Stimulation-Produced Analgesia From the Occipital or Retrosplenial Cortex of Rats Involves Serotonergic and Opioid Mechanisms in the Anterior Pretectal Nucleus

The electrical stimulation of the occipital (OC) or retrosplenial (RSC) cortex produces antinociception in the rat tail-flick test. These cortices send inputs to the anterior pretectal nucleus (APtN) which is implicated in antinociception and nociception. At least muscarinic cholinergic, opioid, and serotonergic mechanisms in the APtN are involved in stimulation-produced antinociception (SPA) from the nucleus. In this study, the injection of 2% lidocaine (.25 mu L) or methysergide (40 and 80 ng/.25 mu L) into the APtN reduced the duration but did not change the intensity of SPA from the OC, whereas both duration and intensity of SPA from the RSC were significantly reduced in rats treated with lidocaine or naloxone (10 and 50 ng/.25 mu L), injected into the ANN. Naloxone or methysegide injected into the APtN was ineffective against SPA from the OC or RSC, respectively. Atropine (100 ng/.25 mu L) injected into the ANN was ineffective against SPA from either the OC or RSC. We conclude that the APtN acts as an intermediary for separate descending pain inhibitory pathways activated from the OC and RSC, utilizing at least serotonin and endogenous opioid as mediators in the nucleus. Perspective: Stimulation-induced antinociception from the retrosplenial or occipital cortex in the rat tail-flick test depends on the activation of separate descending pain inhibitory pathways that utilize the APtN as a relay station. (C) 2011 by the American Pain Society

Role of cytokines in mediating mechanical hypernociception in a model of delayed-type hypersensitivity in mice

In the present study, we used the electronic version of the von Frey test to investigate the role of cytokines (TNF-alpha and IL-1 beta) and chemokines (KC/CXCL-1) in the genesis of mechanical hypernociception during antigen-induced inflammation in mice. The nociceptive test consisted of evoking a hindpaw flexion reflex with a hand-held force transducer (electronic anesthesiometer) adapted with a 0.5 mm(2) polypropylene tip. The intraplantar administration of methylated bovine serum albumin (mBSA) in previously immunized (IM), but not in sham-immunized (SI) mice, induced mechanical hypernociception in a dose-dependant manner. Hypernociception induced by antigen was reduced in animals pretreated with IL-lra and reparixin (a non-competitive allosteric inhibitor of CXCR2), and in TNF receptor type 1 deficient (TNFR1-/-) mice. Consistently, antigen challenge induced a time-dependent release of TNF-alpha, IL-1 beta and KC/CXCL-1 in IM, but not in SI, mice. Consistently, antigen challenge induced a time-dependent release of TNF-alpha, IL-1 beta and KC/CXCL-1 in IM, but not in SI, mice. The increase in TNF-alpha levels preceded the increase in IL-1 beta and KC/CXCL1. Antigen-induced release of IL-1 beta and KC/CXCL1 was reduced in TNFR1-/- mice, and TNF-alpha induced hypernociception was inhibited by IL-lra and reparixin. Hypernociception induced by IL-1 beta in immunized mice was inhibited by indomethacin, whereas KC/CXCL1-induced hypernociception was inhibited by indomethacin and guanethidine, Antigen-induced hypernociception was reduced by indomethacin and guanethidine and abolished by the two drugs combined. Together, these results suggest that inflammation associated with an adaptive immune response induces hypernociception that is mediated by an initial release of TNF-alpha, which triggers that subsequent release of IL-1 beta and KC/CXCL1. The latter cytokines in turn stimulate the release of the direct-acting final mediator, prostanoids and sympathetic amines. (C) 2008 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved.

Serotonergic neurotransmission in the dorsal raphe nucleus recruits in situ 5-HT2A/2C receptors to modulate the post-ictal antinociception

The post-ictal immobility syndrome is followed by a significant increase in the nociceptive thresholds in animals and humans. The aim of this study was to assess the involvement of the dorsal raphe nucleus (DRN) in the post-ictal antinociception. The second aim was to study the role of serotonergic intrinsic mechanisms of the DRN in this hypo-algesic phenomenon. Pentylenetetrazole (PTZ), an ionophore GABA-mediated Cl- influx antagonist, was peripherally used to induce tonic-clonic seizures in Wistar rats. The nociceptive threshold was measured by the tail-flick test. Neurochemical lesions of the DRN, performed with microinjection of ibotenic acid (1.0 mu g/0.2 mu L), caused a significant decrease of tonic-clonic seizure-induced antinociception, suggesting the involvement of this nucleus in this antinociceptive Process. Microinjections of methysergide (1.0 and 5.0 mu g/0.2 mu L), a non-selective serotonergic receptor antagonist, into DRN caused a significant decrease in the post-ictal antinociception in seizing animals, compared to controls, in all post-ictal periods Presently studied. These findings were corroborated by microinjections of ketanserin (at 1.0 and 5.0 mu g/0.2 mu L) into DRN. Ketanserin is an antagonist with large affinity for 5-HT2A/2C serotonergic receptors, which, in this Case, Caused a significant decrease in the tail-flick latencies in seizing animals, compared to controls after the first 20 min following tonic-clonic convulsive reactions. These results indicate that serotonergic neurotransmission of the DRN neuronal clusters is involved in the organization of the post-ictal hypo-algesia. The 5-HT2A/2C receptors of DRN neurons seem to be critically involved in the increase of nociceptive thresholds following tonic-clonic seizures. (c) 2008 Elsevier Inc, All rights reserved.

Endothelins modulate inflammatory reaction in zymosan-induced arthritis: participation of LTB4, TNF-alpha, and CXCL-1

Endothelins (ETs) are involved in inflammatory events, including pain, fever, edema, and cell migration. ET-1 levels are increased in plasma and synovial membrane of rheumatoid arthritis (RA) patients, but the evidence that ETs participate in RA physiopathology is limited. The present study investigated the involvement of ETs in neutrophil accumulation and edema formation in the murine model of zymosan-induced arthritis. Intra-articular (i.a.) administration of selective ETA or ETB receptor antagonists (BQ-123 and BQ-788, respectively; 15 pmol/cavity) prior to i.a. zymosan injection (500 mu g/cavity) markedly reduced knee-joint edema formation and neutrophil influx to the synovial cavity 6 h and 24 h after stimulation. Histological analysis showed that ETA or ETB receptor blockade suppressed zymosan-induced neutrophil accumulation in articular tissue at 6 h. Likewise, dual blockade of ETA/ETB with bosentan (10 mg/kg, i.v.) also reduced edema formation and neutrophil counts 6 h after zymosan stimulation. Pretreatment with BQ-123 or BQ-788 (i.a.; 15 pmol/cavity) also decreased zymosan-induced TNF-alpha production within 6 h, keratinocyte-derived chemokine/CXCL1 production within 24 h, and leukotriene B-4 at both time-points. Consistent with the demonstration that ET receptor antagonists inhibit zymosan-induced inflammation, i.a. injection of ET-1 (1-30 pmol/cavity) or sarafotoxin S6c (0.1-30 pmol/cavity) also triggered edema formation and neutrophil accumulation within 6 h. Moreover, knee-joint synovial tissue expressed ETA and ETB receptors. These findings suggest that endogenous ETs contribute to knee-joint inflammation, acting through ETA and ETB receptors and modulating edema formation, neutrophil recruitment, and production of inflammatory mediators.

P2X(7) receptor activation amplifies lipopolysaccharide-induced vascular hyporeactivity via interleukin-1 beta release

Lipopolysaccharide (LPS) stimulates cytoplasmic accumulation of pro-interleukin (IL)-1 beta. Activation of P2X(7) receptors stimulates conversion of pro-IL-1 beta into mature IL-1 beta, which is then secreted. Because both LPS (in vivo) and IL-1 beta (in vitro) decrease vascular reactivity to contractile agents, we hypothesized the following: 1) P2X(7) receptor activation contributes to LPS-induced vascular hyporeactivity, and 2) IL-1 beta mediates this change. Thoracic aortas were obtained from 12-week-old male C57BL/6 mice. The aortic rings were incubated for 24 h in Dulbecco`s modified Eagle`s medium, LPS, benzoylbenzoyl-ATP (BzATP; P2X(7) receptor agonist), LPS plus BzATP, oxidized ATP (oATP; P2X(7) receptor antagonist), or oATP plus LPS plus BzATP. After the treatment, the rings were either mounted in a myograph for evaluation of contractile activity or homogenized for IL-1 beta and inducible nitric-oxide synthase (iNOS) protein measurement. In endothelium-intact aortic rings, phenylephrine (PE)-induced contractions were not altered by incubation with LPS or BzATP, but they significantly decreased in aortic rings incubated with LPS plus BzATP. Treatment with oATP or IL-1ra (IL-1 beta receptor antagonist) reversed LPS plus BzATP-induced hyporeactivity to PE. In the presence of N(G)-nitro-L-arginine methyl ester or N-([3-(aminomethyl) phenyl] methyl) ethanimidamide (selective iNOS inhibitor), the vascular hyporeactivity induced by LPS plus BzATP on PE responses was not observed. BzATP augmented LPS-induced IL-1 beta release and iNOS protein expression, and these effects were also inhibited by oATP. Moreover, incubation of endothelium-intact aortic rings with IL-1 beta induced iNOS protein expression. Thus, activation of P2X 7 receptor amplifies LPS-induced hyporeactivity in mouse endothelium-intact aorta, which is associated with IL-1 beta-mediated release of nitric oxide by iNOS.

Dual role of hydrogen sulfide in mechanical inflammatory hypernociception

Hydrogen Sulfide (H2S) is an endogenous gas involved in several biological functions, including modulation of nociception. However, the mechanisms involved in such modulation are not fully elucidated. The present Study demonstrated that the pretreatment of mice with PAG, a H2S synthesis inhibitor, reduced LPS-induced mechanical paw hypernociception. This inhibition of hypernociception was associated with the prevention of neutrophil recruitment to the plantar tissue. Conversely, PAG had no effect on LPS-induced production of the hypernociceptive cytokines, TNF-alpha, IL-1 beta and CXCL1/KC and on hypernociception induced by PGE(2), a directly acting hypernociceptive mediator. In contrast with the pro-nociceptive role of endogenous H2S. systemic administration of NaHS, a H2S donor, reduced LPS-induced mechanical hypernociception in mice. Moreover, this treatment inhibited mechanical hypernociception induced by PGE(2), suggesting a direct effect of H2S on nociceptive neurons. The antinociceptive mechanism of exogenous H2S depends on K-(ATP)(+) channels since the inhibition of PGE(2) hypernociception by NaHS was prevented by glibenclamide (K-(ATP)(+) channel blocker). Finally, NaHS did not alter the thermal nociceptive threshold in the hot-plate test, confirming that its effect is mainly peripheral. Taken together, these results suggest that H2S has a dual role in inflammatory hypernociception: 1. an endogenous pro-nociceptive effect due to up-regulation of neutrophil migration. and 2. an antinociceptive effect by direct blockade of nociceptor sensitization modulating K-(ATP)(+) channels. (c) 2008 Elsevier B.V. All rights reserved.

Increased circulating vasopressin may account for ethanol-induced hypertension in rats

BACKGROUND Long-term ethanol intake has been reported to evoke both hypertension and increase of systemic vasopressin levels in rats. METHODS In this work, we investigated the involvement of systemic vasopressin in the hypertension evoked in rats by long-term ethanol (20% vol/vol) intake for 2 weeks, by systemic treatment with the VI-vasopressin receptor antagonist dTyr(CH2)5(Me)AVP (50 mu g/kg). Moreover, plasma arginine-vasopressin (AVP) content was quantified using an AVP radioimmunoassay and the expression of vasopressin mRNA in the supraoptic (SON) and paraventricular (PVN) nuclei was measured using real-time PCR. RESULTS Mild hypertension was observed after 2 weeks of ethanol treatment when compared with control animals. Moreover, an increase in both the expression of vasopressin mRNA and the vasopressin blood content was observed in ethanol-treated rats in comparison to the OF control group. Basal blood pressure levels of ethanol-treated animals were significantly reduced by IV treatment with the V1-vasopressin receptor antagonist dTyr(CH2)5(Me)AVR However, dTyr(CH2)5(Me) AVP had no effect on the blood pressure of control animals. CONCLUSIONS The results indicate that mild hypertension is already observed at an early phase of ethanol consumption in rats. Because the content of circulating vasopressin was increased in ethanol-treated rats and their basal blood pressure returned to control levels after IV treatment with a VI-vasopressin receptor antagonist, it is proposed that increased circulating vasopressin content may mediate the hypertension observed in ethanol-treated rats.

Phlebotomine salivas inhibit immune inflammation-induced neutrophil migration via an autocrine DC-derived PGE(2)/IL-10 sequential pathway

In the present study, we investigated whether saliva from Phlebotomus papatasi and Phlebotomus duboscqi inhibited antigen-induced neutrophil migration and the mechanisms involved in these effects. The pretreatment of immunized mice with salivary gland extracts (SGE) of both phlebotomines inhibited OVA challenge-induced neutrophil migration and release of the neutrophil chemotactic mediators, MIP-1 alpha, TNF-alpha, and leukotriene B-4 (LTB4). Furthermore, SGE treatment enhanced the production of anti-inflammatory mediators, IL-10 and PGE(2). SGE treatments failed to inhibit neutrophil migration and MIP-1 alpha and LTB4 production in IL-10(-/-) mice, also failing in mice treated with nonselective (indomethacin) or selective (rofecoxibe) cyclooxygenase (COX) inhibitors. COX inhibition resulted in diminished SGE-induced IL-10 production, and PGE(2) release triggered by SGE remained increased in IL-10(-/-) mice, suggesting that prostanoids are acting through an IL-10-dependent mechanism. SGE treatments in vivo reduced the OVA-induced lymphoproliferation of spleen-derived cells. Further, the in vitro incubation of bone marrow-derived dendritic cells (DC) with SGE inhibited the proliferation of CD4(+) T cells from OVA-immunized mice, which was reversed by indomethacin and anti-IL-10 antibody treatments. Supporting these results, SGE induced the production of PGE(2) and IL-10 by DC, which were blocked by COX inhibition. These effects were associated with the reduction of DC-membrane expression of MHC-II and CD86 by SGE treatment. Altogether, the results showed that Phlebotomine saliva inhibits immune inflammation-induced neutrophil migration by an autocrine DC sequential production of PGE(2)/IL-10, suggesting that the saliva constituents might be promising therapeutic molecules to target immune inflammatory diseases.

CXCR2-specific chemokines mediate leukotriene B-4-dependent recruitment of neutrophils to inflamed joints in mice with antigen-induced arthritis

Objective. To investigate the mechanism underlying neutrophil migration into the articular cavity in experimental arthritis and, by extension, human-inflammatory synovitis. Methods. Antigen-induced arthritis (AIA) was generated in mice with methylated bovine serum albumin (mBSA). Migration assays and histologic analysis were used to evaluate neutrophil recruitment to knee joints. Levels of inflammatory mediators were measured by enzyme-linked immunosorbent assay. Antibodies and pharmacologic inhibitors were used in vivo to determine the role of specific disease mediators. Samples of synovial tissue and synovial fluid from rheumatoid arthritis (RA) or osteoarthritis patients were evaluated for CXCL1 and CXCL5 expression. Results. High levels of CXCL1, CXCL5, and leukotriene B-4 (LTB4) were expressed in the joints of arthritic mice. Confirming their respective functional roles, repertaxin (a CXCR1/CXCR2 receptor antagonist), anti-CXCL1 antibody, anti-CXCL5 antibody, and MK886 (a leukotriene synthesis inhibitor) reduced mBSA-induced neutrophil migration to knee joints. Repertaxin reduced LTB4 production in joint tissue, and neutrophil recruitment induced by CXCL1 or CXCL5 was inhibited by MK886, suggesting a sequential mechanism. Levels of both CXCL1 and CXCL5 were elevated in synovial fluid and were released in vitro by RA synovial tissues. Moreover, RA synovial fluid neutrophils stimulated with CXCL1 or CXCL5 released significant amounts of LTB4. Conclusion. Our data implicate CXCL1, CXCL5, and LTB4, acting sequentially, in neutrophil migration in AIA. Elevated levels of CXCL1 and CXCL5 in the synovial compartment of RA patients provide robust comparative data indicating that this mechanism plays a role in inflammatory joint disease. Together, these results suggest that inhibition of. CXCL1, CXCL5, or LTB4 may represent a potential therapeutic strategy in RA.

Protective effect of an extract from Ascaris suum in experimental arthritis models

We investigated the effect of an extract from a helminth (Ascaris suum) in zymosan-induced arthritis (ZYA) or collagen-induced arthritis (CIA). Rats and mice, respectively, received 1 mg and 0.1 mg zymosan intra-articularly (i.a.). Test groups received an A. suum extract either per os (p.o.) or intraperitoneally (i.p.) 30 min prior to i.a. zymosan. Controls received saline. Hypernociception was measured using the articular incapacitation test. Cell influx, nitrite, and cytokine levels were assessed in joint exudates. The synovia and distal femoral extremities were used for histopathology. Cartilage damage was assessed through determining glycosaminoglycan (GAG) content. DBA/1J mice were subjected to CIA. The test group received A. suum extract i.p. 1 day after CIA became clinically detectable. Clinical severity and hypernociception were assessed daily. Neutrophil influx was determined using myeloperoxidase activity. The A. suum extract, either i.p. or p.o., significantly and dose-dependently inhibited cell influx and hypernociception in ZYA in addition to reducing GAG loss and ameliorating synovitis. The A. suum extract reduced i.a. levels of NO, interleukin-1 beta (IL-1 beta), and IL-10 but not tumor necrosis factor alpha (TNF-alpha) in rats subjected to ZYA while reducing i.a. IL-10, but not IL-1 beta or TNIT-alpha, levels in mice. Clinically, mice subjected to CIA treated with the A. suum extract had less severe arthritis. Hypernociception, myeloperoxidase activity, and synovitis severity were significantly reduced. These data show that a helminth extract given p.o. protects from arthritis severity in two classical arthritis models. This A. suum effect is species independent and functions orally and parenterally. The results show clinical and structural benefits when A. suum extract is given either prophylactically or therapeutically.

Adenosine actions are preserved in corpus cavernosum from obese and type II diabetic db/db mouse

Introduction. Erectile dysfunction (ED) in diabetes is associated with autonomic neuropathy and endothelial dysfunction. Whereas the nonadrenergic-noncholinergic (NANC)/neurogenic nitric oxide pathway has received great attention in diabetes-associated ED, few studies have addressed sympathetic overactivity. Aim. To test the hypothesis that adenosine-induced inhibition of adrenergic-mediated contractile responses in mouse corpus cavernosum is impaired in the presence of diabetes. Methods. The db/db (obesity and type II diabetes caused by a leptin receptor mutation) mouse strain was used as a model of obesity and type II diabetes, and standard procedures were performed to evaluate functional cavernosal responses. Main Outcome Measures. Increased cavernosal responses to sympathetic stimulation in db/db mice are not associated with impaired prejunctional actions of adenosine. Results. Electrical field stimulation (EFS)-, but not phenylephrine (PE)-, induced contractions are enhanced in cavernosal strips from db/db mice in comparison with those from lean littermates. Direct effects of adenosine, 2-chloro-adenosine, A(1) receptor agonist C-8031 (N6 cyclopentyladenosine), and sodium nitroprusside are similar between the strips from lean and db/db mice, whereas relaxant responses to acetylcholine and NANC stimulation are significantly impaired in the cavernosal strips from db/db mice. 5`-Iodotubercidin (adenosine kinase inhibitor) and dipyridamole (inhibitor of adenosine transport), as well as the A(1) agonist C-8031, significantly and similarly inhibit contractions induced by stimulation of adrenergic nerves in the cavernosal strips from lean and db/db mice. Conclusions. Results from this study suggest that corpora cavernosa from obese and diabetic db/db mice display altered neural-mediated responses that would favor penile detumescence, i.e., increased contractile response to adrenergic nerve stimulation and decreased relaxant responses upon activation of NANC nerves. However, increased cavernosal responses to adrenergic nerve stimulation are not due to impaired negative modulation of sympathetic neurotransmission by adenosine in this diabetic model.

Crucial role of neutrophils in the development of mechanical inflammatory hypernociception

Neutrophil migration is responsible for tissue damage observed in inflammatory diseases. Neutrophils are also implicated in inflammatory nociception, but mechanisms of their participation have not been elucidated. In the present study, we addressed these mechanisms in the carrageenan-induced mechanical hypernociception, which was determined using a modification of the Randall-Sellito test in rats. Neutrophil accumulation into the plantar tissue was determined by the contents of myeloperoxidase activity, whereas cytokines and PGE(2) levels were measured by ELISA and radioimmunoassay, respectively. The pretreatment of rats with fucoidin (a leukocyte adhesion inhibitor) inhibited carrageenan-induced hypernociception in a dose- and time-dependent manner. Inhibition of hypernociception by fucoidin was associated with prevention of neutrophil recruitment, as it did not inhibit the hypernociception induced by the direct-acting hypernociceptive mediators, PGE(2) and dopamine, which cause hypernociception, independent of neutrophils. Fucoidin had no effect on carrageenan-induced TNF-alpha, IL-1 beta, and cytokine-induced neutrophil chemoattractant 1 (CINC-1)/CXCL1 production, suggesting that neutrophils were not the source of hypernociceptive cytokines. Conversely, hypernociception and neutrophil migration induced by TNF-alpha, IL-1 beta, and CINC-1/CXCL1 was inhibited by fucoidin, suggesting that neutrophils are involved in the production of direct-acting hypernociceptive mediators. Indeed, neutrophils stimulated in vitro with IL-1 beta produced PGE(2), and IL-1 beta-induced PGE(2) production in the rat paw was inhibited by the pretreatment with fucoidin. In conclusion, during the inflammatory process, the migrating neutrophils participate in the cascade of events leading to mechanical hypernociception, at least by mediating the release of direct-acting hypernociceptive mediators, such as PGE(2). Therefore, the blockade of neutrophil migration could be a target to development of new analgesic drugs.

Role of cytokines (TNF-alpha, IL-1 beta and KC) in the pathogenesis of CPT-11-induced intestinal mucositis in mice: effect of pentoxifylline and thalidomide

Introduction Irinotecan (CPT-11) is an inhibitor of DNA topoisomerase I and is clinically effective against several cancers. A major toxic effect of CPT-11 is delayed diarrhea; however, the exact mechanism by which the drug induces diarrhea has not been established. Purpose Elucidate the mechanisms of induction of delayed diarrhea and determine the effects of the cytokine production inhibitor pentoxifylline (PTX) and thalidomide (TLD) in the experimental model of intestinal mucositis, induced by CPT-11. Materials and methods Intestinal mucositis was induced in male Swiss mice by intraperitoneal administration of CPT-11 (75 mg/kg) daily for 4 days. Animals received subcutaneous PTX (1.7, 5 and 15 mg/kg) or TLD (15, 30, 60 mg/kg) or 0.5 ml of saline daily for 5 and 7 days, starting 1 day before the first CPT-11 injection. The incidence of delayed diarrhea was monitored by scores and the animals were sacrificed on the 5th and 7th experimental day for histological analysis, immunohistochemistry for TNF-alpha and assay of myeloperoxidase (MPO) activity, tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and KC ELISA. Results CPT-11 caused significant diarrhea, histopathological alterations (inflammatory cell infiltration, loss of crypt architecture and villus shortening) and increased intestinal tissue MPO activity, TNF-alpha, IL-1 beta and KC level and TNF-alpha immuno-staining. PTX inhibited delayed diarrhea of mice submitted to intestinal mucositis and reduced histopathological damage, intestinal MPO activity, tissue level of TNF-alpha, IL-1 beta and KC and TNF-alpha immuno-staining. TLD significantly reduced the lesions induced by CPT-11 in intestinal mucosa, decreased MPO activity, TNF-alpha tissue level and TNF-alpha immuno-staining, but did not reduce the severity of diarrhea. Conclusion These results suggest an important role of TNF-alpha, IL-1 beta and KC in the pathogenesis of intestinal mucositis induced by CPT-11.

Anti-inflammatory effects of red pepper (Capsicum baccatum) on carrageenan- and antigen-induced inflammation

Inflammation is a pivotal component of a variety of diseases, such as atherosclerosis and tumour progression. Various naturally occurring phytochemicals exhibit anti-inflammatory activity and are considered to be potential drug candidates against inflammation-related pathological processes. Capsicum baccatum L. var. pendulum (Willd.) Eshbaugh (Solanaceae) is the most consumed species in Brazil, and its compounds, such as capsaicinoids, have been found to inhibit the inflammatory process. However, the anti-inflammatory effects of C. baccatum have not been characterized. Thus, this study was designed to evaluate the effects of C. baccatum juice in animal models of acute inflammation induced by carrageenan and immune inflammation induced by methylated bovine serum albumin. Pretreatment (30 min) of rats with pepper juice (0.25-2.0 g kg(-1)) significantly decreased leucocyte and neutrophil migration, exudate volume and protein and LDH concentration in pleural exudates of a pleurisy model. This juice also inhibited neutrophil migration and reduced the vascular permeability on carrageenan-induced peritonitis in mice. C. baccatum juice also reduced neutrophil recruitment and exudate levels of pro-inflammatory cytokines TNF-alpha, and IL-1 beta in mouse inflammatory immune peritonitis. Furthermore, we demonstrated that the main constituent of C. baccatum juice, as extracted with chloroform, is capsaicin. In agreement with this, capsaicin was able to inhibit the neutrophil migration towards the inflammatory focus. To our knowledge, this is the first demonstration of the anti-inflammatory effect of C. baccatum juice and our data suggest that this effect may be induced by capsaicin. Moreover, the anti-inflammatory effect induced by red pepper may be by inhibition of pro-inflammatory cytokine production at the inflammatory site.