leukotriene-b4 and Pain

Topics: Animals; Anti-Inflammatory Agents; Arachidonic Acids; Capillary Permeability; Edema; Eicosanoic Acids; Erythema; Fever; Humans; Hyperalgesia; Inflammation; Leukocytes; Leukotriene B4; Lipoxygenase Inhibitors; Muscle, Smooth, Vascular; Pain; Prostaglandin Antagonists; Prostaglandins; SRS-A

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Capillary Permeability; Edema; Fever; Humans; Inflammation; Leukotriene B4; Lipoxygenase; Lymphocytes; Pain; Phagocytes; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Regional Blood Flow

Our objective was to evaluate the efficacy, the gastroduodenal safety, and the effects on arachidonic acid products of meloxicam, a new acidic enolic non-steroidal anti-inflammatory drug which preferentially inhibits cyclo-oxygenase-2 over cyclo-oxygenase-1, versus piroxicam in patients with osteoarthritis of the knee. Meloxicam 7.5 mg or piroxicam 20 mg daily was administered for 4 weeks in this double-blind parallel-groups randomised study. The efficacy for pain relief of the two tested medications was assessed by means of visual analogue scale and other clinical parameters. Pre- and post-treatment endoscopies were performed, and the findings were scored and recorded. The gastric fluid was aspirated at each time and prostaglandin E2, thromboxane B2 and leukotriene B4 were determined by ELISA. There was no significant difference between the groups regarding the primary efficacy. Changes in endoscopic findings by means of Lanza score showed statistically significant differences between the two treatment groups in favour of meloxicam at all sites--gastric, duodenal and total. Within-group comparisons showed a statistically significant difference (worsening) in gastric and total score with piroxicam, but no significant difference with meloxicam. The frequency of clinically relevant cases (total score >2) also showed a statistically significant worsening in the piroxicam group. The better GI tolerability of meloxicam was also suggested by fewer adverse GI events and no withdrawals due to adverse events compared with piroxicam. The pre-/post-study gastric juice concentration of PGE2, TXB2, and LTB4 in the meloxicam group was 135.2 +/- 85.8/71.2 +/- 32.2, 116.3 +/- 81.7/99.4 +/- 107.5 and 388 +/- 321/223 +/- 98 pg/ml respectively. The pre-/post-study gastric juice concentration of PGE2, TXB2 and LTB4 in the piroxicam group was 105.7 +/- 43.1/68.2 +/- 34.9, 94.0 +/- 50.9/105.9 +/- 121.1 and 625 +/- 1574/828 +/- 1464 pg/ml, respectively. Both meloxicam and piroxicam significantly inhibited gastric PGE2 levels after 4 weeks' treatment; however, there was no difference between these two groups. Neither of these medications had an effect on TXB2. Only meloxicam inhibited LTB4 concentration significantly, and the between-groups difference was significant. Meloxicam 7.5 mg once daily had better gastrointestinal tolerability and an efficacy comparable to that of piroxicam 20 mg over 4 weeks in patients with osteoarthritis of the knee.

Topics: Adult; Aged; Arachidonic Acid; Cyclooxygenase Inhibitors; Digestive System; Dinoprostone; Double-Blind Method; Endoscopy, Digestive System; Female; Gastric Juice; Humans; Leukotriene B4; Male; Meloxicam; Middle Aged; Osteoarthritis, Knee; Pain; Pain Measurement; Piroxicam; Safety; Thiazines; Thiazoles; Thromboxane B2

Our aim was to determine the amounts of eicosanoids in blood and synovial tissue of patients with knee arthrosis and to examine the effects of 2 doses of tepoxalin (50 mg twice, 200 mg twice), administered p.o. for 3.5 days. Concentrations of leukotriene B4 (LTB4, LTC4, and thromboxane B2 (TXB2) were measured in blood before and after oral administration of tepoxalin and release of prostaglandin E2 (PGE2), 6-keto-PGF1alpha, and LTC4 was measured in incubation media of synovial tissue, taken at surgery from patients treated with tepoxalin. Radioimmunoassay (RIA) was used to determine the levels of the eicosanoids. LT and TXB2 release was reduced by tepoxalin in both doses used. Under these conditions, PGE2, 6-keto-PGF1alpha, and LTC4 release from synovial tissue was detectable only after stimulation with calcium ionophore A23187. Washed synovial tissue, in which tepoxalin concentrations should be reduced, released higher amounts of all eicosanoids measured than directly incubated synovial tissue did. Pain after tepoxalin administration was significantly reduced. Relevant drug concentrations were detected in plasma and synovial fluid. Tepoxalin was well tolerated and had no marked adverse effects. At 400 mg, tepoxalin is a dual inhibitor of cyclooxygenase (CO) and 5-lipoxygenase (5-LO) in blood and synovial tissue.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arthritis; Arthroplasty, Replacement, Knee; Dinoprostone; Double-Blind Method; Drug Administration Schedule; Female; Humans; Knee Joint; Leukotriene Antagonists; Leukotriene B4; Leukotriene C4; Male; Middle Aged; Pain; Pain Measurement; Premedication; Pyrazoles; Radioimmunoassay; Synovial Membrane; Thromboxane B2

Leukotriene B4 (LTB4) is a potent lipid mediator involved in the recruitment and activation of neutrophils, which is an important feature of tissue injury and inflammation. The biological effects of LTB4 are primarily mediated through the high-affinity LTB4 receptor, BLT1. Postoperative incisional pain is characterized by persistent acute pain at the site of tissue injury and is associated with local inflammation. Here, we compared the role of LTB4-BLT1 signaling in postoperative incisional pain between BLT1-knockout (BLT1KO) and wild-type (BLT1WT) mice. A planter incision model was developed, and mechanical pain hypersensitivity was determined using the von Frey test before and after incision. Local infiltration of neutrophils and inflammatory monocytes was quantified by flow cytometry. Inflammatory cytokine levels in the incised tissue were also determined. Mechanical pain hypersensitivity was significantly reduced in BLT1KO mice compared to BLT1WT mice at 2, 3, and 4 days after incision. LTB4 levels in the tissue at the incision site peaked 3 hours after the incision. Infiltrated neutrophils peaked 1 day after the incision in both BLT1KO and BLT1WT mice. The accumulation of inflammatory monocytes increased 1-3 days after the incision and was significantly more reduced in BLT1KO mice than in BLT1WT mice. In BLT1KO mice, Interleukin-1β and Tumor Necrosis Factor-α levels 1 day after the incision were significantly lower than those of BLT1WT mice. Our data suggest that LTB4 is produced and activates its receptor BLT1 in the very early phase of tissue injury, and that LTB4-BLT1 signaling exacerbates pain responses by promoting local infiltration of inflammatory monocytes and cytokine production. Thus, LTB4-BLT1 signaling is a potential target for therapeutic intervention of acute and persistent pain induced by tissue injury.

Topics: Animals; Cytokines; Hypersensitivity; Inflammation; Interleukin-1beta; Leukotriene B4; Mice; Mice, Knockout; Nociception; Pain; Receptors, Leukotriene B4; Tumor Necrosis Factor-alpha

Some studies suggest that 5-lipoxygenase (5-LOX) inhibition or leukotriene receptor antagonism may effectively attenuate different kinds of pain. In the present study, we investigated whether esculetin (which, among other actions, potently inhibits 5-LOX) possesses analgesic activity in acute non-inflammatory pain and acute inflammatory pain models in rats. We also examined the effects of zileuton, a selective 5-LOX inhibitor, on esculetin activity. Plasma concentrations of leukotriene B4 (LTB4 ) after administration of esculetin were also determined. Esculetin (1.25-20 mg/kg, i.p.) dose-dependently alleviated hyperalgesia and exhibited antinociceptive effects in both experimental models. The greatest effect of esculetin was observed with a dose of 20 mg/kg. In carrageenan-induced inflammatory pain in rats, 20 mg/kg esculetin reversed or mitigated hyperalgesia, increasing the threshold to mechanical stimuli from a control value of -23.8 ± 1.8% to 15.2 ± 2.2% (P < 0.01) and that to thermal stimuli from -52.5 ± 6.1% to -9.5 ± 3.9% (P < 0.01). In non-inflammatory pain, after esculetin (20 mg/kg) administration the threshold values to mechanical and thermal stimuli increased to 75.9 ± 4.2% and 59.2 ± 4.3%, respectively (P < 0.01 for both). Zileuton (30 mg/kg, p.o.) alone slightly but significantly increased the pain threshold in the non-inflammatory and inflammatory acute pain models. Pretreatment with 30 mg/kg, p.o., zileuton significantly enhanced the analgesic activity of 5 mg/kg, i.p., esculetin in both pain models. Moreover, esculetin (10 mg/kg, i.p.) decreased LTB4 concentrations in the blood from 244 ± 29 pg/mL in the control group to 185 ± 11 pg/mL (P < 0.005). The results of the present study suggest the involvement of the 5-LOX pathway in esculetin analgesia.

Topics: Analgesia; Analgesics; Animals; Arachidonate 5-Lipoxygenase; Disease Models, Animal; Hydroxyurea; Hyperalgesia; Inflammation; Leukotriene B4; Lipoxygenase Inhibitors; Male; Pain; Pain Threshold; Rats; Umbelliferones

To study the antalgic and antiphlogistic functions and mechanism of ronggudingtong (RGDT) plaster (traditional Chinese medicine).. The painful models were established with hot plate test or acetic acid writhing and the inflammatory models were established with daubing dimethylbenzene on auricle or injecting formaldehyde in toe or synovial envelope to study the antalgic and antiphlogistic functions of RGDT Plaster. The total protein and leukotriene B4(LTB4) in inflammatory exudate were detected to investigate the antalgic and antiphlogistic mechanism of RGDT plaster. The mice were randomly divided into different groups (n = 11), on the basis of drug using, the indexes of pain threshold, swelling degree were observed. Sixty-six mice were used to establish gasbag synovitis model and randomly divided into normal control group,model control group, positive control group (Voltaren gel 0.8 mg/d)and low/medium/high dosage RGDT plaster treating groups(30 mg/d, 60 mg/d, 120 mg/d).. 30 mg/d, 60 mg/d,120 mg/d RGDT plaster could upgrade the pain thresholds, remit auricular and foot swelling (P < 0.05, P < 0.01), and degrade total protein and LTB4 in inflammatory exudates (P < 0.05, P < 0.01).. RGDT plaster has some antalgic and antiphlogistic functions, and one of the mechanisms is depressing synthesis of LTB4.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Leukotriene B4; Medicine, Chinese Traditional; Mice; Pain

5-Lipoxygenase (LOX) is an important arachidonic acid-metabolizing enzyme producing leukotrienes and other proinflammatory lipid mediators with potent pathophysiological functions in asthma and other inflammatory diseases. 4-(3-(4-(1-Methyl-1H-pyrazol-5-yl)phenylthio)phenyl)-tetrahydro-2H-pyran-4-carboxamide (PF-4191834) is a novel, selective non-redox 5-lipoxygenase inhibitor effective in inflammation and pain. In vitro and in vivo assays were developed for the evaluation of a novel 5-LOX inhibitor using conditions of maximal enzyme activity. PF-4191834 exhibits good potency in enzyme- and cell-based assays, as well as in a rat model of acute inflammation. Enzyme assay results indicate that PF-4191834 is a potent 5-LOX inhibitor, with an IC(50) = 229 +/- 20 nM. Furthermore, it demonstrated approximately 300-fold selectivity for 5-LOX over 12-LOX and 15-LOX and shows no activity toward the cyclooxygenase enzymes. In addition, PF-4191834 inhibits 5-LOX in human blood cells, with an IC(80) = 370 +/- 20 nM. This inhibitory concentration correlates well with plasma exposures needed for in vivo efficacy in inflammation in models of inflammatory pain. The combination of potency in cells and in vivo, together with a sustained in vivo effect, provides PF-4191834 with an overall pharmacodynamic improvement consistent with once a day dosing.

Topics: Animals; Asthma; Chromatography, Liquid; Disease Models, Animal; Humans; Inflammation; Leukocytes; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mass Spectrometry; Oxidation-Reduction; Pain; Pyrazoles; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Spectrophotometry; Sulfides

To compare levels of bradykinin (BK), leukotriene B4 (LTB4), prostaglandin E2 (PGE2), and substance P (SP) between successful and unsuccessful cases of arthrocentesis of temporomandibular joint disorders (TMDs).. A total of 66 joints in 66 patients with TMDs who underwent arthrocentesis were evaluated in this study. Synovial fluid diluted with saline solution was aspirated from the superior joint compartment before arthrocentesis and their concentrations of BK, LTB4, PGE2, and SP were determined by enzyme-linked immunosorbent assay. The differences in the detection rate and concentration of each mediator between successful cases and unsuccessful cases of arthrocentesis were analyzed statistically.. Arthrocentesis was successful for 77% (51/66) of the joints. The mean detection rate of LTB4 was significantly (P < .05) higher in the unsuccessful cases (47%) than in the successful cases (16%). The mean concentration of BK was significantly (P < .0005) higher in the unsuccessful cases (425 pg/mL) than in the successful cases (144 pg/mL). There was also a statistical correlation between the detection of LTB4 and PGE2 (P < .01).. Increased levels of BK and LTB4 in the synovial fluid of patients with TMDs may indicate that arthrocentesis is less likely to be a successful treatment.

Topics: Adolescent; Adult; Aged; Bradykinin; Dinoprostone; Female; Humans; Joint Dislocations; Leukotriene B4; Male; Middle Aged; Osteoarthritis; Pain; Paracentesis; Prognosis; Statistics, Nonparametric; Substance P; Synovial Fluid; Temporomandibular Joint Disorders

1. The antinociceptive effect of risedronate in experimental pain models in rats and mice was investigated in the present study. 2. Rats received zymosan intra-articularly (i.art.) into the right knee joint and the nociceptive response was assessed using the articular incapacitation test. Joint washouts were used for determining cell influx, tumour necrosis factor (TNF)-alpha and leukotriene (LT) B4 levels. 3. Mice received either zymosan (1 mg) or acetic acid (0.6%) i.p. and the nociceptive response was measured as the number of writhings between 0 and 30 min after the stimuli. Control animals received i.p. injections of saline. 4. Groups were pretreated with risedronate (5-500 microg/kg, s.c.) and compared with vehicle (saline)-treated (NT) animals. One group of rats was cotreated with the micro-opioid receptor antagonist naloxone (2 mg/kg, s.c.) prior to risedronate, followed by 1 mg zymosan i.art. 5. Risedronate, at 100 and 500 microg/kg, significantly and dose-dependently inhibited the nociceptive response in the writhings test (P < 0.05), inhibiting responses to acetic acid by 65.4 and 49.2%, respectively, and to zymosan by 72.9 and 71.9%, respectively. 6. Pretreatment with risedronate also significantly (P < 0.05) and dose-dependently inhibited the articular incapacitation in zymosan-arthritis. 7. Risedronate, at 50 microg/kg, significantly inhibited TNF-alpha release as compared with the NT group (39.4 +/- 9.8 vs 145.6 +/- 43.3 pg/mL TNF-alpha, respectively). 8. Risedronate, at 50 and 100 microg/kg, significantly inhibited LTB4 release into the joints compared with the NT group (2883.1 +/- 73.2, 1911.5 +/- 205.3 and 4709.9 +/- 237.2 pg/mL, respectively). These effects of risedronate were associated with a significant reduction in the inflammatory cell infiltration. 9. Cotreatment with risedronate and naloxone did not reverse the antinociceptive effects of risedronate in zymosan-arthritis. 10. This is the first demonstration that risedronate displays intrinsic antihypernociceptive activity. This effect is associated with reduced cell infiltration and inhibition of TNF-alpha and LTB4 release and is not linked to an endogenous opioid-release mechanism.

Topics: Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Diphosphonates; Disease Models, Animal; Dose-Response Relationship, Drug; Etidronic Acid; Inflammation; Leukotriene B4; Male; Mice; Pain; Pain Measurement; Rats; Rats, Wistar; Risedronic Acid; Tumor Necrosis Factor-alpha; Zymosan

This study investigated role of spinal lipoxygenase metabolites in induction of hyperalgesia and development of opioid analgesic tolerance. In the rat, nociception was measured using formalin and tail-flick tests. Intrathecal administration of leukotriene receptor agonist (LTB4) augmented the second phase of the formalin response and marginally increased sensitivity to acute thermal stimulation in the tail-flick test, responses suppressed by 6-(6-(3R-hydroxy-1E,5Z-undecadien-1-yl)-2-pyridinyl)-1,5S-hexanediol (U75302), a leukotriene BLT receptor antagonist. Treatment with 15-hydroxyperoxyeicosatetranoic acid (HPETE) increased phase II formalin activity, but had no effect on tail-flick responses. 12-HPETE failed to produce an effect in either nociceptive test. In the second part of this study, chronic spinal morphine for 5 days produced progressive decline in morphine antinociception and loss in analgesic potency. These effects were attenuated by co-administration of morphine with selective and nonselective lipoxygenase inhibitors. These results suggest involvement of lipoxygenase metabolites in both pain modulation and induction of opioid tolerance at the spinal level.

Topics: Analgesics, Opioid; Animals; Benzoquinones; Dose-Response Relationship, Drug; Drug Tolerance; Flavanones; Formaldehyde; Hindlimb; Hyperalgesia; Injections, Spinal; Leukotriene B4; Leukotrienes; Lipid Peroxides; Lipoxygenase; Lipoxygenase Inhibitors; Male; Masoprocol; Morphine; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Spinal Cord; Time Factors

Fractionation of an anti-inflammatory extract from Cayaponia tayuya roots yielded two active compounds, identified as 23,24-dihydrocucurbitacin B (1) and cucurbitacin R (2). Both were evaluated for their anti-inflammatory activity on several experimental models of pain and inflammation. In addition, their cytotoxicity and effects on leukotriene B4 (LTB4) formation were evaluated in rat polymorphonuclear leukocytes. Both compounds showed activity in the following models: carrageenan-induced mouse paw oedema (1, 4 mg/kg p.o., 46% inhibition at 3 h), phospholipase A2-induced mouse paw oedema (2, 3 mg/kg i.p., 61% inhibition at 60 min), serotonin-induced mouse paw oedema (1 and 2, 0.5 mg/kg s.c., 73% and 79% inhibition, respectively), 12- O-tetradecanoylphorbol 13-acetate (TPA)-induced acute ear oedema (2, 36% inhibition at 4 mg/kg p.o., and 87% inhibition at 0.1 mg/ear topically). The compounds were also active against the inflammation induced by repeated application of TPA on mouse ears, affecting both the oedema itself (1 and 2 at 0.1 mg/ear, 44% and 56% inhibition, respectively) as well as cell infiltration (68% and 69%, respectively). The activity of both compounds against oedema induced by serotonin was not modified by the glucocorticoid receptor antagonist mifepristone; however, the protein synthesis inhibitor cycloheximide abolished the anti-inflammatory response in both cases. Neither compound modified the production of LTB4 in rat polymorphonuclear leukocytes, nor did they exhibit analgesic properties at the dose assayed.

Topics: Administration, Cutaneous; Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cucurbitaceae; Cucurbitacins; Dose-Response Relationship, Drug; Edema; Female; Leukocytes; Leukotriene B4; Mice; Pain; Phospholipases A; Phospholipases A2; Phytotherapy; Plant Extracts; Plant Roots; Rats; Rats, Wistar; Tetradecanoylphorbol Acetate; Triterpenes

The synthetic chalcone derivative 1-(2,3,4-trimethoxyphenyl)-3-(3-(2-chloroquinolinyl))-2-propen-1-one (TQ) was evaluated for its immunomodulatory and anti-inflammatory efficacy in vitro and in vivo.. Human neutrophils and lymphocytes from healthy volunteers and RAW 264.7 murine macrophages. Swiss mice and Lewis rats were randomly divided into groups of six animals.. TQ was orally administered in all in vivo assays (10-30 mg/kg).. Elastase, superoxide and LTB(4) release were assayed in human neutrophils, NO/PGE(2) production and NF-kappaB activation in RAW 264.7, and (3)H thymidine incorporation in human lymphocytes. Zymosan-stimulated air pouches, DNFB-DTH, PBQ-induced writhings and formalin-induced pain were assayed in mice. Adjuvant-induced arthritis was tested in rats. Dunnett's t-test was employed for statistical analysis.. Human T-cell proliferation, neutrophil functions and NO/PGE(2) production in murine macrophages were inhibited by TQ (IC(50) in the microM range), which showed anti-inflammatory, immunomodulatory and analgesic effects.. Our findings indicate the potential interest of TQ in the modulation of some immune and inflammatory responses probably by NF-kappaB inhibition.

Topics: Adjuvants, Immunologic; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Blotting, Western; Cell Division; Chalcone; Chalcones; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Edema; Electrophoretic Mobility Shift Assay; Humans; Hypersensitivity, Delayed; In Vitro Techniques; Indicators and Reagents; Isoenzymes; Leukocyte Elastase; Leukotriene B4; Luminescent Measurements; Lymphocyte Activation; Macrophage Activation; Membrane Proteins; Mice; Neutrophil Activation; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitrites; Pain; Pain Measurement; Phospholipases A; Prostaglandin-Endoperoxide Synthases; Quinolines

Neutrophil activation with the release of intracellular granule contents has been observed in sickle cell disease (SCD). Because leukotriene B(4) (LTB(4)), a 5-lipoxygenase metabolite of arachidonic acid in neutrophils, is a chemoattractant and enhances neutrophil adhesion to endothelium, we assessed plasma levels of this metabolite in controls (n = 9) and individuals with SCD, SS genotype, both in basal "steady state" (n = 37) and during episodes of vaso-occlusion (n = 10) and acute chest syndrome (n = 5). Thirteen patients with SCD, SC genotype, in steady state were also studied. Although no significant differences were noted between the control (136 +/- 32 fmol/mL) and SC genotype (177 +/- 83 fmol/mL, P >.15), LTB(4) levels were markedly increased in patients with SS genotype in basal steady state (207 +/- 64 fmol/mL, P <.003) compared with those in controls. Values were further increased during vaso-occlusion (264 +/- 94 fmol/mL) and acute chest syndrome (363 +/- 124 fmol/mL). These levels were significantly different from measurements taken during steady state (P <.04 and P <.0001, respectively). No correlation was noted between LTB(4) level and total white cell or neutrophil count. Additionally, the significant correlation noted in SCD between increased levels of plasma LTB(4) and soluble L-selectin (P <.03) reflects neutrophil activation. We also observed an effect of LTB(4) on red cell-endothelial adhesion at concentrations that appear clinically relevant (1-10 pmol/mL) with concomitant up-regulation of mRNA for the endothelial vitronectin receptor. These properties of LTB(4) are relevant to disease pathophysiology, providing further evidence of the contribution of the neutrophil to the proinflammatory and proadhesive phenotype in SCD.

Topics: Adolescent; Adult; Anemia, Sickle Cell; Cell Adhesion; Chest Pain; Child; Child, Preschool; Endothelium, Vascular; Erythrocytes; Fetal Hemoglobin; Gene Expression; Genotype; Hemoglobins; Humans; L-Selectin; Leukocyte Count; Leukotriene B4; Neutrophils; Pain; Receptors, Vitronectin; Reference Values; Reticulocyte Count; RNA, Messenger; Syndrome; Vascular Diseases

CI-986 is a potent inhibitor of 5-lipoxygenase and cyclooxygenase pathway product biosynthesis from rat basophilic leukemia (RBL) cells. Because metabolites from these pathways have proinflammatory properties, CI-986 was evaluated in several acute and chronic models of inflammation and hyperalgesia. The compound inhibited swelling in the carrageenan footpad edema, Mycobacterium foot-pad edema and adjuvant arthritis models of inflammation with ID40 values of 1.0, 7.7., and 7.2 mg/kg, respectively. It was roughly equivalent in potency to the standard selective cyclooxygenase inhibitor, naproxen (ID40 = 0.7, 6.3, and 3.8 mg/kg, respectively). CI-986 was also evaluated in the acetic acid induced writhing hyperalgesia assay (ID50 = 0.23 mg/kg) and was approximately equipotent with indomethacin (ID50 = 0.87 mg/kg). Although the effects of CI-986 were similar to those of standard nonsteroidal antiinflammatory drugs (NSAIDs) in the inflammation models, its gastrointestinal profile was unique. CI-986 caused no gastrointestinal irritation at doses up to 200 mg/kg in acute and chronic studies. In contrast, standard NSAIDs caused ulcers at doses of 3.7-37 mg/kg after a single dose. Moreover, CI-986 inhibited the release of LTC4 and PGE2 by gastric mucosa and reduced mucosal and vascular damage induced by oral administration of absolute ethanol to rats. These results indicate that CI-986 is a potent nonulcerogenic antiinflammatory agent with novel pharmacologic properties.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Arthritis, Experimental; Cyclooxygenase Inhibitors; Dinoprost; Disease Models, Animal; Ethanol; Female; Gastritis; Inflammation; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mice; Pain; Rats; Rats, Wistar; Thiadiazoles; Tumor Cells, Cultured

The magnitude and temporal production of PGI2, PGE2 and LTB4 were measured in the mouse peritoneal cavity for a 15 min period following the intraperitoneal injection of either acetic acid, phenyl-p-benzoquinone (PBQ) or zymosan. For each algogenic substance, PGI2 (assayed as the stable metabolite, 6-keto-PGF1 alpha) represented the major eicosanoid with lower levels of PGE2 also detected. Zymosan induced the greatest 6-keto-PGF1 alpha production among the three algogenic agents, but only a weak writhing response was observed. LTB4 was detected in the peritoneal lavage only after zymosan. The magnitude of eicosanoid production did not correlate with the writhing response induced by the algogenic agents, even though the inhibition of both 6-keto-PGF1 alpha and writhing by several peripheral analgesics was positively correlated. PGI2, (100 ng), 6-keto-PGF1 alpha (1 microgram) and PGE2 (100 ng) did not induce writhing. However, only PGI2 acted synergistically with acetic acid to produce writhing. Presumably due to the short biological lifetime of PGI2, this synergism was noted only when PGI2 was administered after the acetic acid. These results suggest that PGI2 acts to sensitize the animal for the writhing response.

Topics: Acetates; Analgesics; Animals; Benzoquinones; Dinoprostone; Epoprostenol; Leukotriene B4; Male; Mice; Pain; Quinones; Radioimmunoassay; Reference Values; Zymosan

Hyperalgesia onset latencies of inflammatory mediators were quantified by measuring the threshold of the nociceptive flexion reflex in the rat at 1 min intervals after intradermal injection. Prostaglandin E2 and 8(R), 15(S)-dihydroxyicosa-(5E,9,11,13Z)-tetraenoic acid induced hyperalgesia with short onset latencies, compatible with a direct action on primary afferent nociceptors. Bradykinin, norepinephrine and leukotriene B4 induced hyperalgesia with a significant delay in onset, compatible with their known indirect mechanisms of producing hyperalgesia. We propose that use of this approach, rapid frequent measurement of nociceptive threshold, can be used to determine the hierarchy of action of mediators in hyperalgesic mechanisms.

Topics: Animals; Bradykinin; Dinoprostone; Hyperalgesia; Hyperesthesia; Inflammation; Leukotriene B4; Nociceptors; Norepinephrine; Pain; Prostaglandins E; Rats; Rats, Inbred Strains

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Arachidonic Acid; Arachidonic Acids; Bradykinin; Brain Chemistry; Chemistry; Flurbiprofen; History, 20th Century; Humans; Inflammation; Leukotriene B4; Neurotransmitter Agents; Pain; Propionates; Research; SRS-A

Induction of hyperalgesia by leukotriene B4 (LTB4), a potent chemotactic factor for polymorphonuclear leukocytes (PMNLs), depends on the generation by cutaneous PMNLs of mediators that are probably derived from the 15-lipoxygenation of arachidonic acid. The capacity of dihydroxyeicosatetraenoic acid (diHETE) products of the 15-lipoxygenation of arachidonic acid in PMNL to elicit hyperalgesia was evaluated by assessing the effects of intradermal injection of synthetic diHETEs on the pressure nociceptive threshold in rats. (8R,15S)-Dihydroxyeicosa-(5E-9,11,13Z)-tetraenoic acid [(8R,15S)-diHETE] produced a dose-dependent hyperalgesia, as measured by decrease in threshold for paw withdrawal. The isomer (8S,15S)-diHETE antagonized in a dose-dependent manner this hyperalgesia due to (8R,15S)-diHETE but did not suppress prostaglandin E2-induced hyperalgesia. (8S,15S)-DiHETE produced a dose-dependent hypoalgesia, as reflected by an increase in nociceptive threshold, suggesting a contribution of endogenous (8R,15S)-diHETE to normal nociceptive threshold. The hypoalgesic effect of (8S,15S)-diHETE was blocked by corticosteroids but not by the cyclooxygenase inhibitor indomethacin. Neither (8R,15S)-dihydroxyeicosa-(5,15E-9,11Z)-tetraenoic acid nor (8R,15S)-dihydroxyeicosa-(5,11E-9,13Z)-tetraenoic acid exhibited any hyperalgesic or hypoalgesic activity. The stereospecificity of the effect of (8R,15S)-diHETE suggests that the induction of hyperalgesia is a receptor-dependent phenomenon and that (8S,15S)-diHETE may be an effective receptor-directed antagonist. The (8R,15S)-diHETE and (8S,15S)-diHETE from PMNL, keratinocytes, and other epithelial cells may modulate normal primary afferent function and contribute to inflammatory hyperalgesia.

Topics: Animals; Arachidonate Lipoxygenases; Arachidonic Acid; Arachidonic Acids; Cyclooxygenase Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Indomethacin; Leukotriene B4; Lipoxygenase; Male; Neutrophils; Pain; Prednisolone; Prostaglandins E; Rats; Rats, Inbred Strains

Bradykinin was injected retrogradely into a branch of the splenic artery of lightly anesthetized dogs, and the reflex hypertensive response was used as an indicator of the nociception. The reflex hypertensive response to low doses of bradykinin (less than 1 nmol), but not to high doses (3-5 nmol), was markedly suppressed by infusion of indomethacin (0.54 mumol/min) into the splenic artery. During indomethacin infusion, the reflex hypertensive response to low doses of bradykinin was potentiated dose dependently by the following arachidonic acid metabolites (ED50): prostaglandin (PG)I2 (2.9 nmol) greater than or equal to PGH2 (4.4) greater than PGE2 (14) = thromboxane (TX)A2(15) greater than PGD2 (greater than 100). Leukotrienes B4, C4 and D4 showed practically no activity. This potentiating effect lasted up to 20 min after injection, particularly with PGE2. These results may not exclude the role of PGI2 as a major candidate for involvement in bradykinin-induced nociception, although a selective TX synthetase inhibitor (OKY-046) showed a weak analgesic effect (only 1/30 that of indomethacin).

Topics: Animals; Bradykinin; Dogs; Drug Synergism; Fatty Acids, Unsaturated; Female; Indomethacin; Injections, Intra-Arterial; Leukotriene B4; Male; Pain; Pain Measurement; Prostaglandins; Splenic Artery; SRS-A; Thromboxanes

Intraperitoneal injection of zymosan in mice induced rapid extravasation and accumulation of plasma protein in the peritoneal cavity. Neutrophils began to appear in the peritoneal cavity after a lag period of approximately 3 hours. The injected mice exhibited a pain response (writhing) during the first 30 minutes after injection, but writhing ceased before protein or cell accumulation had reached maximum levels. The injection of zymosan induced synthesis of PGE2 (measured by RIA) which reached maximum levels at 30 minutes, then declined slowly. Peptido-leukotriene levels (detected by bioassay, RIA and HPLC) increased rapidly after injection, reached a peak within an hour of injection and declined to undetectable levels within 4 hours. The early peptido-LT was predominantly LTC4, while later, LTE4 was the major component. LTD4 levels remained low throughout and no LTB4 was detected at any time. Indomethacin treatment elevated levels of peptido-LTs, reduced PGE2 levels and inhibited writhing. Phenidone reduced peptido-LT levels. In vitro studies demonstrated that zymosan stimulates LTC4 synthesis by peritoneal cells whereas LTE4, LTD4, LTB4 or monoHETES were not detectable (using HPLC methods). The source of enzymes responsible for the in vivo metabolism of LTC4 to LTD4 and LTE4 could not be identified.

Topics: Animals; Arachidonate Lipoxygenases; Cell Aggregation; Dinoprostone; In Vitro Techniques; Indomethacin; Inflammation; Injections, Intraperitoneal; Leukotriene B4; Leukotriene E4; Lipoxygenase; Male; Mice; Mice, Inbred Strains; Pain; Prostaglandins E; Proteins; SRS-A; Zymosan

During inflammation, pain receptors are sensitized by inflammatory mediators causing hyperalgesia. Leukotriene B4 (LTB4) is a potent chemoattractant for polymorphonuclear leukocytes in humans in vivo. In the present study we have demonstrated a reduction of the pain threshold in humans after intracutaneous deposition of LTB4. The pain threshold was quantitated by the "Marstock" method in which the testsubject reversed the direction of the temperature change of a thermostimulator whenever a painful temperature was reached. This enabled a quantitative description of the persons pain sensibility. After intracutaneous infiltration of LTB4 (10 microM) a highly significant decrease in the pain threshold could be detected as compared to control with a maximum effect between 6 and 24 h. The decrease in the pain threshold amounted to less than 15% when compared to control and corresponds with the published kinetics of the influx of polymorphonuclear leukocytes. These results support the hypothesis that LTB4 produces hyperalgesia indirectly through recruitment of polymorphonuclear leukocytes and not via a direct effect on the pain receptors. Inhibition of the lipoxygenase might be an advantageous adjunct to the effect of the Non Steroidal Anti-Inflammatory Drugs.

Topics: Humans; Hyperalgesia; Hyperesthesia; Leukotriene B4; Pain; Sensory Thresholds

Topics: Humans; Jaw Cysts; Leukotriene B4; Osteolysis; Pain; Prostaglandin Antagonists; Prostaglandins

Leukotrienes (LT's) and prostaglandins (PG's) have been proposed as mediators of vascular permeability changes in inflammatory reactions. Also, prostaglandins, especially of the E-type, have been shown to enhance pain responses. In the present studies in rats, the effects of LTB4 and LTD4 on edema and pain thresholds were examined in combination with PGE1 and/or brewer's yeast. Subplantar injections of LTD4 or LTB4 induced small increases in paw thickness which were potentiated by the co-administration of PGE1. LTD4 alone had no significant effect on the development of the yeast paw edema. LTB4 was found to reduce significantly the yeast edema and this reduction could be reversed by administration PGE1. A small but significant decrease in pain threshold was caused by PGE1 and this was significantly enhanced in the presence of LTD4. LTB4, like PGE1, was found to cause slight hyperalgesia but no synergy between the two agents was observed. LTD4 was found to have no effect on the initial hypoalgesia or subsequent development of hyperalgesia caused by brewer's yeast. Both LTB4 and PGE1, however, prevented the initial hypoalgesia and significantly reduced the latency for development of yeast induced hyperalgesia. These effects of LTB4 are discussed in terms of possible release of cyclooxygenase products.

Topics: Alprostadil; Animals; Female; Hindlimb; Inflammation; Leukotriene B4; Pain; Prostaglandins E; Rats; Rats, Inbred Strains; SRS-A; Vocalization, Animal