Analgesic activity of methanol extract of Eupatorium adenophorum Spreng. leaves

The methanol extract of the leaves of E. adenophorum (100, 200 and 300 mg/kg, po) showed significant analgesic activity, as compared to standard drugs diclofenac sodium and pentazocine, employing acetic acid-induced writhing test, tail immersion test and tail flick test models.     

Antinociceptive activity of methanolic extract of leaves of Achyranthes aspera Linn. (Amaranthaceae) in animal models of nociception

Antinociceptive activity of methanolic extract of leaves of A. aspera was studied by peripheral/non-narcotic model of nociception like acetic acid induced writhing syndrome test and central/narcotic models like hot plate and tail flick tests. The methanolic extract of the plant, administered orally (@ 300, 600 and 900 mg/kg, body weight) and the standard drug (piroxicam; 10 mg/kg body weight, po) produced significant analgesic activity in acetic acid induced writhing syndrome as compared to the vehicle treated control group. In the hot plate analgesic test, in A. aspera at the above doses and the standard drug treated group (morphine sulphate @ 1.5 mg/kg, ip), the duration of reaction time (sec) increased dose dependently and significantly compared to the control group. In the tail flick test, the plant extract produced dose dependant increase in reaction time which was significantly higher in the test and standard group compared to the control group. The plant possesses significant antinociceptive property as evidenced in all the animal models of nociception. It might possibly exert its effect through diverse mechanism that may involve both central and peripheral pathways. The preliminary phytochemical investigation revealed the presence of steroids, alkaloids and triterpene in the methanolic extract of leaves of A. aspera which may be responsible for its antinociceptive activity.     

Inhibition of <Emphasis Type="SmallCaps">d</Emphasis>-Amino-Acid Oxidase Activity Induces Pain Relief in Mice

(1). We investigated the effects of inhibiting d-amino-acid oxidase (DAO) activity on nociceptive responses through the use of mutant ddY/DAO⁻ mice, which lack DAO activity, and through the application of a selective inhibitor of DAO, sodium benzoate, in the tail flick test, hot-plate test, formalin test, and acetic acid-induced writhing test. (2). Compared with normal ddY/DAO⁺ mice, ddY/DAO⁻ mice showed significantly prolonged tail withdrawal latency in the tail flick test and licking/jumping latency in the hot-plate test, as well as significantly reduced duration of licking/biting in the late phase of the formalin test and the number of abdominal writhing in the acetic acid-induced writhing test. (3). In addition, we investigated the effects of sodium benzoate in Kunming mice having normal DAO activity. (4). Intravenous administration of sodium benzoate (400 mg/kg) significantly inhibited pain responses of the late phase of the formalin test and abdominal writhing responses in the acetic acid-induced writhing test, with no effects on the early phase flinch responses in the formalin test, nociceptive responses in the tail flick test, or hot-plate test. (5). These results suggest that DAO acts as a pro-nociceptive factor in pain, particularly chronic pain, transmission and modulation, and may be a target for pain treatment.     

Elucidation of possible mechanism of analgesic action of Valeriana wallichii DC chemotype (patchouli alcohol) in experimental animal models

Valeriana wallichii (Family Valerianaceae), popularly named as Indian valerian, exists as three chemotypes. Aim of the study was to evaluate the effect of V. wallichii chemotype (patchouli alcohol) extract (DCME) and essential oil (VPAEO) on experimental models of nociception and to elucidate its possible mechanism of action. Analgesic effect was evaluated using acetic acid induced writhing and tail flick model. DCME and VPAEO (40 and 80 mg/kg, p.o.) significantly inhibited the number of writhings as compared to vehicle treated group. None of the doses of DCME and VPAEO exhibited any effect in tail flick model suggesting only peripheral analgesic activity. When studied for mechanism of action in acetic acid induced writhing, subeffective dose of essential oil significantly potentiated the effect of aspirin while no potentiation was seen in case of extract. These data suggest that essential oil VPAEO exerted peripheral analgesic via inhibition of prostaglandin synthesis.     

Synthesis of a potent enkephalin analog, Tyr-D-Thr-Gly-Phe-delta 3 Pro-NH2, and some of its biological activities

The enkephalin analog, H-Tyr-D-Thr-Gly-Phe-delta 3 Pro-NH2 X HCl (VI) ([D-Thr2, delta 3 Pro5]-enkephalinamide), has been synthesized by conventional methods in solution and purified to homogeneity by reversed phase HPLC. The analog is a potent analgesic agent. For evaluation of some of its biological activity a related compound [D-Thr2, Thz5]-enkephalinamide (XI) was also synthesized in solution. Anti-diarrhea activity was evaluated in mice by the intravenous route for anti-DL-5-hydroxytryptophan (5-HTP) induced diarrhea activity. Analgesic activity was assayed by the method of Nilsen in mice using the intravenous route, and by a modified tail flick test in rats and the acetic acid writhing test in mice following subcutaneous administration. Within the constraints of the assays the two analogs are approximately equipotent. Both are less active than [D-Ala2, MePhe4, Met(0)ol]-enkephalinol (XII). Earlier receptor binding studies of compound XI indicated enhanced affinity for the mu receptor and little for the delta receptor. By comparison this may also be the case for compound VI.     

Analgesic effects of dynorphin-A and morphine in mice

To investigate whether or not dynorphin-A is analgesic, the effect of this peptide was tested in comparison with that of morphine in mice. Dynorphin-A produced a potent analgesic effect in the acetic acid writhing and tail pinch tests, but a weak effect in the tail flick test when given by intracerebroventricular injection. In contrast, morphine caused a potent analgesia in all the tests. Dynorphin-A was more effective when given by intrathecal injection than by intracerebroventricular injection, whereas morphine was equipotent by both injection routes. The results suggest that dynorphin-A is analgesic and that its analgesia may be differentiated from that of morphine.     

Synthesis of new 1-phenyl-3-{4-[(2E)-3-phenylprop-2-enoyl]phenyl}-thiourea and urea derivatives with anti-nociceptive activity

Chalcones or 1,3-diaryl-2-propen-1-ones are known to be useful for treating pain, inflammation, and certain diseases although their uses have not been scientifically verified. Due to the limitations of opioid and NSAID therapy, there is a continuing search for new analgesics. A series of novel new 1-phenyl-3-{4-[(2E)-3-phenylprop-2-enoyl]phenyl}-thiourea and urea derivatives were synthesized and evaluated against writhing test in mice, following the aromatic substitution pattern proposed by Topliss. The results of the preliminary bioassays indicate that compound 3 presents promising anti-nociceptive activity in acetic acid-, formalin-, and glutamate-induced pain in mice, compared with some well-known non-steroidal anti-inflammatory and analgesic drugs.     

Analgesic activity of the aqueous seed extract of Hunteria umbellata (K. Schum.) Hallier f. in rodents

The analgesic effect and possible mechanism(s) of action of 50-200 mg/kg of the aqueous seed extract of H. umbellata (HU) were investigated in different experimental models of analgesia using the tail flick, tail immersion, acetic acid-induced writhing tests and formalin-induced algesia. Oral pre-treatment with 50-200 mg/kg of HU caused significant and dose related analgesic effect in the treated rats in all the experimental models used. This analgesia was mediated via central and peripheral mechanisms. Overall, the results showed that HU possesses analgesic effect which lends support to its folkloric use in the local management of pain.     

Antinociceptive properties of acetylenic thiophene and furan derivatives: evidence for the mechanism of action

The aim of the present study was to evaluate the antinociceptive potential of the acetylenic thiophene and furan derivatives: 3-(furan-2-il) prop-2-yn-1-ol 1, 1-(thiofen-2-il) pent-1yn-3-ol 2 and 4-(thiofen-2-il)-2-metilbut-3-yn-2-ol 3 on three different pain models in mice. The pain models evaluated were the acetic acid-induced writhing, capsaicin-induced pain and the tail immersion test. The possible mechanisms involved in the antinociceptive effect of these compounds were also investigated. Thus, the acetylenic thiophene and furan derivatives presented antinociceptive effect in the pain tests caused by chemical agents. Statistical analysis showed that compounds 1 and 3 increased the latency for tail withdrawal in the tail immersion test (phasic pain). Besides, the role of the opioidergic, muscarinic cholinergic and dopaminergic systems in the acetic acid-induced writhing was examined. The antinociceptive effect of compounds 2 and 3 was prevented by pretreatment with naloxone (1 mg/kg, s.c), but not by atropine (5 mg/kg, s.c) or metoclopramide (1 mg/kg, s.c). Neither naloxone nor metoclopramide prevented the antinociceptive effect caused by compound 1, while the pretreatment with atropine antagonized the antinociceptive action of this compound. The compounds 1-3 used in this study did not reveal any motor impairment to mice in the open field. The results suggest that compounds 2 and 3 induced antinociception in the abdominal writhing test and that their effects are mediated by opiodergic receptors, while the antinociceptive effect of compound 1 may involve muscarinic cholinergic receptors.     

Antinociceptive activity of a neurosteroid tetrahydrodeoxycorticosterone (5alpha-pregnan-3alpha-21-diol-20-one) and its possible mechanism(s) of action

The present study investigates the effects of a neurosteroid tetrahydrodeoxycorticosterone (5alpha-pregnan-3alpha-21-diol-20-one) in two experimental models of pain sensitivity in mice. Tetrahydrodeoxycorticosterone (2.5, 5 mg/kg, i.p.) dose dependently decreased the licking response in formalin test and increased the tail flick latency (TFL) in tail flick test. Bicuculline (2 mg/kg, i.p.), a GABA(A) receptor antagonist blocked the antinociceptive effect of tetrahydrodeoxycorticosterone in TFL test but failed to modulate licking response in formalin test. Naloxone (1 mg/kg, i.p.), an opioid antagonist effectively attenuated the analgesic effect of tetrahydrodeoxycorticosterone in both the models. Tetrahydrodeoxycorticosterone pretreatment potentiated the antinociceptive response of morphine, an opioid compound and nimodipine, a calcium channel blocker in formalin as well as TFL test. Thus, tetrahydrodeoxycorticosterone exerts an analgesic effect, which may be mediated by modulating GABA-ergic and/or opioid-ergic mechanisms and voltage-gated calcium channels.     

Molecular docking and analgesic studies of Erythrina variegata?s derived phytochemicals with COX enzymes

Secondary metabolites from plants are a good source for the NSAID drug development. We studied the analgesic activity of ethanolic extract of Erythrina variegata L. (Fabaceae) followed by molecular docking analysis. The analgesic activity of Erythrina variegata L. is evaluated by various methods viz., acetic acid-induced writhing test, hot plate and tail immersion test. Subsequently, molecular docking analysis has been performed to identify compounds having activity against COX-1 and COX-2 enzymes by using GOLD docking fitness. The result of preliminary phytochemical screening revealed that the extract contains alkaloids and flavonoids. In analgesic activity tests, the extract at the doses of 50, 100 and 200 mg/kg body weight (b.w.) produced a increase in pain threshold in a dose dependent manner. In acetic acid induced writhing test, the inhibitory effect was similar to the reference drug diclofenac sodium. The extract showed 18.89% writhing inhibitory effect at the dose 200 mg/kg b.w., whereas diclofenac sodium showed 79.42% inhibition of writhing at a dose of 10 mg/kg b.w. The results of tail immersion and hot plate test also showed potential analgesic activity of the extract which is also comparable to the standard drug morphine (5 mg/kg b.w.). Docking studies shows that phaseollin of Erythrina variegata L. has the best fitness score against the COX-1 which is 56.64 and 59.63 for COX- 2 enzyme. Phaseollin of Erythrina variegata L. detected with significant fitness score and hydrogen bonding against COX-1 and COX-2 is reported for further validation.     

Fluorine bearing sydnones with styryl ketone group: synthesis and their possible analgesic and anti-inflammatory activities

In continuation of structure activity relationship studies, a panel of fluorine containing sydnones with styryl ketone group 4-[1-oxo-3-(substituted aryl)-2-propenyl]-3-(3-chloro-4-fluorophenyl)sydnones 2a-i, was synthesized as better analgesic and anti-inflammatory agents. The title compounds were formed by condensing 4-acetyl-3-(3-chloro-4-fluorophenyl)sydnone with various substituted aryl aldehydes, characterized by spectral studies and evaluated at 100 mg\kg b.w., p.o. for analgesic, anti-inflammatory and ulcerogenic activities. Compounds 2c and 2e showed good analgesic effect in acetic acid-induced writhing while none showed significant activity in hot plate assay in mice. In carrageenan-induced rat paw oedema test, compound 2c and 2f exhibited good anti-inflammatory effect at 3rd h, whereas compounds 2c, 2e, 2d, 2g and 2h showed activity in croton oil induced ear oedema assay in mice. Compounds 2c and 2e were less ulcerogenic than ibuprofen in rats, when tested by ulcer index method. Compounds with electron attracting substituents such as 2c and 2e were found to be promising in terms of the ratio of efficacy and adverse effect. These compounds generally exhibited better activity than those of earlier series signifying fluorine substitution.     

Anti-inflammatory and analgesic activity of Indian Hypericum perforatum L

A standardised 50% aqueous ethanolic extract of the Indian variety of Hypericum perforatum (IHp) was examined for its putative anti-inflammatory and analgesic activity at the doses of 100 and 200 mg/kg, po. The experimental paradigms used were carrageenan induced pedal edema and cotton pellet induced granuloma for anti-inflammatory activity, whereas the tail flick, hot plate and acetic acid induced writhing methods were used to asses analgesic activity. Indomethacin (20 mg/kg, ip) was used as the standard anti-inflammatory drug. Pentazocine (10 mg/kg, ip) and aspirin (25 mg/kg, ip), both clinically used analgesics, were used as standard analgesics for comparison. IHp extract showed significant anti-inflammatory and analgesic activity at both dose levels, in all the paradigms used. Additionally, IHp potentiated the anti-inflammatory activity of indomethacin and analgesic activities of pentazocine and aspirin.     

Unique spirocyclopiperazinium salt. Part 4: modification of dispirocyclopiperazinium (DSPZ) salts as analgesics

In order to improve the analgesic activity of lead compound 7a, two series of dispirocyclopiperazinium (DSPZ) salts 9a-h, 10a-e and compounds 14, 15 were synthesized and evaluated for their in vivo analgesic activity both by acetic acid induced writhing test and hot plate test. Compounds 9h, 14, and 15 exhibited better analgesic activities than 7a. Several important structure-activity relationships were revealed from this study: (1) the introduction of aryl group would obviously improve the activity; (2) it was favorable to enhance the analgesic activity and reduce the toxicity to incorporate alkyl group with suitable length in the molecule; (3) carbamate analogues displayed lower toxicity than carboxylic ester analogues; (4) hydroxylation and chlorination of lead compound could increase the analgesic activity in hot plate test.     

Antinociceptive activity of a 3(2H)-pyridazinone derivative in mice.

The antinociceptive activity of a 3(2H)-pyridazinone derivative (18a) was investigated in mice. 18a administered at doses which did not change either motor coordination or locomotor activity was able to induce antinociceptive effects in four nociceptive tests, the hot plate test, the tail flick test, the writhing test, and the formalin test. In the hot plate and tail flick test, 18a-induced antinociception was observed both after intraperitoneal administration and after intracerebroventricular injection thus indicating 18a has a central site of action. The pretreatment with the opioid antagonist naloxone, the alpha2-antagonist yohimbine or the GABA(B) antagonist CGP 35348 did not change 18a-induced antinociception in the hot plate test and in the tail flick test. Pretreatment with nicotinic antagonist mecamylamine did not change 18a effects either. A reversion of the 18a effects was observed after pretreatment with the muscarinic antagonists atropine and pirenzepine. Binding experiments revealed that 18a binds to muscarinic receptors, suggesting that 18a antinociception is mediated by central muscarinic receptors. The above findings together with the lack of parasympathomimetic cholinergic side effects indicate useful clinical application for this compound.     

Synthesis and biological activity evaluation of lignan lactones derived from (-)-cubebin

The anti-inflammatory and analgesic effects of three dibenzylbutyrolactone lignans, (-)-hinokinin (2), (-)-6,6'-dinitrohinokinin (3), and (-)-6,6'-diaminohinokinin (4), obtained by partial synthesis from (-)-cubebin (1), were investigated using different animal models. It was observed that compounds (1) and (2) inhibited the edema formation in the rat paw edema assay at the same level and that all responses were dose dependent. Also, at the dose of 30 mg/kg, compounds 1, 2, 3, and 4 inhibited the edema formation by 53%, 63%, 54%, and 82%, respectively, at the third hour of the experiment. In the acetic acid-induced writhing test in mice, compounds 2 and 4 produced inhibition levels of 97% and 92%, respectively, while 3 displayed lower effect (75%), which was still higher than 1. The assayed compounds neither displayed activity in the cell migration test nor in the hot plate test.     

I3-naringenin-II8--4'OMe-eriodictyol: a new potential analgesic agent isolated from Rheedia gardneriana leaves

This paper describes the isolation, identification and analgesic activity of a new biflavonoid from Rheedia gardneriana leaves, which correspond to I3-naringenin-II8-4'-OMe-eriodictyol (GB-2a-II-4'-OMe) (1), with a methoxyl group in position 4 of ring-II. Its structure was determined by spectroscopic data and confirmed by an alkaline hydrolysis. Its analgesic effect was evaluated in a writhing test and a formalin test in mice. It was found that this compound exhibits potent and dose-related analgesic action in both experimental models, with ID50's values of 4.5 micromol/kg against the writhing test and 8.2 and 6.8 micromol/kg against the first and second phase of the formalin test, respectively. It was several times more potent than some well-known analgesic drugs used as reference.     

Bioactivity-guided fractionation for analgesic properties and constituents of Vitex negundo L. seeds

This study was undertaken to ascertain the analgesic properties of Vitex negundo L. seeds and to isolate and characterize the active constituents. Among the 80% ethanol extract and some fractions with different polarity, the acetoacetate fraction showed the highest anti-nociceptive activity in acetic acid-induced writhing test in ICR mice. The analgesic bioguided isolation of the acetoacetate fraction yielded two major lignans: 6-hydroxy-4-(4-hydroxy-3-methoxy-phenyl)-3-hydroxymethyl-7-methoxy-3, 4-dihydro-2-naphthaldehyde (1) and vitedoamine A (2). Given orally, compound (1), which was more productive, produced significant inhibitions on chemical nociception induced by intraperitoneal acetic acid and subplantar formalin injections and exhibited notable anti-inflammatory activities in dimethyl benzene-induced ear edema test in a dose-dependent manner. Since co-administration of naloxone fails to antagonize the analgesic activity of compound (1) in the formalin test, we suggest that compound (1) possesses potent analgesic effects which are most likely to be mediated by its anti-inflammatory activity rather than through opioid receptor system and therefore could partially explain the anti-nociceptive effect of V. negundo L. seeds.     

Analgesic and anti-inflammatory activity of the proanthocyanidin shellegueain A from Polypodium feei METT.

Analgesic and antiinflammatory activity of proanthocyanidin isolated from Polypodium feei roots has been tested using acetic acid-induced writhing and carrageenan-induced paw edema methods, respectively. The compound at doses of 50 and 100 mg/kg significantly decreased writhing responses of mice induced by 0.7 % acetic acid along the 60 min test in a dose-dependent manner. The compound at a dose of 100 mg/kg gave the percent protection of 76.23 higher than that of acetylsalicylic acid (59.84 %) at a dose of 50 mg/kg. In the antiinflammatory test, this compound caused significant inhibition of the rats' plantar edema induced by 1 % of carrageenan, but this activity was observed only at a higher dose (200 mg/kg). These findings suggest that proanthocyanidin of P. feei roots might have analgesic and antiinflammatory activity, and its mechanism of action might be due to the inhibition of prostaglandin biosynthesis, because the proanthocyanidin fraction had an inhibitory effect on cyclooxygenase, but not on 5-lypoxygenase enzymes.     

Analgesic activity of morphiceptin, beta-casomorphin-4, and deltakephalin in normotensive Wistar-Glaxo and spontaneously hypertensive rats

The effects of intraventricular injection of beta-casomorphin-4, morphiceptin and deltakephalin (DTLET) on hot water tail flick and tail compression responses were investigated in Wistar Albino Glaxo (WAG) and spontaneously hypertensive rats (SHR). The effects of the mu agonist morphiceptin (20 nmol/rat), as assessed by the tail compression test, were significantly greater in SHR rats but did not differ between both strains when measured by tail flick latency. Opioid agonist deltakephalin (2 nmol/rat) in both tests elicited stronger analgesic effects in SHR as compared to WAG and these effects were blocked by naloxone in both tests used. beta-Casomorphin-4 exhibits moderate activity for mu receptors. In the tail flick test peptide (60 nmol/rat) produced an increase in latencies in SHR rats that was significantly greater than was observed in WAG rats. Naloxone pretreatment abolished the analgesic activity of beta-casomorphin-4 solely in the tail compression test in SHR. Analysis of the slopes of the dose-response curves seems to suggest that differences between the activity of these opioid peptides in SHR and WAG rats are based on a difference in the density and affinity of the subpopulation of the opioid receptors in these strains of rats.