Evaluation of the anti-inflammatory and anti-nociceptive effects of different antidepressants in the rat.

The present study was designed to compare the anti-inflammatory and anti-nociceptive effects of different classes of antidepressant drugs on the carrageenan paw oedema and tail-electric stimulation assays in the rat. Drugs were intraperitoneally administered 30 min prior to carrageenan or nociceptive testing. The non-selective noradrenaline (NA) and serotonin (5-HT) reuptake inhibitors imipramine, amitriptyline and clomipramine displayed anti-inflammatory activity in the carrageenan model of paw inflammation. The maximal degree of oedema inhibitions seen with these agents were 28.8, 41.5 and 46.8% for 5, 10 and 20 mg kg(-1) amitriptyline, 26.2, 38.2 and 51.4% for 3.75, 7.5 and 15 mg kg(-1) imipramine and 51.2 and 54.1% for 16 and 32 mg kg(-1) clomipramine, respectively. The heterocyclic agent trazodone significantly inhibited paw oedema by 46 and 41% at 1 and 2h after dosing at the highest dose (40 mg kg(-1)) examined. Fluoxetine, a selective 5-HT reuptake inhibitor (SSRI) caused dose-related reduction of paw oedema, with 20.7% inhibition at the dose of 10 mg kg(-1). In contrast, sertraline, another SSRI caused dose-dependent enhancement of paw oedema. All antidepressant drugs in the study showed anti-nociceptive properties in the tail-electric stimulation assay with amitriptyline and trazodone being the most effective in this respect. Taken together, data in the present study confirm anti-inflammatory and anti-nociceptive effect for some antidepressant drugs and indicate that SSRIs differently affects inflammation.     

Antinociceptive and anti-inflammatory properties of the hydroalcoholic extract of stems from Equisetum arvense L. in mice.

In this study, antinociceptive and anti-inflammatory effects of hydroalcoholic extract of stem from Equisetum arvense in mice were evaluated. The extract (10, 25, 50 and 100mgkg(-1), i.p.), reduced the writhing induced by acetic acid in 49, 57, 93 and 98%, respectively. In the formalin test, 50 and 100mgkg(-1) (i.p.) extract, reduced in 80 and 95% the licking activity in the first phase, but in the second phase only the latter dose diminished the licking time (35%). In both phases, naloxone failed to revert the analgesic effect of the extract. In the hot-plate test, the extract at 100 and 200mgkg(-1) does not change the latency to licking or jumping. In the carrageenan-induced paw oedema, the extract at 50mgkg(-1), reduced the paw oedema 2h (25%) and 4h (30%) after carrageenan administration. The dose of 100mgkg(-1) caused reduction of the paw oedema (29%) only 4h after carrageenan administration. These results indicate that this extract exhibits an antinociceptive effect in chemical models of nociception which is not related to the opioid system, as well as anti-inflammatory properties.     

The anti-inflammatory effects of the phosphodiesterase inhibitor pentoxifylline in the rat.

The present study aimed to evaluate the anti-inflammatory effects of pentoxifylline (PTX), a non-specific phosphodiesterase inhibitor in the rat. Acute inflammation was induced by subplantar injection of carrageenan (1%) in the rat hind paw. Results showed that intraperitoneal (i.p.) administration of PTX (36 or 72 mg kg(-1)) 30 min prior to carrageenan reduced the paw oedema response in dose-dependent manner with a maximal effect of 18.9 and 40.1%, respectively, at 2h post-carrageenan (P<0.001 and <0.001 at respective doses). Theophylline given at equimolar doses (29.9 or 45.8 mg kg(-1), i.p.) did not reduce the oedema response. With higher doses of PTX (144-300 mg kg(-1), i.p.) the anti-oedema effect of the drug was more pronounced, but mainly confined to the first 2h following carrageenan injection and decreasing rapidly thereafter. PTX (72 mg kg(-1), i.p.) given 30 min after carrageenan challenge reduced the oedema response by 24.7 and 26.2% at 1 and 2h after dosing (P<0.05 and <0.05, respectively). PTX (36 or 72 mg kg(-1), i.p.) co-administered with indomethacin (5 mg kg(-1), i.p.) 30 min before carrageenan had little modulatory effect on the anti-oedema effect of indomethacin, but the higher dose of PTX (144 mg kg(-1), i.p.) reduced the anti-inflammatory effect of indomethacin by 24% at 4h post-carrageenan. PTX (72 mg kg(-1), i.p.) enhanced the anti-oedema effect of the selective COX-2 inhibitor celecoxib (33 mg kg(-1), i.p.) by 55.1% at 4h post-carrageenan. In contrast, the higher dose of PTX (144 mg kg(-1), i.p.) reduced the anti-oedema effect of celecoxib by 46.8% at 4h post-carrageenan. PTX (36 or 72 mg kg(-1)) enhanced the anti-oedema effect of dexamethasone (0.1 mg kg(-1)) with maximal effect of 76 and 104.8% at 2h post-carrageenan (P<0.01 and <0.01 for respective doses). PTX (0.6 mg per paw) given with carrageenan into the rat hind paw reduced the oedema response with a maximal effect of 33.4% at 1h following carrageenan. PTX (0.6 mg per paw) given in the contralateral hind paw reduced the carrageenan-induced paw oedema for 1h by 32.2%. Thus, PTX, when given at doses comparable to those used in man for treatment of circulatory disorders displayed anti-inflammatory in vivo and enhanced the anti-inflammatory effect of a selective COX-2 inhibitor or dexamethasone. PTX may have therapeutic potential as anti-inflammatory agent either alone or in combination with non-steroidal anti-inflammatory drugs or with steroids. There is also an intriguing possibility for the use of topical preparations for the management of local inflammatory conditions.     

Modulation of inflammatory paw oedema by cysteamine in the rat.

Cysteamine, a potent somatostatin depletor, was used in the present study to investigate the role of endogenous somatostatin in acute peripheral inflammation. The acute inflammation was induced by intraplantar injection of carrageenan (1%), histamine (5 micromol), or formalin (2.5%) in the rat hind paw. The induced inflammation and the formation of oedema were determined by measurement of the paw thickness. Given subcutaneously (s.c.) 1 h before carrageenan, cysteamine caused significant, dose-dependent and long-lasting inhibition of rat paw oedema induced by carrageenan. At doses of 12.5, 25, 50 or 100 mg kg (-1), cysteamine significantly inhibited the carrageenan-induced paw oedema at 4 h by 52.3, 40, 40.7 or 26.3%. Cysteamine given at 300 mg kg (-1), a dose well known to deplete tissue somatostatin, reduced oedema by only 16.2% vs control values. Significant inhibition of the carrageenan-induced rat paw oedema was still evident 24 h post-injection at cysteamine doses of 12.5, 25, 50 or 100 mg kg (-1). Given s.c. at 300 mg kg (-1), 4 h prior to carrageenan, cysteamine decreased rat paw oedema at 4 h by 14.9%. Cysteamine (300 mg kg (-1)), 4 h beforehand, had little modulatory effect on the oedema induced by formalin (2.5%) but reduced that caused by intraplantar histamine (5 micromol). The anti-oedematogenic effect of indomethacin, but not that of the selective COX-2 inhibitor celecoxib, was less marked in rats pre-treated with cysteamine at 300 mg kg (-1). Cysteamine (0.3 microg- 0.3 mg paw (-1)) co-administered with carrageenan was devoid of anti-inflammatory effect and even promoted inflammation at low concentrations. Cysteamine given locally alone induced slight paw oedema. These data indicate that systemic cysteamine possesses potent and long-lasting anti-inflammatory effects and modulates the anti-inflammatory effect of cyclooxygenase inhibitors in a model of peripheral inflammation in the rat. The effect of cysteamine is likely to be mediated via central action.     

Studies on the anti-inflammatory effect of fluoxetine in the rat.

The anti-inflammatory activity of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), was studied on the carrageenan-induced paw inflammation in the rat. Fluoxetine (10-60 mg kg(-1)) given intraperitoneally (i.p.) 30 min before carrageenan, displayed marked anti-inflammatory activity, inhibiting paw oedema by 38.6-77.7% at 2 h post-carrageenan. Fluoxetine administered at time of carrageenan injection or 30 min after carrageenan challenge, markedly inhibited the paw oedema response. Rats administered daily fluoxetine (20 mg kg(-1), i.p.) showed significantly decreased inflammatory response to subplantar carrageenan when examined on the 5th and 14th day of fluoxetine injection. Fluoxetine (10 or 20 mg kg(-1), i.p.) co-administered with indomethacin (IND) (20 mg kg(-1), i.p.), celecoxib (10 mg kg(-1), i.p.) or rofecoxib (4.5 mg kg(-1), i.p.) before carrageenan reduced the anti-oedema effect of indomethacin or celecoxib, but had additive effect to that of rofecoxib. The anti-oedema effects of fluoxetine and melatonin or the tricyclic antidepressant imipramine were additive. In contrast, administration of both fluoxetine and the heterocyclic antidepressant trazodone had no greater anti-inflammatory effect than fluoxetine alone. The anti-oedema effect of fluoxetine was partially suppressed by the opioid antagonist naloxone (4 mg kg(-1), i.p.). Fluoxetine (360 or 720 microg per paw) given into the rat paw with carrageenan reduced the oedema response by 25.4 and 35.3% 4 h post-carrageenan, respectively. It is suggested that fluoxetine alone or co-administered with either imipramine or melatonin would be of benefit in the sitting of neuropathic or inflammatory pain conditions. Both the serotonergic and the opioid systems are likely to be involved in the modulating action of fluoxetine on peripheral inflammation.     

Antinociceptive and anti-inflammatory effects of the essential oil from Eremanthus erythropappus leaves

The chemical composition of the essential oil from air-dried leaves of Eremanthus erythropappus was studied. The main compounds were beta-pinene (23.24%), beta-caryophyllene (22.92%), beta-myrcene (10.03%) and germacrene D (9.40%). The essential oil had an LD50 of 2.90 g kg(-1) in mice. Doses of 200 and 400 mg kg(-1) inhibited 10.69% and 27.06% of acetic-acid-induced writhing in mice, respectively. In the formalin-induced nociception test in mice, the essential oil inhibited the first phase of paw licking by 29.13% (400 mg kg(-1)) and the second phase by 32.74% (200 mg kg(-1)) and 37.55% (400 mg kg(-1)). In the hot-plate test in mice, doses of 200 mg kg(-1) and 400 mg kg(-1) significantly increased the reaction time after 30, 60 and 90 min of treatment. Doses of 200 and 400 mg kg(-1) inhibited carrageenan-induced paw oedema in rats by 15.18% and 36.61%, respectively. Doses of 200 and 400 mg kg(-1) administered 4 h before intrapleural injection of carrageenan significantly reduced exudate volume (by 20.20% and 48.70%, respectively) and leucocyte mobilization (by 5.88% and 17.29%, respectively). These results demonstrate that E. erythropappus has analgesic and anti-inflammatory properties, supporting the use of this plant in folk medicine.     

Studies on the anti-inflammatory and anti-nociceptive effects of melatonin in the rat.

The present study aimed to evaluate the anti-inflammatory and anti-nociceptive effects of melatonin in the rat. Acute inflammation was induced by sub-plantar injection of carrageenan (1%) in the rat hind paw. The rats received vehicle or drug 30 min before carrageenan administration and were evaluated for paw oedema at 1, 2, 3, and 4 h post-carrageenan. The induced inflammation and the formation of oedema were determined by measurement of the paw thickness. Nociception was tested by determining vocalization following electrical stimulation of the tail. Given intraperitoneally (i.p.) 30 min before carrageenan, melatonin caused significant and a dose-dependent reduction of hind paw swelling induced by carrageenan. At doses of 0.5 and 1 mg kg(-1), melatonin inhibited the carrageenan-induced oedema by 20.5 and 29.6% versus control values at 4 h post-carrageenan, respectively. Melatonin (0.5 and 1 mg kg(-1), i.p.) 30 min beforehand displayed anti-nociceptive effect in the electric stimulation of the rat tail test, increasing nociceptive thresholds to electrically-induced pain at 4 h post-treatment by 29.6 and 39.5%, respectively. Melatonin given simultaneously with the non-selective COX-1 and COX-2 inhibitor indomethacin (5 mg kg(-1), i.p.) 30 min prior to carrageenan, enhanced the anti-inflammatory effect of the latter in the carrageenan-induced paw oedema model by 23%. Melatonin (0.5 mg kg(-1), i.p.) increased the anti-nociceptive effect of indomethacin (5 mg kg(-1), i.p.). Meanwhile, the anti-inflammatory and anti-nociceptive effect of the highly selective COX-2 inhibitor rofecoxib (2.25 mg kg(-1), i.p.) was only slightly increased by melatonin administration at 0.5 mg kg(-1). Melatonin enhanced the anti-inflammatory effect of cysteamine (300 mg kg(-1), s.c.) in the carrageenan-induced paw oedema. Melatonin (20 and 40 microg per paw) given prior to carrageenan into the rat hind paw was devoid of anti-inflammatory effect. These results indicate that melatonin possesses anti-inflammatory and anti-nociceptive properties in the rat and enhance those of indomethacin. This effect is likely to be centrally mediated.     

Inhibitors of fatty acid amide hydrolase reduce carrageenan-induced hind paw inflammation in pentobarbital-treated mice: comparison with indomethacin and possible involvement of cannabinoid receptors

The in vivo effect of inhibitors of fatty acid amide hydrolase (FAAH) upon oedema volume and FAAH activity was evaluated in the carrageenan induced hind paw inflammation model in the mouse. Oedema was measured at two time points, 2 and 4 h, after intraplantar injection of carrageenan to anaesthetised mice. Intraperitoneal (i.p.) injections of the FAAH inhibitor URB597 (0.1, 0.3, 1 and 3 mg kg(-1)) 30 min prior to carrageenan administration, dose-dependently reduced oedema formation. At the 4 h time point, the ED(50) for URB597 was approximately 0.3 mg kg(-1). Indomethacin (5 mg kg(-1) i.p.) completely prevented the oedema response to carrageenan. The antioedema effects of indomethacin and URB597 were blocked by 3 mg kg(-1) i.p. of the CB(2) receptor antagonist SR144528. The effect of URB597 was not affected by pretreatment with the peroxisome proliferator-activated receptor gamma antagonist bisphenol A diglycidyl ether (30 mg kg(-1) i.p.) or the TRPV1 antagonist capsazepine (10 mg kg(-1) i.p.), when oedema was assessed 4 h after carrageenan administration. The CB(1) receptor antagonists AM251 (3 mg kg(-1) i.p.) and rimonabant (0.5 mg kg(-1) i.p.) gave inconsistent effects upon the antioedema effect of URB597. FAAH measurements were conducted ex vivo in the paws, spinal cords and brains of the mice. The activities of FAAH in the paws and spinal cords of the inflamed vehicle-treated mice were significantly lower than the corresponding activities in the noninflamed mice. PMSF treatment almost completely inhibited the FAAH activity in all three tissues, as did the highest dose of URB597 (3 mg kg(-1)) in spinal cord samples, whereas no obvious changes were seen ex vivo for the other treatments. In conclusion, the results show that in mice, treatment with indomethacin and URB597 produce SR144528-sensitive anti-inflammatory effects in the carrageenan model of acute inflammation.     

Pharmacological investigation of trimetazidine in models of inflammation, pain and gastric injury in rodents

The antinociceptive, anti-inflammatory and gastric effects of trimetazidine (2,3,4-trimethoxybenzyl-piperazine dihydrochloride), a novel anti-ischaemic compound, were evaluated in various animal models. In acute pain models, namely acetic acid-induced writhing, hot-plate assay, tail electric stimulation test, capsaicin-induced pain and the formalin test, trimetazidine (1.8-7.2 mg/kg, i.p.) showed marked antinociceptive effects. Trimetazidine did not produce any behavioural impairment as revealed by the mouse rotarod. The inhibition of writhing response by trimetazidine was reduced by yohimbine, theophylline (and to a certain extent by sulpiride) but not by prazosin, guanethidine, naloxone, atropine, propranolol, haloperidol, domperidone, clozapine, glibenclamide or caffeine. The carrageenan-evoked acute paw oedema was reduced by 19.2-21.2 and 17-18.6% by 3.6 and 7.2 mg/kg trimetazidine, respectively. The drug did not alter the oedema-suppressive effect of indomethacin or dexamethasone, but reduced that of rofecoxib. Trimetazidine at 7.2 mg/kg reduced immobility time in Porsolt's forced-swimming test by 28.9%. The acute gastric mucosal lesions evoked by indomethacin in the rat were inhibited in a dose-dependent manner by co-administration of trimetazidine. In anesthetized rats, trimetazidine potentiated the gastric acid secretory response. This study indicates that trimetazidine possesses antinociceptive and gastric protective properties. The antinociceptive properties of trimetazidine are likely to be centrally mediated, but do not involve opioid pathways.     

Effect of Ginkgo biloba extract on carrageenan-induced acute local inflammation in gamma irradiated rats

The effect of low dose whole-body gamma irradiation on inflammation and its possible modulation by Ginkgo biloba extract (GbE) was studied in the carrageenan-induced paw oedema model. Rats were subjected to two doses of gamma radiation (2 Gy or intermittent radiation at 2 Gy increment delivered daily up to cumulative dose of 4 Gy), 4 h before unilateral subplantar injection of carrageenan. The effect of GbE (25 or 50 mg/kg) administered subcutaneously daily for 3 days was also studied. Local oedema (days 1-3), the content of gamma glutamyl transpeptidase (GTT), malondialdehyde (MDA) and glutathione (GSH) in paw (72 h), were determined. In rats subjected to 4 Gy fraction, paw oedema was significantly reduced 1-4 h post-carrageenan injection (-26.2 to -16.2% vs control group). Moreover, at 24, 48 and 72 h after carrageenan, paw oedema was much reduced in the 2 Gy (-33.6, -46.4, -40%) or 4 Gy (-55, -56, -71.8%) irradiated groups compared to carrageenan unirradiated control. In addition, in irradiated rats, the carrageenan oedema was further significantly reduced by the administration of GbE, the effect of the agent being more marked in those irradiated with 2 Gy fraction. Changes in paw oedema were matched by a reduction in GGT and MDA paw tissue levels, while GSH content decreased in inflamed paw tissue 72 h post-treatment. These results indicate that exposure to 4 Gy fraction decreased the carrageenan-induced paw oedema and that the administration of GbE further lessened the severity of this inflammatory response in irradiated rats. The effects observed may be related in part to the inhibition of GGT activity and MDA production, and partly to augmentation of GSH content in the inflamed paw tissue.     

Endothelin-1-induced ET(A) receptor-mediated nociception, hyperalgesia and oedema in the mouse hind-paw: modulation by simultaneous ET(B) receptor activation

Endothelin-1 causes ET(A) receptor-mediated enhancement of capsaicin-induced nociception in mice. We have assessed if this hyperalgesic effect of endothelin-1 is also accompanied by other pro-inflammatory effects, namely nociception and oedema, and characterized the endothelin ET receptors involved. Intraplantar (i. pl.) hind-paw injection of endothelin-1 (0.3 - 30 pmol) induced graded nociceptive responses (accumulated licking time: vehicle, 20. 5+/-3.3 s; endothelin-1 at 30 pmol, 78.1+/-9.8 s), largely confined to the first 15 min. Endothelin-1 (1 - 10 pmol) potentiated ipsilateral capsaicin-induced (0.1 microgram, i.pl.; at 30 min) nociception (vehicle, 40.2+/-2.6 s; endothelin-1 at 10 pmol, 98.4+/-5.8 s, but 30 pmol was inactive), and caused oedema (increase in paw weight 5 min after capsaicin: vehicle, 46.3+/-2.3 mg; endothelin-1 at 30 pmol, 100.3+/-6.1 mg). Selective ET(B) receptor agonists sarafotoxin S6c (up to 30 pmol) and IRL 1620 (up to 100 pmol) were inactive, whereas endothelin-3 (up to 30 pmol) induced only modest oedema. ET(A) receptor antagonists BQ-123 (1 nmol, i.pl. ) or A-127722-5 (6 micromol kg(-1), i.v.) prevented all effects of endothelin-1 (10 pmol), but the ET(B) receptor antagonist BQ-788 (1 or 10 nmol, i.pl.) was ineffective. BQ-788 (10 nmol, i.pl.) unveiled hyperalgesic effects of 30 pmol endothelin-1 and endothelin-3. Sarafotoxin S6c (30 pmol, i.pl.) did not modify endothelin-1-induced (10 pmol) nociception or oedema, but abolished hyperalgesia. Thus, endothelin-1 triggers ET(A) receptor-mediated nociception, hyperalgesia and oedema in the mouse hind-paw. Simultaneous activation of ET(B) receptors by endothelin-1 or selective agonists can limit the hyperalgesic, but not the nociceptive or oedematogenic, effects of the peptide.     

Therapeutic effect of the endogenous fatty acid amide,palmitoylethanolamide, in rat acute inflammation: inhibition of nitric oxide and cyclo-oxygenase systems

1. The anti-inflammatory activity of the endogenous fatty acid amide palmitoylethanolamide and its relationship to cyclo-oxygenase (COX) activity, nitric oxide (NO) and oxygen free radical production were investigated in the rat model of carrageenan-induced acute paw inflammation and compared with the nonsteroidal anti-inflammatory drug (NSAID) indomethacin. 2. Palmitoylethanolamide (1, 3, 5, 10 mg kg(-1); p.o.) and indomethacin (5 mg kg(-1); p.o.) were administered daily after the onset of inflammation for three days and the paw oedema was measured daily; 24 h after the last dose (fourth day) the rats were killed and the COX activity and the content of nitrite/nitrate (NO(2)(-)/NO(3)(-)), malondialdehyde (MDA), endothelial and inducible nitric oxide synthase (eNOS and iNOS) were evaluated in the paw tissues. 3. Palmitoylethanolamide had a curative effect on inflammation, inhibiting the carrageenan-induced oedema in a dose- and time-dependent manner. This effect was not reversed by the selective CB(2) receptor antagonist (N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3 carboxamide) (SR144528), 3 mg kg(-1) p.o. On the fourth day after carrageenan injection, COX activity and the level of NO(2)(-)/NO(3)(-), eNOS and MDA were increased in the inflamed paw, but iNOS was not present. Palmitoylethanolamide (10 mg kg(-1)) and indomethacin markedly reduced these increases. 4. Our findings show, for the first time, that palmitoylethanolamide has a curative effect in a model of acute inflammation. The inhibition of COX activity and of NO and free radical production at the site of inflammation might account for this activity.     

Acute antiinflammatory and gastric effects of the seleno-organic compound ebselen

Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a seleno-organic compound with glutathione peroxidase-like activity in vitro, was compared with indomethacin, BW 755C, and levamisole as an inhibitor of carrageenan- and CVF (cobra venom factor)-induced paw oedema in the rat. The antiinflammatory potency of ebselen against CVF-induced oedema (ED50 = 56 mg/kg p.o.) was similar to that of BW 755C, while indomethacin was weakly active in this model, and levamisole exerted stronger activity. In the carrageenan model, ebselen exhibited weak inhibitory potency, like BW 755C, while indomethacin markedly inhibited this inflammatory response, and levamisole was inactive. Unlike cyclooxygenase inhibitors, ebselen produced almost no gastric irritation in rats up to 316 mg/kg p.o. Moreover, ebselen inhibited significantly diclofenac-induced gastric intolerance at 31.6 and 316 mg/kg p.o. Thus, ebselen represents a new tool for antiinflammatory therapy.     

Flunoxaprofen, a new non-steroidal anti-inflammatory drug, does not interfere with prostaglandin synthesis in rat gastric mucosa

The anti-inflammatory activity and the eicosanoid generation in rat gastric mucosa after a single oral dose of S-(+)-2(4-fluorophenyl)-alpha-methyl-5-benzoxazolacetic acid (flunoxaprofen, 10 mg/kg) or indomethacin (5 mg/kg) were compared. The two compounds, at the dose used, show a similar degree of anti-inflammatory activity (50% inhibition of carrageenan-induced oedema in rat paw). Moreover flunoxaprofen does not modify the formation of 6-keto-PGF1 alpha by rat gastric mucosa in vitro while indomethacin causes 50% inhibition of gastric cyclooxygenase activity. This biochemical change induced by indomethacin is associated with gastric lesions. Chronic treatment of rats with flunoxaprofen (5 or 50 mg/kg p.o. for 15 days) shows an anti-inflammatory activity in the range of 60-70% inhibition in the rat paw oedema test without gastric mucosa damages and prostaglandin synthesis inhibition.     

Antinociceptive and gastroprotective effects of diterpenes from the flower buds of Egletes viscosa

Centipedic acid and 12-acetoxy-hawtriwaic acid lactone, diterpenes isolated from the flower buds of Egletes viscosa (Asteraceae) were assayed for antinociceptive and gastroprotective activities in animal models of nociception and gastric ulcer. In the chemical nociception induced in mice by intraperitoneal acetic acid and subplantar formalin injections, both diterpenes (25 and 50 mg/kg, p. o.) exerted potent antinociception in a manner similar to indomethacin (5 mg/kg, p. o.). In the formalin test, only the late phase nociceptive response (20 - 25 min) and not the early phase response (0 - 5 min) was inhibited by these diterpenes. However, these compounds were found to be ineffective against thermal nociception in the hot-plate test. Further, the diterpenes reduced the severity of absolute ethanol-induced gastric lesions in rats. At the dose of 50 mg/kg, both centipedic acid and 12-acetoxy hawtriwaic acid suppressed the gastric lesions by 53 % and 63 %, respectively. Against the gastric ulceration induced by indomethacin, only centipedic acid (25 and 50 mg/kg) showed significant inhibition by about 47 - 49 %. The data suggested the gastroprotective and peripheral analgesic properties of diterpenes isolated from E. viscosa.     

B vitamins induce an antinociceptive effect in the acetic acid and formaldehyde models of nociception in mice

The effect of some B vitamins in chemical and thermal models of nociception in mice was investigated. The association thiamine/pyridoxine/cyanocobalamin (TPC, 20-200 mg/kg, i.p. or per os), thiamine, pyridoxine (50-200 mg/kg, i.p.) or riboflavin (3-100 mg/kg, i.p) induced an antinociceptive effect, not changed by naloxone (10 mg/kg, i.p.), in the acetic acid writhing model. Treatment for 7 days with thiamine/pyridoxine/cyanocobalamin (100 or 200 mg/kg, i.p.), thiamine (50 or 100 mg/kg) or pyridoxine (50 or 100 mg/kg) or acute treatment with riboflavin (6 or 12 mg/kg, i.p) inhibited the nociceptive response induced by formaldehyde. The B vitamins did not inhibit the nociceptive response in the hot-plate model. Both 7-day thiamine/pyridoxine/cyanocobalamin (100 mg/kg, i.p.) or acute riboflavin (25 or 50 mg/kg, i.p.) treatment partially reduced formaldehyde-induced hindpaw oedema. The B vitamins antinociceptive effect may involve inhibition of the synthesis and/or action of inflammatory mediators since it was not observed in the hot-plate model, was not reversed by naloxone, only the second phase of the formaldehyde-induced nociceptive response was inhibited, and formaldehyde-induced hindpaw oedema was reduced.     

Acute studies on safety index of nonsteroidal anti-inflammatory drugs in rats

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain and inflammation. Their use is frequently limited by gastrointestinal side effects, ranging from dyspeptic symptoms to life threatening bleeding or perforations of gastroduodenal ulcers. The present study mainly aimed to establish a safety index of NSAIDs in experimental animals. Safety index is based on the ratio of ulcerogenic dose (UD₅₀) and anti-inflammatory dose (ED₅₀). The safety index of preferential COX-2 inhibitor (nimesulide, meloxicam) was investigated using carrageenan-induced paw oedema and acute ulcerogenic model in rats, compared with the classical NSAIDs (naproxen, indomethacin). Meloxicam was found to be the most potent NSAID (ED₅₀ 1.07 mg/kg, p.o.) followed by nimesulide (2.42 mg/kg, p.o.), indomethacin (2.72 mg/kg, p.o.) and naproxen (6.82 mg/kg, p.o.) after 240 min of carrageenan challenge. In acute ulcerogenic study naproxen, indomethacin and meloxicam were found to be ulcerogenic at lower doses (UD₅₀ 14.0, 3.80 and 3.21 mg/kg, p.o.) in comparison to nimesulide (UD₅₀ 24.52 mg/kg, p.o.). Meloxicam, naproxen and indomethacin also produced damage to gastric epithelium (disruption of mucus layer and damage to parietal cells) at ED₅₀ dose level when it was viewed under scanning electron microscope, but nimesulide did not distrub gastric mucosal integrity at ED₅₀ dose. Based on the safety index (Ulcerogenic dose₅₀ /Effective anti-inflammatory dose₅₀) the order of safety of these agents was nimesulide > meloxicam > naproxen > indomethacin.     

Oral antinociception and oedema inhibition produced by NPC 18884, a non-peptidic bradykinin B2 receptor antagonist

This study investigates the antinociceptive and the oedema inhibition properties of the novel non-peptide bradykinin (BK) B2 receptor antagonist, NPC 18884. Given by i.p. or p.o. routes NPC 18884 produced graded and long-lasting (at least 2.5h and 5.0h, respectively, for i.p. and p.o. administration) inhibition of acetic acid-induced abdominal constrictions in mice, with mean ID50 values of 8.3 nmol/kg and 439.9 nmol/kg. NPC 18884 also inhibited kaolin-induced abdominal constrictions (44+/-9% and 48+/-3% of inhibition, for i.p. and p.o. routes, respectively). Given by i.p. or p.o. routes NPC 18884 attenuated both phases of formalin-induced licking, as well as formalin-induced oedema formation. At similar doses NPC 18884 produced significant inhibition of capsaicin-induced nociception. NPC 18884, like HOE 140 given i.p., prevented the nociception caused by BK with mean ID50 values of 0.85 nmol/kg and 0.44 nmol/kg, respectively. Given orally NPC 18884, but not HOE 140, caused graded inhibition of BK-induced nociception (mean ID50 value of 50 nmol/kg). In rats, NPC 18884 given i.p. prevented BK and carrageenan-induced hyperalgesia (mean ID50 values of 6 nmol/kg and 13 nmol/kg), without affecting the hyperalgesia induced by des-Arg9-bradykinin (DABK) or by prostaglandin E2 (PGE2). NPC 18884 given i.p. inhibited the mouse paw oedema induced by tyrosine8-bradykinin or by carrageenan, but had no effect on DABK-induced oedema in mice pre-treated with Escherichia coli endotoxin, or that induced by PGE2. Thus, the novel non-peptide BK B2 receptor antagonist NPC 18884 produces rapid onset, potent and relatively long-lasting oral antinociceptive and oedema inhibition properties. The anti-BK actions of NPC 18884 are quite selective towards the BK B2 receptor-mediated responses.     

Antinociceptive and anti-inflammatory activities of sulphated polysaccharides from the red seaweed Gracilaria cornea

Seaweeds have attracted special interest as good sources of sulphated polysaccharides (SP) for use in pharmaceutical industries and biotechnology. In this study, we evaluated the effects of SP from the red seaweed Gracilaria cornea (Gc-TSP) in nociceptive and inflammatory models. In mice, Gc-TSP (3, 9 or 27 mg/kg) significantly reduced nociceptive responses, as measured by the number of writhes, at all tested doses. In a formalin test, Gc-TSP significantly reduced licking time in both phases of the test at a dose of 27 mg/kg. In a hot-plate test, the antinociceptive effect was observed only in animals treated with 27 mg/kg of Gc-TSP, suggesting that the analgesic effect occurs through a central action mechanism at the highest dose. Gc-TSP (3, 9 or 27 mg/kg) caused only a slight reduction in neutrophil migration in the rat peritoneal cavity. However, lower doses of Gc-TSP (3 and 9 mg/kg) significantly inhibited paw oedema induced by carrageenan, especially at 3 hr after treatment. Reduction in oedema was confirmed by myeloperoxidase activity in the affected paw tissue. In addition, treatment (s.c.) of animals with different doses of Gc-TSP inhibited paw oedema induced by dextran within the first hour in all doses tested. After 14 consecutive days of intraperitoneal administration of Gc-TSP (9 mg/kg), we measured the wet weight of the liver, kidney, heart, spleen and thymus and performed biochemical, haematological and histopathological evaluations. No systemic damage was found. These results indicate that Gc-TSP possesses analgesic and anti-inflammatory effects and is a potentially important tool worthy of further study.