New medicinal properties of mangostins: Analgesic activity and pharmacological characterization of active ingredients from the fruit hull of Garcinia mangostana L.

The fruit hull of Garcinia mangostana L. contains oxygenated and prenylated phenol derivatives, such as xanthones or xanthen-9H-ones, and is used by people in Southeast Asia as a traditional medicine for the treatment of abdominal pain, dysentery, wound infections, suppuration, and chronic ulcer. We isolated the active ingredients from the crude ethanol extract of G.mangostana L. (CEM) and investigated their analgesic effects and underlying mechanisms. CEM at intragastric (i.g.) doses of 0.5, 1, and 3 g/kg clearly exhibited antinociceptive effects in the hot-plate and acetic acid-induced writhing tests in mice. Two isolated compounds, α-mangostin and γ-mangostin, exhibited analgesic effects at doses of 25 and 50 mg/kg (i.g.) in the hot-plate and formalin tests, respectively. CEM at doses of 0.5, 1, and 3 g/kg significantly inhibited xylene-induced release of inflammatory mediators. CEM, α-mangostin, and γ-mangostin each dose-dependently demonstrated the ability to scavenge reactive oxygen species. In conclusion, our results demonstrate that CEM and mangostins possess potent peripheral and central antinociceptive effects in mice and suggest that xanthones may be developed as novel analgesics and anti-inflammatory drugs.     

Effects of novelty and pain on behavior and hippocampal extracellular ACh levels in male and female rats

In vivo microdialysis was used to assess the effects of novelty and pain on hippocampal ACh release in male and female rats. Experiments were carried out during the dark phase and consisted of 2 days of tests: on Day 1, after Baseline 1, animals were exposed to a new cage (Novelty) to which, 30 min later, a plastic cylinder (Object) was introduced. On Day 2, after Baseline 2, the Formalin test (50 μl of formalin 10%, s.c. injected in the dorsal hindpaw) was carried out in the animal's home cage. All behaviors were recorded. The extracellular levels of ACh in the dorsal hippocampus were estimated, in 10-min samples, by assay of ACh in the dialysates by HPLC. On Day 1 the raw values of ACh were higher in females than in males, but no sex difference was present when the percentage of change was considered. In both sexes the Novelty and Object tests induced an increase in ACh levels with respect to Baseline. Higher levels of exploration were present in females than males during the first 10 min of Novelty. On Day 2, ACh release increased in both sexes during the Formalin test. No sex difference in either ACh raw values or the percentages of change were found. Females showed higher levels of licking and lower levels of activity than males. The present study shows that novelty and pain induce similar hippocampal cholinergic activation in male and female rats but different behaviors. The results are discussed in light of the several anatomical and functional sex differences present in the hippocampus.     

鞘内可乐定对福尔马林致痛大鼠行为学的影响机制

目的　探讨可乐定 (Clo)对福尔马林致痛大鼠的行为学影响机制。方法　制备福尔马林致痛模型 ,观察可乐定 (Clo)、NO前体 (L- Arg)和 NOS抑制剂 L- NG-硝基精氨酸甲酯 (L- NAME)对模型鼠缩腿舔爪时间的影响。结果　 Clo组的缩腿舔爪时间 (38.6 0± 17.34) s/ 5 m in显著短于模型鼠组 (15 5 .4 1± 2 2 .0 4 ) s/ 5 m in,预先给予L- Arg或 L- NAME分别能加强或抑制以上作用。结论　可乐定能引起大鼠脊髓背角 NO的释放 ,可能是其产生抗伤害作用的机制之一     

21种动物药饮片中总氨基酸的甲醛法测定

目的 完善动物类中药炮制品的质量控制方法.方法 用甲醛法测定动物类中药炮制品及其生品中总氨基酸的含量.结果 炮制品相对于其生品中总氨基酸含量的变化,主要取决于炮制时间的长短.炮制时间控制在7 min以内的样品,其含量高于生品,反之则低于生品.结论 甲醛法为完善动物类炮制品的质量提供了简便易行的方法.     

神经肽FF对内吗啡肽2镇痛作用的调节

目的：研究神经肽FF （NPFF）对内吗啡肽2（EM-2）在急性痛与炎症痛中镇痛作用的调节。方法雄性昆明系小鼠,体重（20±2） g,侧脑室埋管后,水浴甩尾实验和福尔马林痛实验各随机分为8组,即盐水对照组、EM-2组、NPFF受体拮抗剂RF9组、EM-2+RF9组、低剂量NPFF+EM-2组、中剂量NPFF+EM-2组、高剂量NPFF+EM-2组、高剂量NPFF+RF9+EM-2组,每组8只小鼠。侧脑室注射药物NPFF、EM-2和RF9。小鼠水浴甩尾实验研究NPFF对EM-2中枢镇痛的调节作用,福尔马林痛实验研究NPFF对EM-2急性痛与炎症痛镇痛的调节作用。结果水浴甩尾实验结果显示,EM-27.5 nmol可延长小鼠的甩尾潜伏期, NPFF 5,10,15 nmol可剂量依赖性增强EM-2的镇痛作用。福尔马林痛实验结果显示,EM-215 nmol对第一相急性痛与第二相炎症痛均有镇痛作用, NPFF 10,15,20 nmol可剂量依赖性增强EM-2的镇痛作用。在2个实验中,RF9与NPFF联合给药后,RF9能拮抗NPFF对EM-2镇痛的增强作用。结论在小鼠水浴甩尾实验和福尔马林痛实验中,NPFF通过作用于NPFF受体拮抗剂RF9,剂量依赖性增强EM-2对急性痛和炎症痛的镇痛作用。     

Antinociceptive profile of ring A-reduced progesterone metabolites in the formalin test

The present study investigated the effect of acute systemic administration of six progesterone metabolites on formalin-induced pain in the rat. The 3α-hydroxylated metabolites allopregnanolone and pregnanolone are highly potent positive modulators at the GABA_A receptor and produced a biphasic effect on pain in the formalin test. Dose-dependent antinociception was observed at lower doses (maximal antinociception at 0.16 mg/kg) and was reversed at higher doses. Bicuculline abolished the antinociceptive effect. The 3β-hydroxylated epipregnanolone and isopregnanolone are inactive or only weekly active at the GABA_A receptor, and did not affect formalin-induced pain. 5α- and 5β-dihydroprogesterone have also been shown to have low affinity for the GABA_A receptor, but can be rapidly metabolized to their 3α-hydroxylated counterparts. In the formalin test, they produced a biphasic effect on pain similar to that of pregnanolone and allopregnanolone, but with lower potency. The effect was reversible by bicuculline, showing involvement of the GABA_A receptor, and was blocked by indomethacin, implying that the antinociceptive effect is dependent on their conversion to allopregnanolone or pregnanolone. The results indicate that GABA-ergic progesterone metabolites modulate nociception. A change in levels of GABA-ergic progesterone metabolites, such as is observed in depression, chronic fatigue and premenstrual dysphoric disorder could, therefore, contribute to the pain complaints associated with these disorders.     

Ligustilide attenuates pain behavior induced by acetic acid or formalin

Danggui is a popular traditional Chinese medicinal (TCM) herb, which has long been used clinically to treat primary dysmenorrhoea. In a recent study, we demonstrated that ligustilide (LIG), one of the main compounds of Danggui essential oil, has multiple effects on uterine smooth muscles and possesses a non-specific antispasmodic function, which suggests that LIG might play a major role in the therapeutic activity of Danggui in primary dysmenorrhoea. Since pain is the main syndrome of dysmenorrhea, the present investigation was carried out to evaluate the analgesic activity of LIG in vivo. LIG was intra-gastrically administered to animals. We demonstrated for the first time that LIG could cause a significant dose-related reduction of acetic acid-induced writhing response and formalin-induced licking time in both the early and late phases. These results showed that LIG possessed antinociceptive and anti-inflammatory activities. These findings plus the data we reported recently implied that LIG not only has an active dilatory effect on myometrium but also an effective role in reducing the neurogenic and inflammatory pain, thus having the potential to be developed into an effective drug for the treatment of various pain syndromes including primary dysmenorrhoea.     

Open elevated plus maze-induced antinociception in rats: A non-opioid type of pain inhibition?

CORNÉLIO, A. M. AND NUNES-DE-SOUZA, R. L. Open elevated plus maze-induced antinociception in rats: A non-opioid type of pain inhibition? PHYSIOL BEHAV 00 (0) 000-000, 2008. This study investigated whether antinociception induced by exposure to an open elevated plus-maze (oEPM: four open arms) (i) shows cross-tolerance to morphine (Exp. 1 and 2), (ii) is attenuated by repeated exposure to the oEPM (Exp. 3), (iii) is blocked by systemic treatment with naltrexone (Exp. 4), and (iv) is affected by adrenalectomy (Exp. 5) in rats. Animals were daily treated with morphine (M, 5 mg/kg, i.p.) or distilled water (DW) for 5 consecutive days (antinociceptive tolerance assessed by tail-flick test). Then, rats received formalin 2.5% injection (50 μl) into the right hind paw followed by M or DW injection and 25 min later, time spent licking the injected paw was recorded for 10 min (Exp. 1). Similar procedure was followed in Experiment 2, except that licking response was recorded during exposure to an oEPM or enclosed EPM (eEPM: four enclosed arms) in undrugged rats. Experiment 3 evaluated nociception in rats submitted to 1, 2, 3, 4 or 6 exposures to either eEPM or oEPM (formalin was injected only during the last exposure). Experiment 4 investigated the effects of naltrexone (2.5 mg/kg; s.c.) on nociception during eEPM or oEPM exposure. Nociception was also assessed during eEPM or oEPM exposure in sham and adrenalectomized rats (Exp. 5). The results shown that oEPM-induced antinociception (i) did not display cross-tolerance to morphine, (ii) was unchanged by at least 6 maze re-exposures, (iii) failed to be reversed by naltrexone, and (iv) was not prevented by adrenalectomy.     

Anti-nociceptive and anti-inflammatory activities of the Agastache mexicana extracts by using several experimental models in rodents

Ethnopharmacological relevance

Agastache mexicana is a plant that has long been used in large demand in Mexican folk medicine to treat pain, among others affections. Nevertheless, no scientific data confirming its use have been reported. The aim of this investigation was to examine the spectrum of antinociceptive activity of A. mexicana by using different experimental models of nociception in rodents.

Material and methods

Nociceptive activity was induced 30 min post treatment of different doses of hexane, ethyl acetate and methanol extracts from A. mexicana aerial parts. The writhing test in mice, and the formalin and plantar tests as well as the pain-induced functional impairment assay in rats (PIFIR model) were the experimental nociceptive models used. Antinociceptive response of the organic extracts was compared to that observed with the analgesic drug tramadol.

Results

A. mexicana organic extracts produced a dose-dependent and significant inhibition of the abdominal constrictions caused by 1% acetic acid injection (i.p.) in mice. A maximal antinociceptive effectiveness obtained with tramadol was also observed with the administration of hexane and ethyl acetate extracts in comparison to less effectiveness obtained with the methanol extract. At the same range of doses, A. mexicana organic extracts inhibited the behavioral responses in both phases of the formalin pain test, in which a more intense effect was observed in the inflammatory phase than in the neurogenic stage. With regard to the plantar test and PIFIR model, a significant but not dose-dependent antinociceptive response was observed at specific doses that depended on the organic extract evaluated.

Conclusion

The antinociceptive activity of A. mexicana aerial parts depends on the intensity of the painful stimulus induced and involves different kinds of constituents. Our present results reinforce the use of this species in traditional medicine and its utility for pain treatment mainly associated with inflammation.     

Altered nociceptive response in ADAM11-deficient mice

Mice that lack A Disintegrin And Metalloprotease 11 (ADAM11) protein showed normal responses to stimuli in the von Frey test and the hot plate test, but showed reduced responses in the formalin paw test and acetic acid writhing test. Our results indicate that the cell adhesion-related molecule ADAM11 may play a role in pain transmission and in inflammatory regulation mechanisms underlying changes in the threshold for pain perception.