细辛非挥发性提取物抗炎镇痛作用研究

目的:考察细辛不同煎煮时间的水煎液及不同浓度乙醇提取物是否具有抗炎及镇痛作用,并初步探讨细辛的抗炎镇痛作用机制.方法:采用ICR小鼠,以小鼠耳肿胀法对北细辛(根和根茎)水煎液(提取挥发油后水煎液和临床常用水煎液)和乙醇提取物(95%乙醇提取物和50%乙醇提取物)进行抗炎作用的评价;以热板法对北细辛水煎液进行镇痛作用的评价;并以去肾上腺试验和纳洛酮阻断试验,探讨细辛水煎液的抗炎镇痛机制.结果:二甲苯小鼠耳肿胀试验中,北细辛2种水煎液明显减轻炎症肿胀度,高剂量时抑制率分别为43.20%,和63.69%,而对二甲苯所致去肾上腺小鼠耳肿胀无抑制作用;北细辛95%乙醇提取物和50%乙醇提取物均能抑制小鼠耳肿胀,高剂量时抑制率分别为61.86%和52.56%.在热板试验中,北细辛2种水煎液高、低剂量均使痛反应潜伏期明显延长,镇痛作用在2.0 h达高峰;2.0 h各组痛阈提高率分别为51.27%,62.78%,60.08%和68.00%;经纳洛酮预处理后潜伏期明显缩短,北细辛水煎液未显示镇痛作用.结论:北细辛水煎液有明显的抗炎和镇痛作用.临床常用水煎液的抗炎镇痛作用强于提取挥发油后的水煎液.北细辛乙醇提取物具有显著的抗炎作用,95%乙醇提取物抗炎作用与50%乙醇提取物相当.北细辛水煎液抗炎作用有肾上腺的参与,镇痛作用与阿片受体有关.     

Evaluation of aqueous extract of Felicia muricata leaves for anti-inflammatory,antinociceptive, and antipyretic activities

Context: Felicia muricata Thunb. (Nees) (Asteraceae) leaves are used in folklore medicine of South Africa as an oral remedy for pain and inflammation. However, the efficacy of the plant part is yet to be validated with scientific experiments.

Objective: The current study is an effort to investigate the anti-inflammatory, antinociceptive, and antipyretic activities of aqueous extract of F. muricata leaves.

Materials and methods: The phytochemical screening of aqueous extract of Felicia muricata leaves and the efficacy of the extract at the doses of 50, 100, and 200?mg/kg body weight was investigated in experimental animals using several models of inflammation (paw edema induced by carrageenan and egg albumin), nociception (acetic acid-induced writhing, formalin-induced pain and tail immersion), and fever (brewer’s yeast-induced hyperthermia).

Results: The extract contained alkaloids, flavonoids, tannins, saponins, and phenolics. The extract dose-dependently reduced (P <0.05) the number of writhes and stretches induced by acetic acid, number of licks induced by formalin, paw volumes induced by carrageenan and egg albumin. The reaction time by the tail of the extract-treated animals to the hot water also increased. The extract also reduced hyperthermia induced by brewer’s yeast. The highest dose (200?mg/kg body weight of the extract) produced the best result in all cases.

Discussion and conclusion: This study revealed that the aqueous extract of Felicia muricata leaves possessed anti-inflammatory, antinociceptive and antipyretic activities. These findings have therefore supported the use of aqueous extract of Felicia muricata leaves in the traditional medicine of South Africa as an oral remedy for pains, inflammation, and fever.     

Pain and U-Shaped Dose Responses: Occurrence,Mechanisms, and Clinical Implications

This article assesses pain within the context of the dose response. A substantial number of studies indicate that the dose response for pain-related endpoints is commonly biphasic, being independent of the type of biological model employed, endpoint measured, or agent tested. The quantitative features of the dose response are also remarkably consistent regardless of the receptor pathway that mediates the nociceptive response, indicating a likely downstream message convergence. These findings have important implications for drug discovery, development, and clinical evaluation.     

Anti-nociceptive properties of the xanthine oxidase inhibitor allopurinol in mice: role of A1 adenosine receptors

Background and purpose

Allopurinol is a potent inhibitor of the enzyme xanthine oxidase, used primarily in the treatment of hyperuricemia and gout. It is well known that purines exert multiple effects on pain transmission. We hypothesized that the inhibition of xanthine oxidase by allopurinol, thereby reducing purine degradation, could be a valid strategy to enhance purinergic activity. The aim of this study was to investigate the anti-nociceptive profile of allopurinol on chemical and thermal pain models in mice.

Experimental approach

Mice received an intraperitoneal (i.p.) injection of vehicle (Tween 10%) or allopurinol (10–400 mg kg⁻¹). Anti-nociceptive effects were measured with intraplantar capsaicin, intraplantar glutamate, tail-flick or hot-plate tests.

Key results

Allopurinol presented dose-dependent anti-nociceptive effects in all models. The opioid antagonist naloxone did not affect these anti-nociceptive effects. The non-selective adenosine-receptor antagonist caffeine and the selective A₁ adenosine-receptor antagonist, DPCPX, but not the selective A_2A adenosine-receptor antagonist, {"type":"entrez-protein","attrs":{"text":"SCH58261","term_id":"1052882304","term_text":"SCH58261"}}SCH58261, completely prevented allopurinol-induced anti-nociception. No obvious motor deficits were produced by allopurinol, at doses up to 200 mg kg⁻¹. Allopurinol also caused an increase in cerebrospinal fluid levels of purines, including the nucleosides adenosine and guanosine, and decreased cerebrospinal fluid concentration of uric acid.

Conclusions and implications

Allopurinol-induced anti-nociception may be related to adenosine accumulation. Allopurinol is an old and extensively used compound and seems to be well tolerated with no obvious central nervous system toxic effects at high doses. This drug may be useful to treat pain syndromes in humans.     

A STUDY ON THE ROLE OF CHOLINERGIC AND GAMMA AMINO BUTYRIC ACID SYSTEMS IN THE ANTI-NOCICEPTIVE EFFECT OF GOSSYPIN

1. The participation of cholinergic and gamma amino butyric acid (GABA) neurotransmitter systems in the anti-nociceptive effect of gossypin was investigated using pharmacological tools. 2. Physostigmine potentiated its anti-nociceptive response while atropine failed to modify it significantly. 3. THIP (4,5,6,7-tetra hydroisoxazolo (5,4-C) pyridin-3-ol) and gossypin treatment produced an additive response while bicuculline attenuated the anti-nociceptive response of gossypin. Similar observations were recorded for morphine. 4. It is suggested that cholinergic and GABAergic systems play a role in gossypin-induced anti-nociception.     

Sensitivity to μ-opioid receptor-mediated anti-nociception is determined by cross-regulation between μ- and δ-opioid receptors at supraspinal level

BACKGROUND AND PURPOSE

The perception of pain and its inhibition varies considerably between individuals, and this variability is still unexplained. The aim of the present study is to determine whether functional interactions between opioid receptors are involved in the inter-individual variability in the sensitivity to μ-opioid receptor agonists.

EXPERIMENTAL APPROACH

Anti-nociceptive tests, radioligand binding, stimulation of [³⁵S]GTP–γ–S binding, inhibition of cAMP production and co-immunoprecipitation experiments were performed in two strains of rat (Sprague–Dawley bred at our university – SDU – and Wistar) that differ in their sensitivity to opioids.

KEY RESULTS

The increased anti-nociceptive potency of µ-opioid receptor agonists in SDU rats was reversed by the δ-opioid receptor antagonist, naltrindole. Inhibition of the binding of [³H] naltrindole by µ-opioid receptor agonists was different in brain membranes from SDU and Wistar rats. Differences were also evident in the effect of δ-opioid receptor ligands on the binding of [³⁵S]GTP-γ–S stimulated by µ-opioid receptors agonists. No strain-related differences were detected in spinal cord membranes. The potency of morphine to inhibit cAMP production in brain membranes varied between the strains, in the presence of deltorphin II and naltrindole. Co-immunoprecipitation experiments demonstrated that δ-opioid receptors were associated with μ-opioid receptors to a higher extent in brain synaptosomal fractions from SDU than in those from Wistar rats.

CONCLUSIONS AND IMPLICATIONS

There was increased supraspinal cross-talk between μ and δ-opioid receptors in SDU, as compared with Wistar rats. This was related to an enhanced sensitivity to anti-nociception induced by µ-opioid receptor agonists.     

The role of dopamine receptors in ventrolateral orbital cortex-evoked anti-nociception in a rat model of neuropathic pain

The present study examined the role of dopamine and D₁-and D₂-like dopamine receptors in ventrolateral orbital cortex (VLO)-evoked anti-hypersensitivity in a rat model of neuropathic pain, as well as the possible underlying mechanisms. Results showed that microinjection of apomorphine [(R(−)-apomorphine hydrochloride)], a non-selective dopamine receptor agonist, into the VLO attenuated spared nerve injury (SNI)-induced mechanical allodynia in a dose-dependent manner. This effect was completely blocked by the D₂-like dopamine receptor antagonist S(−)-raclopride(+)-tartrate salt (1.5 μg), but was enhanced by the D₁-like dopamine receptor antagonist SCH23390 (R(+)-SCH-23390 hydrochloride, 5.0 μg). The attenuating effect of apomorphine on mechanical allodynia was mimicked by application of the D₂-like dopamine receptor agonist quinpirole [((−)-quinpirole hydrochloride, 0.5, 1.0, and 2.0 μg)]. In addition, microinjection of larger doses (10 and 20 μg) of SCH23390 into the VLO significantly attenuated allodynia. Furthermore, microinjections of GABA_A receptor antagonists, bicuculline [(+)-bicuculline,(S), 9(R)] and picrotoxin (200 and 300 ng for both drugs), into the VLO attenuated mechanical allodynia. A small dose of bicuculline or picrotoxin (100 ng) resulted in increased quinpirole (0.5 μg)-induced anti-allodynia. In contrast, GABA_A receptor agonists, muscimol hydrochloride (250 ng) or THIP [(2,5,6,7-retrahydroisoxazolo(5,4-c)pyridine-3-ol hydrochloride, 1.0 μg)], blocked quinpirole (2.0 μg)-induced attenuation. These results suggest that the dopaminergic system is involved in mediating VLO-induced anti-hypersensitivity, activation of D₂-like dopamine receptors, and inhibition of D₁-like receptors resulting in anti-hypersensitivity. In addition, the mechanisms of GABAergic disinhibition might be involved in D₂-like receptor mediating effects in neuropathic pain.     

Intraplantar injection of anandamide inhibits mechanically-evoked responses of spinal neurones via activation of CB2 receptors in anaesthetised rats

Anti-nociceptive effects of the endocannabinoid anandamide are well established. Anandamide has, however, also been shown to activate pro-nociceptive vanilloid 1 (VR1) receptors present on primary afferent nociceptors. The aim of the present study was to determine the effect of intraplantar injection of anandamide on dorsal spinal neuronal responses in control rats and rats with hindpaw carrageenan-induced inflammation. Effects of intraplantar administration of anandamide (50 microg in 50 microl) on peripheral mechanically-evoked responses of spinal neurones were studied in halothane-anaesthetised rats in vivo. Responses of spinal neurones to mechanical punctate stimulation (von Frey filaments, 8-80 g) of the peripheral receptive field were similar in non-inflamed rats and rats with hindpaw carrageenan-induced inflammation. Intraplantar injection of anandamide, but not vehicle, significantly (P<0.05) inhibited innocuous and noxious mechanically-evoked responses of spinal neurones in rats with hindpaw inflammation, but not in non-inflamed rats. Co-administration of the cannabinoid (2) (CB(2)) receptor antagonist, SR144528 (10 microg in 50 microl), but not the cannabinoid (1) (CB(1)) receptor antagonist, SR141716A (10 microg in 50 microl), significantly blocked inhibitory effects of anandamide on peripheral evoked neuronal responses in rats with hindpaw inflammation. This study demonstrates inhibitory effects of exogenous anandamide on mechanically-evoked responses under inflammatory conditions in vivo, which are mediated by peripheral CB(2) receptors.     

Structural features of mammalian histidine decarboxylase reveal the basis for specific inhibition

Gout and pain are synonymous, and a study in this issue of the BJP reports a novel anti-nociceptive effect of allopurinol, the drug most commonly used to treat gout. Allopurinol works by inhibiting xanthine oxidase (XO), the enzyme responsible for converting hypoxanthine to uric acid which is deposited as crystals in the joints of gout sufferers. Hypoxanthine is a metabolite of, and a possible precursor to, adenosine. Schmidt et al., find that acute inhibition of XO with allopurinol produces a modest adenosine A₁ receptor-mediated anti-nociceptive effect in common tests of chemical and thermal nociception in mice. A concomitant increase in cerebrospinal fluid levels of adenosine supports their hypothesis that inhibiting XO increases adenosine levels via salvage from hypoxanthine. Elevating endogenous adenosine levels by inhibiting metabolism is a well-established strategy for producing anti-nociception in many preclinical models, but inhibiting XO is likely to be particularly beneficial in some chronic pain states because of the pro-nociceptive reactive oxygen species that are produced by XO activity. Thus, allopurinol may have unexpected benefits in pain associated with chronic inflammation, diabetes and vascular dysfunction.