Synergistic interaction between meloxicam and aminoguanidine in formalin‐induced nociception in mice

Objectives: The objective of this study was to examine the nature of interaction between cyclooxygenase‐2 inhibitor meloxicam and inducible nitric oxide synthase inhibitor aminoguanidine in formalin‐induced nociception in mice and the possible therapeutic advantage. Methods: Antinociceptive effect of meloxicam (1, 3, 10 and 30mg/kg, oral) and aminoguanidine (10, 30, 100 and 300mg/kg, oral) and their combinations was examined in formalin‐induced paw licking model in mice. Analysis of variance and isobolographic method were employed to identify the nature of antinociceptive interaction. Results: Higher doses of meloxicam (10 and 30mg/kg) and aminoguanidine (100 and 300mg/kg) produced significant reduction in paw licking time (antinociceptive) in late phase of formalin‐induced nociception. Combination of sub‐threshold dose of meloxicam (3mg/kg) with increasing doses of aminoguanidine (10, 30, 100 and 300mg/kg) resulted in synergistic antinociceptive effect. Similarly, co‐administration of sub‐threshold dose of aminoguanidine (30mg/kg) with increasing doses of meloxicam (1, 3, 10 and 30mg/kg) produced significant reduction in formalin‐induced paw licking behaviour. The experimental ED₅₀ for combination with their confidence limits are below the confidence interval of theoretical line of additive interaction, suggesting synergistic nature of interaction between meloxicam and aminoguanidine in isobolographic analysis. Conclusion: Co‐administration of meloxicam and aminoguanidine showed synergistic antinociceptive effect which might possibly reduce gastrointestinal toxicity associated with the use of meloxicam.     

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

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

Opioid‐like antinociceptive effects of oral administration of a lectin purified from the seeds of Canavalia brasiliensis

The objective of this study was to evaluate the antinociceptive effects of a lectin from Canavalia brasiliensis (ConBr) when administered orally to murine models of chemical and thermal nociception. ConBr up to 100 mg/kg produced significant and dose‐dependent antinociceptive effects: 81% reduction in abdominal writhing induced by 0.6% acetic acid; 26 and 52% reduction in early‐ and late‐stage paw licking, respectively, induced by 2.5% formalin; and 155% increase in reaction latency (heightened thermal pain threshold). In all models, the antinociceptive effect was reversed by the lectin‐binding carbohydrate α‐d ‐methyl‐mannoside and by the nonselective opioid antagonist naloxone. The antinociceptive effect observed in the formalin test was inhibited by the δ‐selective antagonist naltrindole and the κ‐selective antagonist nor‐binaltorphimine but not by the μ‐selective antagonist cyprodime. In conclusion, when administered orally to Swiss mice, the ConBr lectin displayed antinociceptive activity, both peripheral and central, mediated by the opioid system and involving δ‐and κ‐receptors and the lectin domain.     

Holothuria grisea agglutinin (HGA): the first invertebrate lectin with anti‐inflammatory effects

Holothuria grisea agglutinin (HGA) is a dimeric lectin of molecular mass 228 kDa by gel filtration with monomers of 105 kDa by SDS‐PAGE. The lectin is highly thermostable as it retains full activity for 1 h at 70 °C. Unlike other lectins purified from marine invertebrates, the hemagglutination activity of HGA does not require any divalent metal ions. The affinity analysis of HGA showed that only mucin was able to inhibit the hemagglutinating activity. HGA administered intravenously was tested in classical models of nociception and inflammation. HGA was able to inhibit neutrophil migration into the peritoneal cavity induced by carrageenan. This inhibitory effect was 68% at a dose of 1 mg/kg. In acetic acid‐induced writhing tests, a significant antinociceptive effect was observed by treatment with HGA (0.1; 1 or 10 mg/kg) reducing constrictions by 27, 90 and 84%, respectively. In formalin tests, HGA at a dose of 10 mg/kg showed antinociceptive effect only in the inflammatory phase (phase 2). Nevertheless, in hot‐plate tests, HGA did not show any nociceptive effect. In rota‐rod and open‐field tests, HGA did not alter the animals' behavior. The treatment with HGA 10 mg/kg presented diminished myeloperoxidase activity activity (81.6% inhibition) and raised the circulating levels of NO by 50.4% when compared with the carrageenan group. HGA has demonstrated the ability to modulate the inflammatory response in models of inflammation in vivo. HGA is the first marine invertebrate lectin that showed an anti‐inflammatory effect. This finding opens a new perspective on the potential of lectins from the marine environment.     

PGE2‐induced lasting nociception to heat: Evidences for a selective involvement of A‐delta fibres in the hyperpathic component of hyperalgesia

Animal models for mechanical pressure or heat nociception usually only measure the threshold response latency. In this study, the effect of typical sensitising treatments on the lasting nocifensive behaviour elicited after a supra‐threshold heating stimulus – the hyperpathic component of hypernociception – was assessed. Male Wistar rats received either intra‐plantar (i.pl.) injection of 350 ng PGE₂ (50 μL) or topical application (t.a.) of 100% dimethylsulfoxide (DMSO), and 10 mM capsaicin. One hour after the paw treatments the number of nocifensive events (NNE) was scored hourly (6 h), for 5 min, immediately after a hind paw immersion in hot water (50 °C/7 s). PGE₂, DMSO and capsaicin increased the NNE ‐induced by the supra‐threshold stimuli. Indomethacin (2.5 mg/kg i.p.), given 30 min before paw treatments, completely inhibited NNE in all groups (P < 0.01). However, indomethacin given 60 min after PGE₂ did not reverse this sensitisation. PGE₂ and DMSO did not lower the heat threshold in the paw withdrawal test, although carrageenan and capsaicin were effective (P < 0.05). Capsaicin neonatal treatment (CNT) (50 mg/kg) reduced the sensitisation induced by DMSO and capsaicin (P < 0.01), but not that induced by PGE₂. These data suggest that the heat‐induced lasting nociception is probably conveyed by Að nociceptors, and PGE₂ seems to be more selective to induce this phenomenon than the thermal threshold lowering. In addition, this hyperpathic effect induced by DMSO and capsaicin seems to be indirectly mediated by PGE₂ and C‐fibres.     

Adjuvant effect of caffeine on acetylsalicylic acid anti‐nociception: Prostaglandin E2 synthesis determination in carrageenan‐induced peripheral inflammation in rat

In the present study, we report a synergistic interaction between acetylsalicylic acid (ASA) and caffeine (CAF) on the inhibition of nociception in a model of peripheral inflammation in rat; on the contrary no interaction have been found on anti‐inflammatory effects and peripheral prostaglandin E2 (PGE‐2) synthesis inhibition. Acute inflammation was induced by the subplantar injection of carrageenan into the right hind paw, and the effects of the drugs were evaluated from 0 to 5h. Nociception was assessed using the Randall & Selitto test, and the inflammatory response by plethismometry. Oral administration of ASA (10–400mg/kg) induced dose‐related anti‐nociceptive and anti‐inflammatory effects. On the other hand, oral CAF administration (5–50mg/kg) did not show a dose‐related inhibitory effect, neither on the inhibition of nociception nor on the inflammatory response. To analyze a possible interaction between both drugs a dose—response curve to ASA plus a fixed dose of CAF (5mg/kg) was obtained 3h after the injection of carrageenan, when the inflammatory pain peaked. A fixed dose of CAF was able to improve the anti‐nociceptive, but not the anti‐inflammatory, effects of ASA. We also assessed, by enzyme immunoassay, the effects of the combination on peripheral PGE‐2 levels: CAF did not alter the inhibitory effect of ASA on PGE‐2 synthesis. Our results corroborate the well‐known clinical effects of combining ASA and CAF; on the other hand, we rule out that prostaglandin synthesis inhibition at peripheral sites would be the mechanism responsible of the adjuvant anti‐nociceptive effect of CAF.     

映山红总黄酮抗炎作用的实验研究

目的研究映山红总黄酮(TFR)的抗炎作用及其可能的机制。方法通过二甲苯致小鼠耳肿胀和蛋清致大鼠足爪肿胀模型观察TFR的抗炎作用,并测定大鼠血清和足爪组织中一氧化氮(NO)、丙二醛(MDA)、前列腺素E2(PGE2)的含量和一氧化氮合酶(NOS)活性。结果50、100 mg/kg的TFR能明显抑制二甲苯致小鼠耳片肿胀;25、50、100 mg/kg的TFR可显著抑制蛋清致大鼠足爪的肿胀;在蛋清诱导大鼠足爪肿胀模型中,TFR使血清和脚爪组织屮MDA含量减少,同时脚爪组织中NOS活性、NO和PGE2含量也有显著的下降。结论TFR有一定的抗炎作用,其作用可能与抑制PGE2和NO合成及抗脂质过氧化有关。     

Inhibition of phosphatidylinositol-3 kinase γ reduces pruriceptive, inflammatory, and nociceptive responses induced by trypsin in mice

This study investigated the effects of pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K)γ in the pruriceptive, inflammatory, and nociceptive responses induced by trypsin in mice. The animals were orally treated with the selective PI3Kγ inhibitor AS605240 (0.3-30 mg/kg) 30 minutes beforehand. In separate groups, AS605240 was given by intrathecal (i.t.) or intracerebroventricular (i.c.v.) routes. The control groups received saline at the same schedules. The effects of PI3K blocking were assessed in different experimental assays. The oral treatment with AS605240 produced a marked reduction of scratching behavior elicited by trypsin. Moreover, AS605240 (1 mg/kg) was able to produce a partial but significant inhibition of the scratching bouts elicited by CP 48/80. Interestingly, the i.c.v. and i.t. injection of AS605240 also reduced trypsin-induced itching. The oral administration of AS605240 was found effective in producing a significant and dose-dependent reduction of trypsin-induced paw edema and tumor necrosis factor α production, as well as the neutrophil recruitment, according to myeloperoxidase activity assessment. Likewise, oral AS605240 (1 mg/kg) promoted a significant reduction of spontaneous nociception induced by trypsin in the mouse paw. In contrast, the oral administration of AS605240 did not significantly modify capsaicin-evoked nociception, although this inhibitor was effective when dosed by i.c.v. route. Noteworthy, AS605240 (1 mg/kg) was able to prevent c-Fos and phospho-Akt immunopositivity at the spinal cord of trypsin-injected mice, either into the back of the neck or the paws. To conclude, PI3Kγ inhibition might well represent a valuable alternative for treating inflammatory and painful conditions, as well as pruritus.     

Dissociation of rewarding,anti‐aversive and anti‐nociceptive effects of different classes of anti‐nociceptives in the rat

It was previously shown that morphine more potently reduces the affective as compared to the sensory component of nociception, and this effect is independent of morphine's rewarding properties. Here we investigated whether this finding can be generalized to other classes of anti‐nociceptive drugs. The effect of oxycodone (0–10 mg/kg, i.p.), tramadol (0–10 mg/kg, i.p.), ibuprofen (0–300 mg/kg, i.p.) and pregabalin (0–31.6 mg/kg, i.p.) on negative affect and mechanical hypersensitivity accompanying carrageenan‐induced (0.5% intraplantar) inflammatory nociception was assessed using conditioned place aversion (CPA) and Randall Selitto paw pressure test, respectively. The rewarding effect of these drugs was assessed using conditioned place preference (CPP). All four anti‐nociceptive drugs dose‐dependently reduced carrageenan‐induced CPA and mechanical hypersensitivity. Furthermore all drugs induced CPP, except for ibuprofen. Similar to morphine, oxycodone and tramadol showed a large dissociation of anti‐aversive versus anti‐nociceptive potency, i.e. 10 times more potent against the affective versus the sensory component of nociception. Oxycodone and tramadol were 30 and 10 times more potent to produce CPP in animals under normal versus painful conditions. Ibuprofen and pregabalin also showed a dissociation of anti‐aversive and anti‐nociceptive potency, but less pronounced (i.e. three times more potent against the affective component). However, pregabalin showed no dissociation between rewarding potency under normal versus painful conditions. Taken together, these data suggest that the dissociation of rewarding potency in animals under normal versus painful conditions is limited to drugs with an opioid mechanism of action, while the dissociation of anti‐aversive and anti‐nociceptive potency applies to anti‐nociceptive drugs with different mechanisms of action.     

The mechanisms of antihyperalgesic effect of topiramate in a rat model of inflammatory hyperalgesia

Recent studies have shown that topiramate, a structurally novel anticonvulsant, exerts antinociceptive activity in animal models of neuropathic, acute somatic, and visceral pain. This study was aimed to examine: (i) the effects of systemically and locally peripherally administered topiramate in the rat inflammatory pain model and (ii) the potential role and site(s) of gamma‐aminobutyric acid (GABA), opioid, and adrenergic receptors in topiramate’s antihyperalgesia. Rats received intraplantar (i.pl.) injections of the pro‐inflammatory compound carrageenan. A paw pressure test was used to determine: (i) the effect of systemic and local peripheral topiramate on carrageenan‐induced hyperalgesia and (ii) the effects of systemic and local peripheral bicuculline (selective GABA_A receptor antagonist), naloxone (nonselective opioid receptor antagonist), and yohimbine (selective α₂‐adrenergic receptor antagonist) on topiramate‐induced antihyperalgesia. Systemic topiramate (40–160 mg/kg; p.o.) produced a significant dose‐dependent reduction in the paw inflammatory hyperalgesia induced by carrageenan. The antihyperalgesic effect of systemic topiramate was significantly decreased by systemic bicuculline (0.5–1 mg/kg; i.p.), naloxone (2–5 mg/kg; i.p.), and yohimbine (1–3 mg/kg; i.p.). Local peripheral topiramate (0.03–0.34 mg/paw; i.pl.) also produced significant dose‐dependent antihyperalgesia, which was significantly depressed by local peripheral yohimbine (0.05–0.2 mg/paw; i.pl.) but not by local peripheral bicuculline (0.15 mg/paw; i.pl.) or naloxone (0.1 mg/paw; i.pl.). The results suggest that topiramate produces systemic and local peripheral antihyperalgesia in an inflammatory pain model, which is, at least partially, mediated by central GABA_A and opioid receptors and by peripheral and most probably central α₂‐adrenergic receptors. These findings contribute to better understanding of topiramate’s action in pain states involving inflammation.     

Role of TRPV1 in nociception and edema induced by monosodium urate crystals in rats

Gout is characterized by the deposition of monosodium urate (MSU) crystals. Despite being one of the most painful forms of arthritis, gout and the mechanisms responsible for its acute attacks are poorly understood. In the present study, we found that MSU caused dose-related nociception (ED₅₀ [ie, the necessary dose of MSU to elicit 50% of the response relative to the control value] = 0.04 [95% confidence interval 0.01-0.11] mg/paw) and edema (ED₅₀ = 0.08 [95% confidence interval 0.04-0.16] mg/paw) when injected into the hind paw of rats. Treatment with the selective TRPV1 receptor (also known as capsaicin receptor and vanilloid receptor-1) antagonists SB366791 or AMG9810 largely prevented nociceptive and edematogenic responses to MSU. Moreover, the desensitization of capsaicin-sensitive afferent fibers as well as pretreatment with the tachykinin NK₁ receptor antagonist RP 67580 also significantly prevented MSU-induced nociception and edema. Once MSU was found to induce mast cell stimulation, we investigated the participation of these cells on MSU effects. Prior degranulation of mast cells by repeated treatment with the compound 48/80 decreased MSU-induced nociception and edema or histamine and serotonin levels in the injected tissue. Moreover, pretreatment with the mast cell membrane stabilizer cromolyn effectively prevented nociceptive and edematogenic responses to MSU. MSU induced a release of histamine, serotonin, and tryptase in the injected tissue, confirming mast cell degranulation. Furthermore, the antagonism of histaminergic H1 and serotoninergic receptors decreased the edema, but not the nociception of MSU. Finally, the prevention of the tryptase activity was capable of largely reducing both MSU-induced nociception and edema. Collectively, the present findings demonstrate that MSU produces nociceptive and edematogenic responses mediated by TRPV1 receptor activation and mast cell degranulation.     

原花青素的抗炎作用及其作用机制探讨

目的研究原花青素的抗炎作用及其作用机制。方法以二甲苯致炎小鼠耳片肿胀及角叉菜胶诱发大鼠足爪肿胀模型,分别探讨原花青素对小鼠耳片肿胀及大鼠足爪肿胀的抑制作用。用紫外分光光度法测定足爪炎性渗出液中前列腺素E2（prostaglandin E2,PGE2）的含量。Westerm Blot法和免疫组化法（immunohistochemistry,IHC）检测大鼠足爪中环氧合酶-2（Cyclooxygenase-2,COX2）的表达情况。结果10mg／kg和20mg／kg的原花青素抑制二甲苯致炎小鼠耳片肿胀,原花青素5mg／kg和20．0mg／kgi p在2～5h抑制角叉菜胶诱导的大鼠足爪肿胀。原花青素5mg／kg和20．0mg／kgip能抑制大鼠炎症足爪组织PGE2的生物合成。原花青素5mg／kg和20．0mg／kgip能明显下调COX-2的表达。结论原花青素具有较强的抗炎作用,其抗炎作用可能与抑制COX-2的表达继而下调PGE2的生物合成有关。     

Evaluation of anti-inflammatory effect of derivative (E)-N-(4-bromophenyl)-2-(thiophen-2-ylmethylene)-thiosemicarbazone

The present study aimed to further investigate the anti-inflammatory activity of (E)-N-(4-bromophenyl)-2-(thiophen-2-ylmethylene)-thiosemicarbazone (BTTSC) as well as its antinociceptive effects. The anti-inflammatory activity was assessed using the model of ear edema induced by croton oil-induced and also evaluated in models of paw edema carrageenan-induced and by compound 48/80. Evaluation of the antinociceptive effect was performed through formalin test. In the nociception test induced by formalin the BTTSC showed activity in both phases of the pain, highlighting inflammatory pain, where it was able to reduce the time to paw lick 62.3, 84.30 and 100% at doses of 30, 100 and 300 mg kg⁻¹. The anti-inflammatory activity was performed ear edema induced by croton oil, where none of the doses tested was capable of significantly regress edema. The paw edema carrageenan-induced showed activity compound, where the edema was reduced by 81.9 and 83.2% in the first two times of the experiment at the highest dose used. The paw edema assay induced by compound 48/80, showed that BTTSC after 15 min of the inoculum phlogistic agent showed significant reduction of edema with values of 56.53% at a dose of 30 mg kg⁻¹. Our results suggesting this compound exerts its antinociception effects connected with peripheral mechanisms. Furthermore, the compound was able to act in two phases of inflammation carrageenan-induced, highlighting the initial phase. This suggests an action on the early mediators of inflammation. The paw edema assay induced by compound 48/80 confirmed our hypothesis indicating action of the compound via histamine.     

The Antinociceptive Effect of (-)-Linalool in Models of Chronic Inflammatory and Neuropathic Hypersensitivity in Mice

We used multiple pain models to investigate the effects of (-)-linalool, a monoterpene alcohol present in the essential oil of plants, on chronic inflammatory and neuropathic hypersensitivity in adult Swiss mice. Inflammatory or neuropathic hypersensitivity was induced by intraplantar (i.pl.) injection of complete Freund's adjuvant (CFA) or partial sciatic nerve ligation (PSNL), respectively. Twenty-four hours after CFA injection, we used Von Frey filaments and acetone-evoked cooling to evaluate tactile and thermal hypersensitivity, respectively. A single i.p. injection of (-)-linalool (50 or 200 mg/kg) administered 30 minutes before testing reduced CFA-induced mechanical hypersensitivity. Similarly, (-)-linalool reduced acetone-evoked hypersensitivity up to 4 hours after treatment. Compared with vehicle, (-)-linalool produced a marked reduction in CFA-induced paw edema. (-)-Linalool also reduced mechanical hypersensitivity induced by PSNL 7 days after injury. Multiple (-)-linalool treatments given chronically (twice a day for 10 days; 50 mg/kg, i.p.) significantly reduced mechanical hypersensitivity induced by CFA and PSNL. This multidose strategy did not cause tolerance. We also reasoned that (-)-linalool might reduce nociceptive behavior in response to direct administration of inflammatory mediators. Therefore, we injected the cytokines IL-1β (.1 pg/site) and TNF-α (1 pg/site) intrathecally. (-)-Linalool inhibited the biting response induced by IL-1β and TNF-α.     

Anti-inflammatory activity of herb products from Licania rigida Benth.

PurposeThe objective of the present study was to evaluate the systemic anti-inflammatory activity of the hydroalcoholic extract of the leaves of Licania rigida Benth (EHFLR) on models of systemic inflammation in mice.MethodsThe quantitative chemical profiles of phenolic acids and flavonoids were performed by High-Performance Liquid Chromatography (HPLC). Systemic anti-inflammatory activity was determined from carrageenan and dextran-induced paw edema models and the animals were orally treated (p.o.) with EHFLR at doses of 25, 50, 100 mg/kg, indomethacin (10 mg/kg) for carrageenan-induced paw edema and promethazine (6 mg/kg) for dextran-induced paw edema. The possible mechanisms involved in the anti-inflammatory action of the extract were evaluated by the paw edema models induced by histamine and arachidonic acid, and by the model of carrageenan-induced peritonitis, where vascular permeability and leukocyte migration to the peritoneal cavity were evaluated.ResultsThe results of the HPLC identified the presence of phenolic acids and flavonoids, with chlorogenic acid (1.16%) and Caempferol (0.81%) as the main constituents. From the results, it was concluded that the extract has an LD₅₀ ≥5000 mg/kg when administered orally in mice as this dose did not trigger deaths in any of the observed groups. EHFLR (25 mg/kg) showed a significant antiderematogenic effect on histamine and arachidonic acid-induced paw edema at the third hour of the tests, with a percentage of inhibition of 46.64% and 18.33%, respectively. The extract (25 mg/kg, p.o.) also significantly reduced vascular permeability and leukocyte migration in the peritoneal cavity.ConclusionsIt is concluded that EHFLR exerts a systemic anti-inflammatory action, which seems to depend, at least in part, on the inhibition of arachidonic acid metabolism and the action of vasoactive amines. In addition, the extract reduced the leukocyte migration in the peritoneal cavity, indicating that its action may be linked to the inhibition of pro-inflammatory cytokines.     

The aqueous extract of Solanum melongena inhibits PAR2 agonist-induced inflammation

BACKGROUND: Solanum melongena L. (Solanaceae) has antioxidant, analgesic, hypolipidemic and antiallergic activity. METHODS: The anti-inflammatory effects of the water extract of the S. melongena (SMWE) were investigated in PAR2-mediated mouse paw edema. Paw edema was induced by injection of trypsin or trans-cinnamoyl-LIGRLO-NH(2) (tc-NH(2)) into the hindpaw of mice. The SMWE (1, 5, 10, and 100 mg/kg) was orally administered 1 h before induction of inflammation. RESULTS: At doses of 5, 10, and 100 mg/kg, the SMWE showed significant inhibition of both paw edema and vascular permeability. The SMWE (10 mg/kg) significantly also inhibited PAR2 agonist-induced myeloperoxidase (MPO) activity and tumor necrosis factor (TNF)-alpha expression in paw tissue. CONCLUSION: These results demonstrate that the SMWE inhibits PAR2 agonist-induced mouse paw edema.     

Amelioration of functional,biochemical and molecular deficits by epigallocatechin gallate in experimental model of alcoholic neuropathy

Long term alcohol consumption leads to decreased nociceptive threshold characterized by spontaneous burning pain, hyperalgesia and allodynia. The mechanism involved in this pain includes increased oxidative‐nitrosative stress, release of pro‐inflammatory cytokines and neuronal apoptosis. The present study was designed to explore the protective effect of epigallocatechin‐3‐gallate against alcoholic neuropathic pain in rats. Rats fed with alcohol (35%) for 10 weeks showed markedly decreased tail flick latency in tail‐immersion test (thermal hyperalgesia), vocalization threshold in Randall—Sellito test (mechanical hyperalgesia) and paw‐withdrawal threshold in von‐Frey hair test (mechanical allodynia) along with enhanced oxidative‐nitrosative stress and inflammatory mediators (TNF‐α, IL‐1β and TGF‐β1 levels). Co‐administration of epigallocatechin‐3‐gallate (25–100 mg/kg) significantly and dose‐dependently prevented functional, biochemical and molecular changes associated with alcoholic neuropathy. In conclusion, the current findings suggest the neuroprotective potential of epigallocatechin‐3‐gallate in attenuating the functional, biochemical and molecular alterations associated with alcoholic neuropathy through modulation of oxido‐inflammatory cascade.     

ABT-963 [2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one], a highly potent and selective disubstituted pyridazinone cyclooxgenase-2 inhibitor

Nonsteriodal anti-inflammatory drugs (NSAIDs) are efficacious for the treatment of pain associated with inflammatory disease. Clinical experience with marketed selective cyclooxygenase-2 (COX-2) inhibitors (celecoxib, rofecoxib, and valdecoxib) has confirmed the utility of these agents in the treatment of inflammatory pain with an improved gastrointestinal safety profile relative to NSAID comparators. These COX-2 inhibitors belong to the same structural class. Each contains a core heterocyclic ring with two appropriately substituted phenyl rings appended to adjacent atoms. Here, we report the identification of vicinally disubstituted pyridazinones as potent and selective COX-2 inhibitors. The lead compound in the series, ABT-963 [2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one], has excellent selectivity (ratio of 276, COX-2/COX-1) in human whole blood, improved aqueous solubility compared with celecoxib and rofecoxib, high oral anti-inflammatory potency in vivo, and gastric safety in the animal studies. After oral administration, ABT-963 reduced prostaglandin E2 production in the rat carrageenan air pouch model (ED50 of 0.4 mg/kg) and reduced the edema in the carrageenan induced paw edema model with an ED30 of 1.9 mg/kg. ABT-963 dose dependently reduced nociception in the carrageenan hyperalgesia model (ED50 of 3.1 mg/kg). After 14 days of dosing in the adjuvant arthritis model, ABT-963 had an ED(50) of 1.0 mg/kg in reducing the swelling of the hind paws. Magnetic resonance imaging examination of the diseased paws in the adjuvant model showed that ABT-963 significantly reduced bone loss and soft tissue destruction. ABT-963 is a highly selective COX-2 inhibitor that may have utility in the treatment of the pain and inflammation associated with arthritis.     

Pregabalin reduces muscle and cutaneous hyperalgesia in two models of chronic muscle pain in rats.

Pregabalin is used for treatment of neuropathic pain conditions. The present study evaluated effects of pregabalin in 2 rat models of muscle-induced hyperalgesia: Inflammatory and noninflammatory. Muscle hyperalgesia (withdrawal threshold to compression of the muscle) and cutaneous hyperalgesia of the paw (withdrawal threshold to von Frey filaments) were measured before and after induction of hyperalgesia and after treatment with pregabalin (saline, 10 to 100 mg/kg i.p.). In the inflammatory model, 3% carrageenan injected into 1 gastrocnemius muscle decreased the mechanical withdrawal threshold of the paw bilaterally and the compression withdrawal threshold of the muscle ipsilaterally 2 weeks later. Pregabalin (10 to 100 mg/kg) increased the compression withdrawal threshold of the inflamed muscle when compared with vehicle controls. Pregabalin also increased the mechanical withdrawal threshold of the paw bilaterally, but only with 100 mg/kg. In the noninflammatory model, 2 unilateral injections of acidic saline into the gastrocnemius muscle produced bilateral cutaneous and muscle hyperalgesia 24 hours after the second injection. Pregabalin (10 to 100 mg/kg i.p.) significantly increased the compression withdrawal thresholds of the muscle and the mechanical withdrawal threshold of the paw bilaterally when compared with vehicle. However, pregabalin also has significant motor effects at the higher doses (60 to 100 mg/kg). Therefore, pregabalin reduces both muscle and cutaneous hyperalgesia that occurs after muscle insult in 2 animal models of muscle pain at doses that do not produce ataxia. PERSPECTIVE: This study shows that pregabalin reduces both cutaneous and muscle hyperalgesia in inflammatory and noninflammatory models of muscle pain. Thus, pregabalin may be an effective treatment for people with chronic muscle pain.     

Assessment of Movement-Evoked Pain in Osteoarthritis by the Knee-Bend and CatWalk Tests: A Clinically Relevant Study

Although there are several reports on pain behavioral tests in rat models of knee osteoarthritis (OA), most of them focus on the paw. The aim of this study was to investigate pain-related behaviors on the affected knee joint, the primary source of nociception, in animals with mono-iodoacetate–induced OA, using the knee-bend (which provides information on movement pain) and pin-prick tests, and to evaluate nociception elicited by walking using the CatWalk test. The von Frey and Randall-Selitto tests applied to the paw allowed us to compare our study results with previous studies. A further aim was to compare the behavioral nociceptive responses of the most used doses of mono-iodoacetate, 2 and 3 mg. Knee-bend score of OA animals was higher than those of control animals throughout the study (P < .05). At every time point, the ipsilateral hind-paw load of OA rats, as measured by the CatWalk test, was lower than that of control rats (P < .05), and paw withdraw threshold to von Frey filaments was also decreased (P < .01). No changes were observed in pin-prick and Randall-Selitto tests. Results obtained with the 2 doses of mono-iodoacetate were similar. The knee-bend and CatWalk tests are effective for evaluating movement-related nociception, a hallmark of clinical OA, which was present throughout the experimental period.PerspectiveBehavioral characterization of models of OA pain is important and useful for use in future studies to test pharmacological treatments. Furthermore, it is important to find methods that correlate better with the human symptoms of OA.