mm flexible, nonmetallic, semipermeable dialysis membrane with a molecular cutoff ranging from 3000 to 20,000 Da. The probes were secured to an adjacent tooth with silk suture and the flap closed in the usual fashion using 3-0 chromic gut suture. Sterile lactated Ringer's solution was pumped at 10 μL/min and samples collected at 60-min intervals after the completion of surgery, before pain onset. Subjects randomly received either placebo or ketorolac (30 mg) intravenously 30 min before biopsy or microdialysis sampling. They remained under observation for the first 3 h after surgery to evaluate pain and adverse events and collect samples by microdialysis. During the immediate postoperative period, subjects were allowed one dose of tramadol (100 mg) as a rescue medication, if requested, after 1 h of evaluation. Patients rated their pain intensity every 20 min for the first 3 postoperative hours using a 100-mm visual analog scale. At the conclusion of the observation period, the microdialysis probes were removed. Microdialysis samples were placed on dry ice after each collection period, and stored at -70°C. For the other 30 patients, a preoperative 3 mm punch biopsy was taken from the oral mucosa overlying the impacted third molar and a second biopsy was taken from a different surgical site 3 hours post-surgery. All biopsies were immediately frozen in liquid nitrogen and stored at -70°C until ready for RNA extraction.
Quantitative real-time PCR
Oral mucosal biopsies (n = 60) were used to detect gene expression using ABI Prism 7900 HT Sequence Detection System (Applied Biosystems, Foster City, CA) as described previously [2, 3, 63]. All reagents were purchased from Applied Biosystems and 2 μg of DNase-treated RNA was used to synthesize cDNA using random primers from the High-Capacity cDNA Archive Kit according to the manufacturer's instruction. Polymerase chain reaction was performed with cDNA template using the PCR Master Mix with AmpErase UNG. Sequence-specific primers and TaqMan MGB probes were purchased from Assays-on-Demand Gene expression product. Quantification of gene expression was performed in a 20-μL reaction (384-well plate) and each sample was run in triplicate. The housekeeping gene 18S rRNA was used as endogenous control and negative controls were processed under the same conditions without a cDNA template. Data acquisition was conducted using User Bulletin #2 software (v1.6, Applied Biosystems). The threshold cycle (Ct) of 18S rRNA was used to normalize target gene expression (ΔCt) to correct for experimental variations and average ΔCt was used for comparison of the gene expression in post-surgery tissue versus that in pre-surgery tissue. The relative change in gene expression calculated as 2-ΔΔCt was used to compare different treatment groups.
Quantification of BK and des-Arg9-BK
Microdialysis samples were diluted in cold absolute ethanol (1:8 v/v), incubated overnight at 4°C then centrifugated. The supernatant was evaporated to dryness and the residue of evaporation was stored at - 20°C until the quantification and characterization of immunoreactive kinins. Residues of evaporated ethanol extracts of microdialysates were resuspended in 50 mM Tris-HCl buffer pH 7.4, containing 100 mM NaCl and 0.05% Tween-20. After resuspension, B2 receptor ligands (BK and KD) and B1 receptor ligands (des-Arg9-BK and des-Arg10-KD) were quantified by competitive chemiluminescent enzyme immunoassays as previously described [64, 65]. These methods have been validated and their analytical performances were reported. As described earlier, these immunoassays shows cross reactivity between BK and KD and between des-Arg9-BK and des-Arg10-KD.
Identification of immunoreactive kinins (BK, KD, des-Arg9-BK, des-Arg10-KD) was carried out using HPLC (Agilent 1100 Series system, Agilent Technologies Canada, Mississauga, ON, Canada) as described earlier . Briefly, 40 microdialysis samples were pooled, and extracted with cold ethanol as described above. The residue of samples was dissolved in 200 μl of 5 mM KH2PO4, pH 3.0, 25% acetonitrile with 1% H3PO4. BK, KD, des-Arg9-BK, des-Arg10-KD were separated on a 2-sulfoethyl aspartamide column (PolySULFOETHYL A, The Nest Group Inc., Southborough, MA, USA) using a linear gradient of KCl (0-300 mM) in 5 mM KH2PO4 and 25% acetonitrile (v/v) pH 3 for 30 min. Fractions of 1 ml were collected from minutes 15 to 35, evaporated to dryness before quantification of immunoreactive BK and des-Arg9-BK. Retention time of each immunoreactive fraction was compared to that of standard peptides: des-Arg9-BK (18.6 min), BK (24.1 min), des-Arg10-KD (24.7 min) and KD (29.8 min).
All statistical analyses were conducted using SPSS (v. 16.0, SPSS, Chicago, IL). Paired t-test was used to compare the gene expression in post-surgery tissue versus that in pre-surgery tissue. The relative change in gene expression was expressed as 2-ΔΔCt and was used to compare the change in gene expression in different treatment groups by unpaired t-test. Linear regression analysis was used to examine the association between the fold changes in gene expression (2-ΔΔCt) and the sum of patient-reported pain scores over the first 3 h post-surgery as measured by VAS. In the case of down- regulation, the negative fold change was used. The association among these gene expressed was examined by Pearson's correlation coefficients.
The effect of ketorolac treatment on VAS was assessed using repeated measures two-way ANOVA and the effect of ketorolac treatment on immunoreactive kinins was assessed using three-way ANOVA with two within subject factors (side and time) and one between subjects factor (treatment). A contrast analysis using t-tests with Bonferroni adjustment was used to measure the differences, which were statistically significant. Data did not follow normal distribution, so was transformed to ln(x+1). Results were considered significant at p < 0.05.
- Lee Y-S, Kim H, Brahim JS, Rowan J, Lee G, Dionne RA: Acetaminophen selectively suppresses peripheral prostaglandin E2 release and increases COX-2 gene expression in a clinical model of acute inflammation. Pain 2007, 129: 279–286. 10.1016/j.pain.2006.10.020PubMedView ArticleGoogle Scholar
- Wang X, Hamza M, Gordon SM, Wahl SM, Dionne RA: COX inhibitors down-regulate PDE4D expression in a clinical model of inflammatory pain. Clin Pharmacol Ther 2008, 84: 39–42. 10.1038/sj.clpt.6100501PubMedView ArticleGoogle Scholar
- Wang XM, Wu TX, Hamza M, Ramsay ES, Wahl SM, Dionne RA: Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain 2007, 128: 136–147. 10.1016/j.pain.2006.09.011PubMedView ArticleGoogle Scholar
- Wang X-M, Hamza M, Wu T-X, Dionne RA: Upregulation of IL-6, IL-8 and CCL2 gene expression after acute inflammation: Correlation to clinical pain. Pain 2009, 142: 275–283. 10.1016/j.pain.2009.02.001PubMedView ArticleGoogle Scholar
- Swift JQ, Garry MG, Roszkowski MT, Hargreaves KM: Effect of flurbiprofen on tissue levels of immunoreactive bradykinin and acute postoperative pain. J Oral Maxillofac Surg 1993, 51: 112–117.PubMedView ArticleGoogle Scholar
- Menke JG, Borkowski JA, Bierilo KK, MacNeil T, Derrick AW, Schneck KA, Ransom RW, Strader CD, Linemeyer DL, Hess JF: Expression cloning of a human B1 bradykinin receptor. J Biol Chem 1994, 269: 21583–21586.PubMedGoogle Scholar
- Hess JF, Borkowski JA, Young GS, Strader CD, Ransom RW: Cloning and pharmacological characterization of a human bradykinin (BK-2) receptor. Biochem Biophys Res Commun 1992, 184: 260–268. 10.1016/0006-291X(92)91187-UPubMedView ArticleGoogle Scholar
- Moreau ME, Garbacki N, Molinaro G, Brown NJ, Marceau F, Adam A: The kallikrein-kinin system: current and future pharmacological targets. J Pharmacol Sci 2005, 99: 6–38. 10.1254/jphs.SRJ05001XPubMedView ArticleGoogle Scholar
- Ma QP, Heavens R: Basal expression of bradykinin B(1) receptor in the spinal cord in humans and rats. Neuroreport 2001, 12: 2311–2314. 10.1097/00001756-200108080-00006PubMedView ArticleGoogle Scholar
- Blais C, Marceau F, Rouleau J-L, Adam A: The kallikrein-kininogen-kinin system: lessons from the quantification of endogenous kinins. Peptides 2000, 21: 1903–1940. 10.1016/S0196-9781(00)00348-XPubMedView ArticleGoogle Scholar
- Leeb-Lundberg LMF, Marceau F, Muller-Esterl W, Pettibone DJ, Zuraw BL: International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences. Pharmacol Rev 2005, 57: 27–77. 10.1124/pr.57.1.2PubMedView ArticleGoogle Scholar
- Phagoo SB, Poole S, Leeb-Lundberg LMF: Autoregulation of bradykinin receptors: agonists in the presence of interleukin-1beta shift the repertoire of receptor subtypes from B2 to B1 in human lung fibroblasts. Mol Pharmacol 1999, 56: 325–333.PubMedGoogle Scholar
- Campos MM, Souza GEP, Calixto JB: Modulation of kinin B1 but not B2 receptors-mediated rat paw edema by IL-1[beta] and TNF[alpha]. Peptides 1998, 19: 1269–1276. 10.1016/S0196-9781(98)00087-4PubMedView ArticleGoogle Scholar
- Fernandes ES, Passos GF, Campos MM, de Souza GEP, Fittipaldi JF, Pesquero JL, Teixeira MM, Calixto JB: Cytokines and neutrophils as important mediators of platelet-activating factor-induced kinin B 1 receptor expression. Br J Pharmacol 2005, 146: 209–216. 10.1038/sj.bjp.0706327PubMedView ArticleGoogle Scholar
- Passos GF, Fernandes ES, Campos MM, Araujo JGVC, Pesquero JL, Souza GEP, Avellar MCW, Teixeira MM, Calixto JB: Kinin B1 receptor up-regulation after lipopolysaccharide administration: role of proinflammatory cytokines and neutrophil influx. J Immunol 2004, 172: 1839–1847.PubMedView ArticleGoogle Scholar
- Levy D, Zochodne DW: Increased mRNA expression of the B1 and B2 bradykinin receptors and antinociceptive effects of their antagonists in an animal model of neuropathic pain. Pain 2000, 86: 265–271. 10.1016/S0304-3959(00)00256-6PubMedView ArticleGoogle Scholar
- Sufka KJ, Roach JT: Stimulus properties and antinociceptive effects of selective bradykinin B1 and B2 receptor antagonists in rats. Pain 1996, 66: 99–103. 10.1016/0304-3959(96)02990-9PubMedView ArticleGoogle Scholar
- Pesquero JB, Araujo RC, Heppenstall PA, Stucky CL, Silva JA, Walther T, Oliveira SM, Pesquero JL, Paiva ACM, Calixto JoB, et al.: Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors. Proc Natl Acad Sci USA 2000, 97: 8140–8145. 10.1073/pnas.120035997PubMedView ArticleGoogle Scholar
- Shin J, Cho H, Hwang SW, Jung J, Shin CY, Lee S-Y, Kim SH, Lee MG, Choi YH, Kim J, et al.: Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia. Proc Natl Acad Sci USA 2002, 99: 10150–10155. 10.1073/pnas.152002699PubMedView ArticleGoogle Scholar
- Lembeck F, Popper H, Juan H: Release of prostaglandins by bradykinin as an intrinsic mechanism of its algesic effect. Naunyn Schmiedebergs Arch Pharmacol 1976, 294: 69–73. 10.1007/BF00692786PubMedView ArticleGoogle Scholar
- Kumazawa T, Mizumura K: Chemical responses of polymodal receptors of the scrotal contents in dogs. J Physiol 1980, 299: 219–231.PubMedView ArticleGoogle Scholar
- Sauer SK, Schäfer D, Kress M, Reeh PW: Stimulated prostaglandin E2 release from rat skin, in vitro. Life Sci 1998, 62: 2045–2055. 10.1016/S0024-3205(98)00176-3PubMedView ArticleGoogle Scholar
- Averbeck B, Peisler M, Izydorczyk I, Reeh PW: Inflammatory mediators do not stimulate CGRP release if prostaglandin synthesis is blocked by S(+)-flurbiprofen in isolated rat skin. Inflamm Res 2003, 52: 519–523. 10.1007/s00011-003-1209-1PubMedView ArticleGoogle Scholar
- Pethö G, Derow A, Reeh PW: Bradykinin-induced nociceptor sensitization to heat is mediated by cyclooxygenase products in isolated rat skin. Eur J Neurosci 2001, 14: 210–218. 10.1046/j.0953-816x.2001.01651.xPubMedView ArticleGoogle Scholar
- Mayer S, Izydorczyk I, Reeh PW, Grubb BD: Bradykinin-induced nociceptor sensitisation to heat depends on COX-1 and COX-2 in isolated rat skin. Pain 2007, 130: 14–24. 10.1016/j.pain.2006.10.027PubMedView ArticleGoogle Scholar
- Gerdle B, Hilgenfeldt U, Larsson B, Kristiansen J, Søgaard K, Rosendal L: Bradykinin and kallidin levels in the trapezius muscle in patients with work-related trapezius myalgia, in patients with whiplash associated pain, and in healthy controls - A microdialysis study of women. Pain 2008, 139: 578–587. 10.1016/j.pain.2008.06.012PubMedView ArticleGoogle Scholar
- Marceau F, Regoli D: Bradykinin receptor ligands: therapeutic perspectives. Nat Rev Drug Discov 2004, 3: 845–852. 10.1038/nrd1522PubMedView ArticleGoogle Scholar
- Bastian S, Loillier B, Paquet JL, Pruneau D: Stable expression of human kinin B 1 receptor in 293 cells: pharmacological and functional characterization. Br J Pharmacol 1997, 122: 393–399. 10.1038/sj.bjp.0701380PubMedView ArticleGoogle Scholar
- Couture R, Harrisson M, Vianna RM, Cloutier F: Kinin receptors in pain and inflammation. Eur J Pharmacol 2001, 429: 161–176. 10.1016/S0014-2999(01)01318-8PubMedView ArticleGoogle Scholar
- Regoli D, Marceau F, Barabe J: De novo formation of vascular receptors for bradykinin. Can J Physiol Pharmacol 1978, 56: 674–677.PubMedView ArticleGoogle Scholar
- Wotherspoon G, Winter J: Bradykinin B1 receptor is constitutively expressed in the rat sensory nervous system. Neurosci Lett 2000, 294: 175–178. 10.1016/S0304-3940(00)01561-5PubMedView ArticleGoogle Scholar
- Phagoo SB, Yaqoob M, Herrera-Martinez E, McIntyre P, Jones C, Burgess GM: Regulation of bradykinin receptor gene expression in human lung fibroblasts. Eur J Pharmacol 2000, 397: 237–246. 10.1016/S0014-2999(00)00323-XPubMedView ArticleGoogle Scholar
- Larrivee J-F, Bachvarov DR, Houle F, Landry J, Huot J, Marceau F: Role of the mitogen-activated protein kinases in the expression of the kinin B1 receptors induced by tissue injury. J Immunol 1998, 160: 1419–1426.PubMedGoogle Scholar
- Schanstra JP, Bataille E, Marin Castano ME, Barascud Y, Hirtz C, Pesquero JB, Pecher C, Gauthier F, Girolami JP, Bascands JL: The B1-agonist [des-Arg10]-kallidin activates transcription factor NF-kappaB and induces homologous upregulation of the bradykinin B1-receptor in cultured human lung fibroblasts. J Clin Invest 1998, 101: 2080–2091. 10.1172/JCI1359PubMedView ArticleGoogle Scholar
- Pan ZK, Zuraw BL, Lung CC, Prossnitz ER, Browning DD, Ye RD: Bradykinin stimulates NF-κB activation and interleukin 1β gene expression in cultured human fibroblasts. J Clin Invest 1996, 98: 2042–2049. 10.1172/JCI119009PubMedView ArticleGoogle Scholar
- Shirasaki H, Kanaizumi E, Himi T: Immunohistochemical localization of the bradykinin B1 and B2 receptors in human nasal mucosa. Mediators Inflamm 2009, 2009: 102406. 10.1155/2009/102406PubMedView ArticleGoogle Scholar
- Brechter AB, Persson E, Lundgren I, Lerner UH: Kinin B1 and B2 receptor expression in osteoblasts and fibroblasts is enhanced by interleukin-1 and tumour necrosis factor-[alpha]. Effects dependent on activation of NF-[kappa]B and MAP kinases. Bone 2008, 43: 72–83. 10.1016/j.bone.2008.02.003PubMedView ArticleGoogle Scholar
- Dlamini Z, Bhoola KD: Upregulation of tissue kallikrein, kinin B1 receptor, and kinin B2 receptor in mast and giant cells infiltrating oesophageal squamous cell carcinoma. J Clin Pathol 2005, 58: 915–922. 10.1136/jcp.2004.021444PubMedView ArticleGoogle Scholar
- Modéer T, Andurén I, Yucel-Lindberg T: Bradykinin Synergistically Stimulates Interleukin 6 Production in Human Gingival Fibroblasts Challenged with Interleukin 1 or Tumour Necrosis Factor [alpha]. Cytokine 1998, 10: 26–31. 10.1006/cyto.1997.0255PubMedView ArticleGoogle Scholar
- Brunius G, Domeij H, Gustavsson A, Yucel-Lindberg T: Bradykinin upregulates IL-8 production in human gingival fibroblasts stimulated by interleukin-1beta and tumor necrosis factor alpha. Regul Pept 2005, 126: 183–188. 10.1016/j.regpep.2004.09.005PubMedView ArticleGoogle Scholar
- Koyama S, Sato E, Numanami H, Kubo K, Nagai S, Izumi T: Bradykinin Stimulates Lung Fibroblasts to Release Neutrophil and Monocyte Chemotactic Activity. Am J Respir Cell Mol Biol 2000, 22: 75–84.PubMedView ArticleGoogle Scholar
- Huang CD, Tliba O, Panettieri RA Jr, Amrani Y: Bradykinin induces interleukin-6 production in human airway smooth muscle cells: modulation by Th2 cytokines and dexamethasone. Am J Respir Cell Mol Biol 2003, 28: 330–338. 10.1165/rcmb.2002-0040OCPubMedView ArticleGoogle Scholar
- Wang PH, Cenedeze MA, Campanholle G, Malheiros DM, Torres HA, Pesquero JB, Pacheco-Silva A, Camara NO: Deletion of bradykinin B1 receptor reduces renal fibrosis. Int Immunopharmacol 2009, 9: 653–657. 10.1016/j.intimp.2008.10.018PubMedView ArticleGoogle Scholar
- Klein J, Gonzalez J, Duchene J, Esposito L, Pradere JP, Neau E, Delage C, Calise D, Ahluwalia A, Carayon P, et al.: Delayed blockade of the kinin B1 receptor reduces renal inflammation and fibrosis in obstructive nephropathy. Faseb J 2009, 23: 134–142. 10.1096/fj.08-115600PubMedView ArticleGoogle Scholar
- Marney AM, Ma J, Luther JM, Ikizler TA, Brown NJ: Endogenous bradykinin contributes to increased plasminogen activator inhibitor 1 antigen following hemodialysis. J Am Soc Nephrol 2009, 20: 2246–2252. 10.1681/ASN.2009050505PubMedView ArticleGoogle Scholar
- Dos Santos AC, Roffe E, Arantes RM, Juliano L, Pesquero JL, Pesquero JB, Bader M, Teixeira MM, Carvalho-Tavares J: Kinin B2 receptor regulates chemokines CCL2 and CCL5 expression and modulates leukocyte recruitment and pathology in experimental autoimmune encephalomyelitis (EAE) in mice. J Neuroinflammation 2008, 5: 49. 10.1186/1742-2094-5-49PubMedView ArticleGoogle Scholar
- Lee CH, Shieh DC, Tzeng CY, Chen CP, Wang SP, Chiu YC, Huang CY, Hsu CJ, Fong YC, Tang CH: Bradykinin-induced IL-6 expression through bradykinin B2 receptor, phospholipase C, protein kinase Cdelta and NF-kappaB pathway in human synovial fibroblasts. Mol Immunol 2008, 45: 3693–3702. 10.1016/j.molimm.2008.06.007PubMedView ArticleGoogle Scholar
- Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D: The capsaicin receptor: A heat-activated ion channel in the pain pathway. Nature 1997, 389: 816–824. 10.1038/39807PubMedView ArticleGoogle Scholar
- Southall MD, Li T, Gharibova LS, Pei Y, Nicol GD, Travers JB: Activation of Epidermal Vanilloid Receptor-1 Induces Release of Proinflammatory Mediators in Human Keratinocytes. Journal of Pharmacology and Experimental Therapeutics 2003, 304: 217–222. 10.1124/jpet.102.040675PubMedView ArticleGoogle Scholar
- Stander S, Moormann C, Schumacher M, Buddenkotte J, Artuc M, Shpacovitch V, Brzoska T, Lippert U, Henz BM, Luger TA, et al.: Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures. Exp Dermatol 2004, 13: 129–139. 10.1111/j.0906-6705.2004.0178.xPubMedView ArticleGoogle Scholar
- Engler A, Aeschlimann A, Simmen BR, Michel BA, Gay RE, Gay S, Sprott H: Expression of transient receptor potential vanilloid 1 (TRPV1) in synovial fibroblasts from patients with osteoarthritis and rheumatoid arthritis. Biochem Biophys Res Commun 2007, 359: 884–888. 10.1016/j.bbrc.2007.05.178PubMedView ArticleGoogle Scholar
- Miyamoto R, Tokuda M, Sakuta T, Nagaoka S, Torii M: Expression and Characterization of Vanilloid Receptor Subtype 1 in Human Dental Pulp Cell Cultures. Journal of Endodontics 2005, 31: 652–658. 10.1097/01.don.0000155259.22746.aePubMedView ArticleGoogle Scholar
- Reilly CA, Taylor JL, Lanza DL, Carr BA, Crouch DJ, Yost GS: Capsaicinoids Cause Inflammation and Epithelial Cell Death through Activation of Vanilloid Receptors. Toxicol Sci 2003, 73: 170–181. 10.1093/toxsci/kfg044PubMedView ArticleGoogle Scholar
- Veronesi B, Carter JD, Devlin RB, Simon SA, Oortgiesen M: Neuropeptides and capsaicin stimulate the release of inflammatory cytokines in a human bronchial epithelial cell line. Neuropeptides 1999, 33: 447–456. 10.1054/npep.1999.0761PubMedView ArticleGoogle Scholar
- Cesare P, Dekker LV, Sardini A, Parker PJ, McNaughton PA: Specific involvement of PKC-epsilon in sensitization of the neuronal response to painful heat. Neuron 1999, 23: 617–624. 10.1016/S0896-6273(00)80813-2PubMedView ArticleGoogle Scholar
- Rajpal S, Gerovac TA, Turner NA, Tilghman JI, Allcock BK, McChesney SL, Miranpuri GS, Park SW, Resnick DK: Antihyperalgesic effects of vanilloid-1 and bradykinin-1 receptor antagonists following spinal cord injury in rats. J Neurosurg Spine 2007, 6: 420–424. 10.3171/spi.2007.6.5.420PubMedView ArticleGoogle Scholar
- Ueda H: Molecular mechanisms of neuropathic pain-phenotypic switch and initiation mechanisms. Pharmacol Ther 2006, 109: 57–77. 10.1016/j.pharmthera.2005.06.003PubMedView ArticleGoogle Scholar
- Katanosaka K, Banik RK, Giron R, Higashi T, Tominaga M, Mizumura K: Contribution of TRPV1 to the bradykinin-evoked nociceptive behavior and excitation of cutaneous sensory neurons. Neurosci Res 2008, 62: 168–175. 10.1016/j.neures.2008.08.004PubMedView ArticleGoogle Scholar
- Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, Earley TJ, Patapoutian A: Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 2004, 41: 849–857. 10.1016/S0896-6273(04)00150-3PubMedView ArticleGoogle Scholar
- Szallasi A, Cortright DN, Blum CA, Eid SR: The vanilloid receptor TRPV1: 10 years from channel cloning to antagonist proof-of-concept. Nat Rev Drug Discov 2007, 6: 357–372. 10.1038/nrd2280PubMedView ArticleGoogle Scholar
- DomBourian MG, Turner NA, Gerovac TA, Vemuganti R, Miranpuri GS, Tureyen K, Satriotomo I, Miletic V, Resnick DK: B1 and TRPV-1 receptor genes and their relationship to hyperalgesia following spinal cord injury. Spine 2006, 31: 2778–2782. 10.1097/01.brs.0000245865.97424.b4PubMedView ArticleGoogle Scholar
- Kanai Y, Nakazato E, Fujiuchi A, Hara T, Imai A: Involvement of an increased spinal TRPV1 sensitization through its up-regulation in mechanical allodynia of CCI rats. Neuropharmacology 2005, 49: 977–984. 10.1016/j.neuropharm.2005.05.003PubMedView ArticleGoogle Scholar
- Wang XM, Wu TX, Lee YS, Dionne RA: Rofecoxib regulates the expression of genes related to the matrix metalloproteinase pathway in humans: implication for the adverse effects of cyclooxygenase-2 inhibitors. Clin Pharmacol Ther 2006, 79: 303–315. 10.1016/j.clpt.2005.12.306PubMedView ArticleGoogle Scholar
- Raymond P, Drapeau G, Raut R, Audet R, Marceau F, Ong H, Adam A: Quantification of des-Arg9-bradykinin using a chemiluminescence enzyme immunoassay: application to its kinetic profile during plasma activation. J Immunol Methods 1995, 180: 247–257. 10.1016/0022-1759(94)00320-VPubMedView ArticleGoogle Scholar
- Décarie A, Drapeau G, Closset J, Couture R, Adam A: Development of digoxigenin-labeled peptide: Application to chemiluminoenzyme immunoassay of bradykinin in inflamed tissues. Peptides 1994, 15: 511–518. 10.1016/0196-9781(94)90214-3PubMedView ArticleGoogle Scholar
- Désormeaux A, Moreau ME, Lepage Y, Chanard J, Adam A: The effect of electronegativity and angiotensin-converting enzyme inhibition on the kinin-forming capacity of polyacrylonitrile dialysis membranes. Biomaterials 2008, 29: 1139–1146. 10.1016/j.biomaterials.2007.11.019PubMedView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.