Lactobacillus casei-induced polyarthritis in Lewis rats: histopathological scoring system for evaluation of anti-rheumatic drugs.

A histopathological scoring system which grades drug effects on cellular infiltration, pannus formation, cartilage degradation and bone resorption in L. casei-induced polyarthritis in rats is described. Reference anti-rheumatic and anti-inflammatory agents administered on days 2-60 after induction of arthritis were evaluated for effects on paw swelling weekly and graded histopathologic changes on day 60. This animal model affords a tool to evaluated therapeutic agents on the joint destruction resulting from chronic inflammation.     

骨湿宁治疗风湿性关节炎的实验研究

目的：观察骨湿宁的主要药理作用。方法：采用佐剂，角叉菜胶，尿酸钠等引发大鼠关节炎症或疼痛模型，小鼠热板，醋酸扭体法以及腹腔毛细血管通透性来评价骨湿宁的抗炎，镇痛作用。结果：骨湿宁能抑制大鼠佐剂性关系炎的原发性和继发性病变；抑制角叉菜胶所致的大鼠炎症肿胀；对由大鼠尿酸钠关节炎致痛，小鼠热板，醋酸扭体致痛均有明显的镇痛作用；并具有降低小鼠腹腔毛细血管通透性，抑制大鼠棉球致组织增生的作用。结论：骨湿宁具有一定的抗炎，镇痛作用。     

Effects of captopril and losartan on thermal and chemical induced pain in mice

Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers antagonists (ARAs) are widely used compounds in various cardiovascular disorders. ACEIs, but not ARAs, inhibit the enzyme dipeptidyl carboxypeptidase which is involved in the conversion of angiotensin I to II and degradation of kinins like bradykinin and substance P. Bradykinin and substance P are potent mediators of inflammation and pain. Hence the study was undertaken to evaluate the effects of captopril (an ACEI) and losartan (an ARA-AT1 receptor antagonist) on thermal and chemical induced nocioception by employing hot plate and acetic acid induced writhing tests respectively in mice. Inbred albino mice weighing between 25-30 g were used and they were divided into two sets, each set containing 7 groups. Control groups received normal saline and the remaining six groups received three doses (0.5, 1 and 2 mg/kg) of captopril and three doses (0.5, 1 and 2 mg/kg) of losartan. Drugs were administered intraperitoneally fifteen minutes before placing the animal over the hot plate or 30 minutes before injecting 0.6% acetic acid. Both drugs dose dependently reduced the reaction time in hot plate method. In chemical induced writhing test, both the drugs reduced the latency of onset of writhing and in captopril pretreated groups, acetic acid induced sustained abdominal contraction without any intermittent relaxation. However, in losartan pretreated animals acetic acid just increased the number of writhings without sustained abdominal contraction. Thus, our study suggests that both drugs have hyperalgesic effects.     

Inhibition of prostaglandin biosynthesis as the mechanism of analgesia of aspirin-like drugs in the dog knee joint.

A method has been developed to measure the analgesic action of aspirin-like drugs in knee joints of anaesthetized dogs. Bradykinin, injected into the joint cavity, induced a reflex rise in blood pressure which was dose-dependent; this was used as a measure of nociceptive activity. The joint cavity became more sensitive to bradykinin as the experiment proceeded, or when a low concentration of prostaglandin E1 or E2 was infused locally. The increase in sensitivity with time was prevented by local injection of aspirin or indomethacin, but that induced by exogenous prostaglandin infusion was not. Injections of carrageenin into dog knee joints increased the prostaglandin E2 content of synovial fluid by up to 160 ng per joint; indomethacin prevented this increase. These experiments support our previous conclusion that local biosynthesis of a prostaglandin (induced by mild trauma) sensitizes pain receptors to mechanical or chemical stimuli. Aspirin-like drugs are analgesic because they prevent prostaglandin biosynthesis, thereby preventing this sensitization.     

尼美舒利醇质体抗炎镇痛作用与皮肤刺激性研究

目的考察尼美舒利醇质体经皮给药的镇痛抗炎作用及皮肤刺激性。方法采用小鼠热板法和醋酸扭体法观察尼美舒利醇质体的止痛作用;建立大鼠佐剂性关节炎模型,观察尼美舒利醇质体对大鼠足肿胀及滑膜关节组织的影响;利用健康豚鼠观察尼美舒利醇质体皮肤刺激反应。结果与对照组比较,中、高剂量尼美舒利醇质体能明显提高小鼠自身的热痛阈值（P＜0.05）;并能使醋酸致小鼠扭体次数显著减少（P＜0.05）;抗炎实验结果表明,尼美舒利醇质体对佐剂引起的大鼠足肿胀关节炎有明显的抑制作用（P＜0.05）;尼美舒利醇质体对豚鼠无皮肤刺激作用。结论尼美舒利醇质体具有明显的抗炎、镇痛作用,且皮肤刺激性较小,是一种有效的经皮给药制剂。     

Fasitibant chloride, a kinin B₂ receptor antagonist, and dexamethasone interact to inhibit carrageenan-induced inflammatory arthritis in rats

BACKGROUND AND PURPOSE

Bradykinin, through the kinin B₂ receptor, is involved in inflammatory processes related to arthropathies. B₂ receptor antagonists inhibited carrageenan-induced arthritis in rats in synergy with anti-inflammatory steroids. The mechanism(s) underlying this drug interaction was investigated.

EXPERIMENTAL APPROACH

Drugs inhibiting inflammatory mediators released by carrageenan were injected, alone or in combination, into the knee joint of pentobarbital anaesthetized rats 30 min before intra-articular administration of carrageenan. Their effects on the carrageenan-induced inflammatory responses (joint pain, oedema and neutrophil recruitment) and release of inflammatory mediators (prostaglandins, IL-1β, IL-6 and the chemokine GRO/CINC-1), were assessed after 6 h.

KEY RESULTS

The combination of fasitibant chloride (MEN16132) and dexamethasone was more effective than each drug administered alone in inhibiting knee joint inflammation and release of inflammatory mediators. Fasitibant chloride, MK571, atenolol, des-Arg⁹-[Leu⁸]-bradykinin (B₂ receptor, leukotriene, catecholamine and B₁ receptor antagonists, respectively) and dexketoprofen (COX inhibitor), reduced joint pain and, except for the latter, also diminished joint oedema. A combination of drugs inhibiting joint pain (fasitibant chloride, des-Arg⁹-[Leu⁸]-bradykinin, dexketoprofen, MK571 and atenolol) and oedema (fasitibant chloride, des-Arg⁹-[Leu⁸]-bradykinin, MK571 and atenolol) abolished the respective inflammatory response, producing inhibition comparable with that achieved with the combination of fasitibant chloride and dexamethasone. MK571 alone was able to block neutrophil recruitment.

CONCLUSIONS AND IMPLICATIONS

Bradykinin-mediated inflammatory responses to intra-articular carrageenan were not controlled by steroids, which were not capable of preventing bradykinin effects either by direct activation of the B₂ receptor, or through the indirect effects mediated by release of eicosanoids and cytokines.     

四抗感冒口服液镇痛作用的实验研究

目的：研究四抗感冒口服液（CCD）的镇痛作用。方法：应用热诱发小鼠疼痛反应模型和冰醋酸诱导小鼠扭体反应模型观察CCD对疼痛的抑制作用。结果：CCD5.0g/kg和10.0g/kg可明显延长小鼠热痛反应潜伏期（P＜0．05，P＜0．01），提高小鼠的痛阈值，且维持时间较阿司匹林长；CCD10．0g/kg与20．0g/kg对小鼠扭体反应次数有明显抑制作用（P＜0．01）。结论：CCD具有镇痛作用，且作用维持时间较长。     

Dual effect of nitric oxide donor on adjuvant arthritis

The effect of medical use of NO donors on the pathogenesis of arthritis is still yet unclear. We investigated the effects of the NO donor, sodium nitroprusside (SNP), on the pathogenesis of adjuvant-induced arthritis in rats. Rats were given SNP intraperitoneally either from day 5 to day 14 (as a prophylactic protocol) or from day 16 to day 25 (as a therapeutic protocol) after inoculation of adjuvant. SNP administration, whether prophylactic or therapeutic, in doses of 0.1 and 1 mg/kg/d significantly aggravated pathogenesis of adjuvant arthritis in rats. SNP-treated rats showed significant (P < 0.05) increase in arthritis index, hind paw volume, ankle joint diameter and hyperalgesia compared with control adjuvant arthritic rats. However, in adjuvant rats given the smallest dose of SNP (0.01 mg/kg/d), arthritis index, volume of hind paws, ankle joint diameter, body weight loss, and hyperalgesia were significantly lower than that of control adjuvant rats. After 30 d of the induction of adjuvant arthritis, TNF alpha levels exhibited insignificant changes either in control adjuvant rats or in rats given SNP compared with control non adjuvant rats. IL-10 levels in adjuvant control rats and adjuvant rats given 1 mg or 0.1 mg/kg/d from day 15 to day 25 were significantly lower than that of control non adjuvant rats. Histopathology examination of ankle joint showed that large doses of SNP (1 mg or 0.1 mg/kg/d) increased the mononuclear cells infiltration and erosion of cartilage induced by adjuvant while the infiltration of the inflammatory cells in the synovium of adjuvant rats treated with 0.01 mg/kg/d was minimal and the pannus was inhibited with alleviation of erosion of articular cartilage. Prophylactic small dose of SNP improved the histological status more than the therapeutic small dose. The present work reveals that SNP administration, either prophylactic or therapeutic, was deleterious in higher doses. However, the smallest dose used 0.01 mg/kg/d attenuates joint inflammation, hyperalgesia and body weight loss in adjuvant arthritic rats. These results suggest that small dose of NO donor may exert partial protective effects while the safety of the clinical use of NO donors, in higher doses, in patients with rheumatoid arthritis is questioned.     

Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents

BACKGROUND AND PURPOSE: Rheumatoid arthritis (RA) is a chronic inflammatory disease. Histone deacetylase inhibitors (HDACi), a new class of anti-cancer agents, have recently been reported to exhibit potent anti-inflammatory activities. A proof of concept study was carried out with suberoylanilide hydroxamic acid (SAHA) and MS-275, two HDACi currently undergoing clinical investigations for various oncological indications. EXPERIMENTAL APPROACH: The anti-rheumatic effects of SAHA and MS-275 were assessed in both mouse and rat collagen induced arthritis (CIA) models. KEY RESULTS: SAHA exhibited moderate prophylactic efficacy. It attenuated paw swelling due to inflammation, decreased bone erosion in both mice and rats and reduced slightly the RA-induced bone resorption in rats. However, SAHA could not inhibit the onset of arthritis. In contrast, MS-275 displayed dramatic anti-rheumatic activities. In prophylactic intervention, high doses of MS-275 prevented bone erosion and markedly delayed the onset of arthritis; at low doses, MS-275 strongly attenuated paw swelling, bone erosion, and bone resorption associated with RA. Furthermore, the therapeutic efficacy of MS-275 was also documented. After the onset of arthritis, it could stop the disease progression and joint destruction. An anti inflammatory effect of MS-275 was also confirmed through its capacity to decrease serum IL-6 and IL-1beta levels in the CIA induced mouse model. The anti-rheumatic activity of MS-275 was also confirmed through histological observation. No synovial hyperplasia, pannus formation, cartilage or bone destruction were observed in the high dose prophylactic intervention in mice. CONCLUSION AND IMPLICATION: This study strongly supported HDACi as an innovative therapeutic strategy for RA.     

不同产地藏药独一味的镇痛、抗炎作用比较研究

目的 :研究不同产地独一味的镇痛、抗炎作用。方法 :镇痛作用采用小鼠热板法和扭体法 ;抗炎作用采用小鼠耳二甲苯致炎和小鼠腹腔毛细血管通透性法。结果 :独一味对小鼠热板法和醋酸扭体法所致的疼痛反应有明显的抑制作用 ;能显著抑制二甲苯引起的小鼠耳肿胀 ;对醋酸腹腔毛细血管通透性有明显的抑制作用 ,说明独一味具有抗炎、镇痛作用。结论 :三产地的独一味在镇痛、抗炎方面 ,作用基本一致     

Attempts to Antagonize the Effect of Histamine on the Cold–Stimulated Thyrotropin Secretion in Male Rats

Abstract: Histamine given directly into the 3rd ventricle inhibits the enhancement of thyrotropin secretion induced by cold–exposure (4°, 30 min.) in male rats. This effect was antagonized neither by mepyramine, a H₁–receptor antagonist, nor by cimetidine, a H₂–receptor antagonist. Histamine would not have an indirect mechanism of action through adrenergic α₁– or α₂–receptors in rat hypothalamus, since pretreatment with neither phenoxybenzamine nor yohimbine had any effect on histamine suppressed TSH cold–response. Further, it was also tested if histamine could decrease the TSH secretion through cholinergic–, GABA–, serotonergic– or dopaminergic receptors but no results supporting such a mechanism of action were obtained. The effect of histamine was not modified by pretreatment with naloxone or desipramine either. Imidazole acetic acid, IAA, a metabolite of histamine, had no effect on cold–induced TSH secretion. It is concluded that the effect of exogenous histamine on cold–stimulated TSH secretion is not mediated through H₁– or H₂–receptors. Histamine may decrease brain noradrenergic activity which is important in the generation of TSH cold–response. In addition, the effect of exogenous histamine might be due to decreased endogenous histaminergic activity in rat brain     

国产与进口二氟尼柳的实验性镇痛和抗炎作用的比较

目的 :观察国产二氟尼柳 (diflunisal)的镇痛和抗炎作用。方法 :镇痛用小鼠热板法和醋酸引起的小鼠扭体模型实验 ,抗炎用二甲苯引起的小鼠耳肿胀和角叉菜胶引起的大鼠足跖肿胀实验。结果 :镇痛实验结果表明国产二氟尼柳可显著延长小鼠热板法的痛阈值 ,抑制醋酸引起小鼠扭体模型的ED50 为 1 2 .46mg·kg-1(9.79～ 1 5 .86mg·kg-1) ;抗炎实验表明二氟尼柳抑制二甲苯引起小鼠耳肿胀的ED50 为 1 1 .1 0mg·kg-1(8.93～1 3 .81mg·kg-1) ,抑制角叉菜胶引起大鼠足跖肿胀的ED50 (用药后 6h)为 1 0 .5 6mg·kg-1(8.47～ 1 3 .1 7mg·kg-1)。结论 :国产二氟尼柳的镇痛和抗炎作用与进口品相近。     

Attempts to antagonize the effect of histamine on the cold-stimulated thyrotropin secretion in male rats

Histamine given directly into the 3rd ventricle inhibits the enhancement of thyrotropin secretion induced by cold-exposure (4 degrees, 30 min.) in male rats. This effect was antagonized neither by mepyramine, a H1-receptor antagonist, nor by cimetidine, a H2-receptor antagonist. Histamine would not have an indirect mechanism of action through adrenergic alpha 1- or alpha 2-receptors in rat hypothalamus, since pretreatment with neither phenoxybenzamine nor yohimbine had any effect on histamine suppressed TSH cold-response. Further, it was also tested if histamine could decrease the TSH secretion through cholinergic-, GABA-, serotonergic- or dopaminergic receptors but no results supporting such a mechanism of action were obtained. The effect of histamine was not modified by pretreatment with naloxone or desipramine either. Imidazole acetic acid, IAA, a metabolite of histamine, had no effect on cold-induced TSH secretion. It is concluded that the effect of exogenous histamine on cold-stimulated TSH secretion is not mediated through H1- or H2-receptors. Histamine may decrease brain noradrenergic activity which is important in the generation of TSH cold-response. In addition, the effect of exogenous histamine might be due to decreased endogenous histaminergic activity in rat brain.     

痹痛宁颗粒抗炎镇痛的实验研究

目的研究痹痛宁颗粒的抗炎镇痛作用。方法小鼠耳廓肿胀、大鼠足跖肿胀等实验观察其抗炎作用;通过热板法和醋酸扭体法观察其镇痛作用。结果痹痛宁颗粒能显者抑制二甲苯所致小鼠耳廓肿胀,蛋清致大鼠足跖肿胀,提高热板法疼痛模型小鼠痛阈值,抑制醋酸所致小鼠扭体痛反应。结论痹痛宁颗粒具有显著的抗炎、镇痛作用,应进—步深入探讨其抗炎、镇痛的作用机制。     

白英提取物镇痛抗炎作用的实验研究

目的：初步探讨中药白英提取物的镇痛抗炎作用？方法：取白英的水提取物和乙醇提取物,应用醋酸致小鼠扭体法、小鼠热板法研究是镇痛作用;应用二甲苯致小鼠耳廓肿胀法和大鼠角叉莱胶足跖肿胀法研究其镇痛抗炎作用、结果：白英水提取物和乙醇提取物可减少醋酸致小鼠扭体次数,延长小鼠舔足时间;减轻二甲苯致小鼠耳廓肿胀程度,减小角叉莱胶致足跖肿胀程度。但水提取物作用强于乙醇提取物。结论：中药白英有一定的镇痛抗炎作用,其水提取物的镇痛抗炎作用比乙醇提取物效果明显。     

桂皮醛解热镇痛抗炎作用的实验研究

目的：观察桂皮醛解热镇痛抗炎作用。方法：采用酵母发热大鼠模型，观察桂皮醛解热作用；采用小鼠扭体法和热板法，观察桂皮醛镇痛作用；通过小鼠耳肿胀及对腹腔毛细血管通透性的影响观察桂皮醛抗炎作用。结果：桂皮醛能显著减轻酵母所致大鼠发热反应，明显提高热板痛阈和抑制醋酸所致扭体反应，亦能显著抑制腹腔毛细血管通透性的增高及二甲苯所致小鼠耳廓肿胀。结论：桂皮醛具有明显的解热镇痛抗炎作用。     

Antinociceptive activity of carvacrol (5‐isopropyl‐2‐methylphenol) in mice

Objectives Carvacrol (5‐isopropyl‐2‐methylphenol) is a monoterpenic phenol which is present in the essential oil of oregano and thyme. We have investigated the behavioural effects of carvacrol in animal models of pain, such as acetic acid‐induced abdominal constriction, formalin and hot‐plate tests in mice. The spontaneous motor activity of animals treated with carvacrol was investigated using open‐field and rotarod tests. Methods Carvacrol was administered orally, at single doses of 50 and 100 mg/kg while indometacin (5 mg/kg), morphine (7.5 mg/kg) and diazepam (2 mg/kg) were used as standard drugs. Naloxone (1 mg/kg) and l ‐arginine (150 mg/kg) were used to elucidate the possible antinociceptive mechanism of carvacrol on acetic acid‐induced abdominal constriction and formalin tests. Key findings The results showed that carvacrol produced significant inhibitions on nociception in the acetic acid‐induced abdominal constriction, formalin and hot‐plate tests. In the open‐field and rotarod tests carvacrol did not significantly impair the motor performance. The effect of the highest dose of carvacrol in mice in the acetic acid‐induced abdominal constriction and formalin tests were not reversed by naloxone or l ‐arginine. Conclusions Based on these results, it has been suggested that carvacrol presents antinociceptive activity that may not act through the opioid system nor through inhibition of the nitric oxide pathway.     

通天口服液抗炎镇痛作用研究

目的观察通天口服液的抗炎镇痛作用和对血流变学的影响。方法用二甲苯所致小鼠耳廓及乙酸引起小鼠毛细血管通透性的增高试验,观察该药的抗炎作用,用乙酸扭体法研究其镇痛作用;用WTP-B1型毛细血管血液黏度计测定血液流变学指标。结果通天口服液对二甲苯所致小鼠耳廓肿胀有明显的抑制作用,并抑制乙酸所致小鼠毛细血管通透性的增高,对乙酸扭体法和热板法镇痛实验的研究显示通天口服液具有明显的镇痛效应,并能降低小鼠全血高切?低切的血黏度。结论通天口服液具有明显的抗炎镇痛作用。     

1,6-二(4-苯乙基-1-甲基-1-哌嗪基)己烷二溴化物的镇痛活性研究

目的　研究哌嗪类新化合物 1,6 二 (4 苯乙基 1 甲基 1 哌嗪基 )己烷二溴化物 (97 9 G4 )的镇痛作用及机制。方法　通过醋酸扭体模型、热板、甩尾、纳洛酮拮抗试验及豚鼠回肠离体标本研究样品的镇痛活性及机制。结果　sc 97 9 G4 5mg·kg-1即可有效抑制小鼠扭体反应 (P <0 0 5 ) ,ID50为 8 8mg·kg-1;sc 4 0mg·kg-1、icv 2 5 μg·kg-1均可延长热板实验的舔足阈 (P <0 0 5 ) ;sc 2 0mg·kg-1可延长甩尾试验的潜伏期 (P <0 0 1) ;纳洛酮可拮抗其镇痛活性 ;97 9 G4可激动豚鼠回肠离体标本上的阿片受体。结论　 97 9 G4具有的镇痛活性 ,主要作用部位在中枢 ,其镇痛活性可被纳洛酮拮抗 ,但作用特点有别于吗啡     

仙鹤草提取物镇痛抗炎试验的实验研究

目的:初步探讨中药仙鹤草提取物的镇痛抗炎作用.方法:取仙鹤草的水提取物和乙醇提取物,应用醋酸致小鼠扭体法、小鼠热板法、二甲苯致小鼠耳廓肿胀法和大鼠角叉菜胶足跖肿胀法研究其镇痛抗炎作用.结果:仙鹤草乙醇提取物和水提起物可减少醋酸致小鼠扭体次数,延长小鼠舔足时间,减轻二甲苯致小鼠耳廓肿胀程度,减小角叉菜胶致足跖肿胀程度;乙醇提取物作用强于水提取物.结论:中药仙鹤草乙醇提取物具有明显的镇痛抗炎作用.