Potent Antinociceptive Activity Research Articles

Evaluation of Olea europaea L. and Tamarix aphylla leaves extracts in the management of pain, pyrexia and allergy in mice and rats

A huge amount of information, related to herbals is based exclusively on historical beliefs. Therefore, we aim to provide scientific validation for some of the traditional uses attributed to Olea europaea (OE) and Tamarix aphylla (TA). To achieve this, we conducted experiments to ensure the safety of the aqueous extract of OE and the methanolic extract of TA. Subsequently, we investigated the peripheral and central antinociceptive activity, antipyretic properties, and anti-allergic activities using albino mice and Wistar rats. Both plant extracts at the doses of 100, 200 and 400 mg produced potent antinociceptive activity (p < 0.05) in a dose-dependent manner using acetic acid-induced writhing reflex and tail immersion assay. Additionally, both plants produced remarkable antipyretic activity comparable with paracetamol (100 mg) manifested by a significant (p < 0.05) reduction of brewer’s yeast-induced pyrexia in rat. Both OE and TA resulted in a potent reduction in leukocytosis and eosinophilia induced by milk in mice.

Structure-Activity Relationship of 7-Chloro-4-(Phenylselanyl) Quinoline: Novel Antinociceptive and Anti-Inflammatory Effects in Mice.

The 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) shows promise for its antinociceptive and anti-inflammatory properties. Here, we explored the structure-activity relationship of 4-PSQ and its analogues: 7-chloro-4-[(4-fluorophenyl) selanyl]quinoline (a), 7-chloro-4-{[3-trifluoromethyl)phenyl] selanyl} quinoline (b), 4-((3,5-Bis(trifluoromethyl)phenyl) selanyl-7-chloroquinoline (c), 7-chloro-4-[(2,4,6-trimethyl)selanyl]quinolinic acid (d) and 7-chloroquinoline-4-selenium acid (e) in models of acute inflammation and chemical, thermal and mechanical nociception in mice, alongside in silico analysis. Compounds a (-F), b (-CF3), c (-Bis-CF3), d (-CH3), e (-OOH), and 4-PSQ exhibited antinociceptive effects in chemical and thermal nociception models, except d (-CH3) and e (-OOH) in the hot plate test. None induced locomotor changes. In silico, only c (-Bis-CF3) showed low gastrointestinal absorption, and c (-Bis-CF3) and e (-OOH) lacked blood-brain barrier penetration, suggesting e (-OOH) lacked central antinociceptive effect. These compounds had higher COX-2 affinity than COX-1. Our findings suggest substituent insertion alters 4-PSQ's efficacy as an antinociceptive and anti-inflammatory agent.

Microwave-assisted green synthesis of silver nanoparticles using Mitragyna parvifolia bark extract and their biological activities: an economical and environment-friendly approach

ABSTRACT Nowadays, nanotechnology is extensively employed in the medical profession. In this study, we used the aqueous extract of the bark of Mitragyna parvifolia to synthesize silver nanoparticles (AgNPs) by microwave-assisted green synthesis. The synthesis of AgNPs was confirmed by visual color change to brown color and characteristic surface plasmon resonance peak at 432 nm. The hydrodynamic diameter of the AgNPs was 171.81 nm having a zeta potential of −24.14 mV; Fourier Transmission Infrared Spectroscopy confirmed the presence of different functional groups on the NP surface; Scanning Electron Microscope and High-Resolution Transmission Electron Microscopy indicated predominantly circular shape of nanoparticle; Selected Area Electron Diffraction and X-ray Diffraction analyses determined the crystalline structure of AgNPs. Energy-Dispersive X-ray indicated the elemental composition and formation of AgNPs. The AgNPs were screened at different concentrations for antioxidant activity, antimicrobial, and anticancer potential in breast cancer cells (MCF-7 and MDA-MB-231). The AgNPs exhibited remarkable antioxidant, antimicrobial, and anticancer activities. The sedative and antinociceptive activities were also tested on Swiss albino mice, which showed mild sedative and very potent antinociceptive activity. However, detailed mechanistic studies are warranted in the future for clinical application of the AgNPs as a biologically active agent as well as a carrier for drug delivery.

Profiling of antioxidant properties and identification of potential analgesic inhibitory activities of Allophylus villosus and Mycetia sinensis employing in vivo, in vitro, and computational techniques

Ethnopharmacological relevanceThe traditional use of plants for medicinal purposes, called phytomedicine, has been known to provide relief from pain. In Bangladesh, the Chakma indigenous community has been using Allophylus villosus and Mycetia sinensis to treat various types of pain and inflammation. Aim of the studyThe object of this research is to evaluate the effectiveness of these plants in relieving pain and their antioxidant properties using various approaches such as in vitro, in vivo, and computational techniques. Additionally, the investigation will also analyse the phytochemicals present in these plants. Materials and methodsWe conducted in vivo analgesic experiment on Swiss albino mice and in-silico inhibitory activities on COX-2 & 15-LOX-2 enzymes. Assessment of DPPH, Anti Radical Activities (ARA), FRAP, H2O2 Free Radical Scavenging, Reducing the power of both plants performed significant % inhibition with tolerable IC50. Qualitative screening of functional groups of phytochemicals was précised by FTIR and GC-MS analysis demonstrated phytochemical investigations. ResultsThe ethyl acetate (EtOAc) fractioned Mycetia sinensis extract as well as the ethanoic extract and all fractioned extracts of Allophylus villosus have reported a significant percentage (%) of writhing inhibition (p < 0.05) with the concentrated doses 250 mg as well as 500 mg among the Swiss albino mice for writhing observation of analgesic effect. In the silico observation, a molecular-docking investigation has performed according to GC-MS generated 43 phyto-compounds of both plants to screen their binding affinity by targeting COX-2 and 15-LOX-2 enzymes. Consequently, in order to assess and ascertain the effectiveness of the sorted phytocompounds, ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) investigation, DFT (Density-functional theory) by QM (Quantum mechanics), and MDS (Molecular dynamics simulation) were carried out. As the outcome, compounds like 5-(2,4-ditert-butylphenoxy)-5-oxopentanoic acid; 2,4-ditert-butylphenyl 5-hydroxypentanoate; 3,3-diphenyl-5-methyl-3H-pyrazole; 2-O-(6-methylheptan-2-yl) 1-O-octyl benzene-1,2-dicarboxylate and dioctan-3-yl benzene-1,2-dicarboxylate derived from the ethnic plant A. villosus and another ethnic plant M. sinensis extracts enchants magnificent analgesic inhibitions and performed more significant drug like activities with the targeted enzymes. ConclusionsPhytocompounds from A. villosus &M. sinensis exhibited potential antagonist activity against human 15-lipoxygenase-2 and cyclooxygenase-2 proteins. The effective ester compounds from these plants performed more potential anti-nociceptive activity which could be used as a drug in future.

Discovery of N′-benzyl-3-chloro-N-((1S,3R,4R)-3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)cyclohexyl)benzenesulfonamide as a novel selective KOR ligand

The effective management of moderate to severe pain often relies on the use of analgesic agents. However, the widespread utility of these medications is hindered by the occurrence of several undesirable side effects. In light of this challenge, there is growing interest in the development of κ opioid receptor (KOR) agonists, which have shown promise in mitigating these adverse effects. In this study, leveraging the structural scaffold of compound D (our previous study), we embarked on the design, synthesis, and evaluation of a series of N′-benzyl-3-chloro-N- ((1S,3R,4R)-3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxyphenyl)cyclohexyl)benzenesulfonamide derivatives. These compounds were subjected to comprehensive in vitro and in vivo test. Through systematic structure-activity relationship (SAR) exploration, we successfully identified compound 23p (Ki(KOR):1.9 nM) as a highly selective KOR ligand of new chemotype. 23p showed high clearance in vitro PK test, and abdominal contraction test showed potent antinociceptive effect. 23p and its O-demethyl metabolite 25 were both found in the plasma of mouse, 25 also showed potent affinity toward KOR (Ki(KOR): 3.1 nM), both they contribute to the analgesic effect. Moreover, 23p exhibited potent antinociceptive activity in abdominal constriction test, which was effectively abolished by pre-treatment of nor-BNI, a selective KOR antagonist.

Novel endomorphin analogues CEMR-1 and CEMR-2 produce potent and long-lasting antinociception with a favourable side effect profile at the spinal level.

Endomorphins have shown great promise as pharmaceutics for the treatment of pain. We have previously confirmed that novel endomorphin analogues CEMR-1 and CEMR-2 behaved as potent μ agonists and displayed potent antinociceptive activities at the supraspinal and peripheral levels. The present study was undertaken to evaluate the antinociceptive properties of CEMR-1 and CEMR-2 following intrathecal (i.t.) administration. Furthermore, their antinociceptive tolerance and opioid-like side effects were also determined. The spinal antinociceptive effects of CEMR-1 and CEMR-2 were determined in a series of pain models, including acute radiant heat paw withdrawal test, spared nerve injury-induced neuropathic pain, complete Freund's adjuvant-induced inflammatory pain, visceral pain and formalin pain. Antinociceptive tolerance was evaluated in radiant heat paw withdrawal test. Spinal administration of CEMR-1 and CEMR-2 produced potent and prolonged antinociceptive effects in acute pain. CEMR-1 and CEMR-2 may produce their antinociception through distinct μ receptor subtypes. These two analogues also exhibited significant analgesic activities in neuropathic, inflammatory, visceral and formalin pain at the spinal level. It is noteworthy that CEMR-1 showed non-tolerance-forming analgesic properties, while CEMR-2 exhibited substantially reduced antinociceptive tolerance. Furthermore, both analogues displayed no or reduced side effects on conditioned place preference response, physical dependence, locomotor activity and gastrointestinal transit. The present investigation demonstrated that CEMR-1 and CEMR-2 displayed potent and long-lasting antinociception with a favourable side effect profile at the spinal level. Therefore, CEMR-1 and CEMR-2 might serve as promising analgesic compounds with minimal opioid-like side effects.

Evaluation of Anti-nociceptive and Anti-Inflammatory Effects of Markhamia tomentosa Cream Co-Formulated with Eucalyptus Oil

Background: Pain is a noxious, sensory, and emotional experience due to intense stimuli. Pain is intimately linked with nociception. The clinical therapies available at the moment for pain are tricyclic antidepressants, non -steroidal anti-inflammatory drugs, and opioids. There is a need to develop and investigate safer alternatives that minimise the chances of psychological or physical drug dependence and drug dose tolerance. The purpose of this research is to develop an anti-inflammatory and anti-nociceptive formulation (Markhamia tomentosa cream co-formulated with Eucalyptus oil as a permeation enhancer) and evaluate its efficacy. Methods: In this study, Markhamia tomentosa was extracted from its leaves using maceration technique. A qualitative screening of the Markhamia tomentosa ethanolic extract (EEMT) was carried out. Five emulsions (A1-A5) containing varying compositions of Markhamia tomentosa were developed, and a negative control (an emulsion that did not contain Markhamia tomentosa or Eucalyptus oil) was also developed using fusion method. The anti-inflammatory and anti-nociceptive properties of the topical creams were evaluated using mice paw-licking and xylene-induced ear oedema tests. Diclofenac and aspirin administered at 20 mg/kg and 50mg/kg orally, respectively, were used as standards. All experiments were carried out in triplicates. Results: The phytochemical investigation of the Markhamia tomentosa extract showed a marked presence of key phyto-constituents such as saponins, flavonoids, alkaloids, and terpenoids. A1 and A2 had significantly higher percentage of nociception inhibition at phase I—neurogenic and phase II—inflammatory stages compared to Diclofenac 20 mg/kg. A1 and A3 had anti-inflammatory properties more potent than Aspirin 50mg/kg. In both tests, the negative controls did not show any level of potency. All results in this investigation were expressed as mean ± S.D (n=3) and (p&lt;0.05) for all data sets. Formulation A1 had the highest concentration of EEMT. No rash, erythema, or oedema was observed in the Draize test implying that the formulations are safe for topical application. Conclusion: Markhamia tomentosa and eucalyptus oil cream showed potent anti-nociceptive and anti-inflammatory activity. Markhamia tomentosa cream co-formulated with Eucalyptus oil as a permeation enhancer can be used effectively as a non-opioid, anti-nociceptive, and anti-inflammatory cream topically for pain and its symptoms

Structure-Activity Relationships of a Novel Cyclic Hexapeptide That Exhibits Multifunctional Opioid Agonism and Produces Potent Antinociceptive Activity.

The cyclic peptide c[d-Lys2, Asp5]-DN-9 has recently been identified as a multifunctional opioid/neuropeptide FF receptor agonist, displaying potent analgesic activity with reduced side effects. This study utilized Tyr-c[d-Lys-Gly-Phe-Asp]-d-Pro-NH2 (0), a cyclic hexapeptide derived from the opioid pharmacophore of c[d-Lys2, Asp5]-DN-9, as a chemical template. We designed, synthesized, and characterized 22 analogs of 0 with a single amino acid substitution to investigate its structure-activity relationship. Most of these cyclic hexapeptide analogs exhibited multifunctional activity at μ and δ opioid receptors (MOR and DOR, respectively) and produced antinociceptive effects following subcutaneous administration. The lead compound analog 15 showed potent agonistic activities at the MOR, κ opioid receptor (KOR), and DOR in vitro and produced a strong and long-lasting analgesic effect through peripheral MOR and KOR in the tail-flick test. Further biological evaluation identified that analog 15 did not cause significant side effects such as tolerance, withdrawal, or reward liability.

Argentatin C Analogues with Potential Antinociceptive Activity and Other Triterpenoid Constituents from the Aerial Parts of Parthenium incanum.

Four new triterpenes, 25-dehydroxy-25-methoxyargentatin C (1), 20S-hydroxyargentatin C (2), 20S-hydroxyisoargentatin C (3), and 24-epi-argentatin C (4), together with 10 known triterpenes (5-14) were isolated from the aerial parts of Parthenium incanum. The structures of 1-4 were elucidated by detailed analysis of their spectroscopic data, and the known compounds 5-14 were identified by comparison of their spectroscopic data with those reported. Since argentatin C (11) was found to exhibit antinociceptive activity by decreasing the excitability of rat and macaque dorsal root ganglia (DRG) neurons, 11 and its new analogues 1-4 were evaluated for their ability to decrease the excitability of rat DRG neurons. Of the argentatin C analogues tested, 25-dehydroxy-25-methoxyargentatin C (1) and 24-epi-argentatin C (4) decreased neuronal excitability in a manner comparable to 11. Preliminary structure-activity relationships for the action potential-reducing effects of argentatin C (11) and its analogues 1-4, and their predicted binding sites in pain-relevant voltage-gated sodium and calcium channels (VGSCs and VGCCs) in DRG neurons are presented.

Chemical composition and biological activities of Lonicera caprifolium L. (Caprifoliaceae) essential oil

This work aimed to investigate the chemical composition, antioxidant activity, antinociceptive effect, and wound healing activity of the Lonicera caprifolium L. flower essential oil (LCEO). Linalool (16.42%), d-limonene (9.99%), and α-cadinol (10.65%) were the most prevalent components of the LCEO. The LCEO revealed moderate DPPH and ABTS radical-scavenging activity. LCEO exhibited potent antinociceptive activity in acetic acid-induced writhing and hot plate-induced pain model; LCEO reduced 73.88 ± 2.78% of writhing and significantly increased pain withdrawal latency in the mice, respectively. The LCEO also presented a potent wound healing effect, with 98.08 ± 1.37% wound closure on the 12th day of treatment. The results of the study demonstrate antioxidant and wound healing potential with antinociceptive effect. To the best of our knowledge, this is the first report on the bioactivities of L. caprifolium L. essential oil.

ОЦЕНКА АНТИНОЦИЦЕПТИВНОЙ АКТИВНОСТИ НОВЫХ ПРОИЗВОДНЫХ Α-ЦИАНОТИОАЦЕТАМИДА НА МОДЕЛИ ОСТРОЙ ВОСПАЛИТЕЛЬНОЙ РЕАКЦИИ

The antinociceptive activity of new derivatives of α-cyanothioacetamide was evaluated in the formalin test, which reflects an acute inflammatory reaction. For the study, a standard model of an acute inflammatory reaction was used: laboratory animals were subplantarly injected with 0.1 ml of 5% formalin (algogen) into the right hind limb. The α-cyanothioacetamide samples studied were injected intragastrically at 1 ml at a dose of 5 mg/kg 1.5 hours before the experiment. The comparison drug was chosen as Analgin JSC "Pharmstandard" at a dose of 7 mg/kg. For one hour after injection, the number of pain reactions was recorded according to the method of 4 types of behavioral response. We have identified the potential antinociceptive activity of new derivatives of α-cyanothioacetamide, which allows them to be used for a detailed study.

Indole alkaloids from the bark of Acacia confusa and their potential antinociceptive and anti-inflammatory activities

A pair of novel trimeric indole alkaloid enantiomers [(±)-8], five new bisindole alkaloids [4–7 and (±)-9], and three pairs of new monomeric indole alkaloid enantiomers [(±)-1–(±)-3], together with seven known alkaloids (10–16), were isolated from the bark of Acacia confusa. Their structures were determined on the basis of spectroscopic methods, especially by NMR data analyses combined with single-crystal X-ray diffraction and electronic circular dichroism analyses. Compounds 4 and 11–16 exhibited significant antinociceptive activities in an acetic acid-induced writhing test. Compounds (+)-9 and (−)-9 displayed anti-inflammatory activities through the inhibition of the NF-κB pathway, with inhibitory rates of 68.9% and 59.5%, respectively, at a concentration of 10 µM.

ZYKR1, a novel, potent, and peripherally selective kappa opioid receptor agonist reduces visceral pain and pruritus in animal models

Opioid receptor agonists are effective analgesic agents. Central activation of the mu and/or kappa opioid receptors (KOR) is associated with CNS side effects, which limits their effectiveness. Recent studies indicated that peripherally restricted, selective KOR agonists were potent analgesics and devoid of CNS-related side effects. To confirm this hypothesis, we designed a novel, potent, and peripherally restricted KOR-selective agonist, ZYKR1. The analgesic efficacy, brain penetration and safety of ZYKR1 were assessed in pre-clinical models. ZYKR1 showed KOR agonistic activity in the cAMP assay, with an EC50 of 0.061 nM and more than 105-fold selectivity over the mu and delta opioid receptors (EC50 > 10 μM). ZYKR1 was not found to bind mu, delta opioid, and NOP receptors in radioligand binding assays. ZYKR1 produced concentration-dependent inhibition of electrically evoked contractions in isolated mouse vas deferens with an IC50 of 1.6 nM ZYKR1 showed peripheral restriction and potent analgesic efficacy in various in-vivo animal models (acetic acid induced visceral pain mouse model, ED50: 0.025 mg/kg, IV; ovariohysterectomy induced postoperative pain rat model, ED50: 0.023 mg/kg, IV; and C48/80 induced pruritus mouse model, ED50: 0.063 mg/kg, IV). In addition, ZYKR1 was devoid of motor coordination, physical dependence, dysphoria, and respiratory depression at 30, 400, 10 and 10-fold of efficacy dose, respectively. In conclusion, ZYKR1 has potent antinociceptive action in visceral pain and pruritus with limited CNS side effects in preclinical models owing to its peripheral restriction.

Inhibition of phosphodiesterase-4 in the spinal dorsal horn ameliorates neuropathic pain via cAMP-cytokine-Cx43 signaling in mice.

BackgroundThe spinal phosphodiesterase‐4 (PDE4) plays an important role in chronic pain. Inhibition of PDE4, an enzyme catalyzing the hydrolysis of cyclic adenosine monophosphate AMP (cAMP), produces potent antinociceptive activity. However, the antinociceptive mechanism remains largely unknown. Connexin43 (Cx43), a gap junction protein, has been shown to be involved in controlling pain transduction at the spinal level; restoration of Cx43 expression in spinal astrocytes to the normal levels reduces nerve injury‐induced pain. Here, we evaluate the novel mechanisms involving spinal cAMP‐Cx43 signaling by which PDE4 inhibitors produce antinociceptive activity.MethodsFirst, we determined the effect of PDE4 inhibitors rolipram and roflumilast on partial sciatic nerve ligation (PSNL)‐induced mechanical hypersensitivity. Next, we observed the role of cAMP‐Cx43 signaling in the effect of PDE4 inhibitors on PSNL‐induced mechanical hypersensitivity.ResultsSingle or repeated, intraperitoneal or intrathecal administration of rolipram or roflumilast significantly reduced mechanical hypersensitivity in mice following PSNL. In addition, repeated intrathecal treatment with either of PDE4 inhibitors reduced PSNL‐induced downregulation of cAMP and Cx43, and upregulation of proinflammatory cytokines tumor necrosis factor‐α (TNF‐α) and interleukin‐1β. Furthermore, the antinociceptive effects of PDE4 inhibitors were attenuated by the protein kinase A (PKA) inhibitor H89, TNF‐α, or Cx43 antagonist carbenoxolone. Finally, PSNL‐induced upregulation of PDE4B and PDE4D, especially the PDE4B subtype, was reduced by treatment with either of the PDE4 inhibitors.ConclusionsThe results suggest that the antinociceptive effect of PDE4 inhibitors is contributed by increasing Cx43 expression via cAMP‐PKA‐cytokine signaling in the spinal dorsal horn.

Repurposed oral tapentadol as an intravenous drug of abuse in opioid dependence

We present to you a case series of a group of individuals who presented to us with a history of intravenous drug abuse of repurposed oral tapentadol. Tapentadol is a synthetic benzenoid with a dual mode of action, as an agonist for the μ-opioid receptor and a norepinephrine reuptake inhibitor, with potential anti-nociceptive activity. The prevalence of current opioid use in India is reported to be 4% in males and 0.2% in females. Limited availability and difficulty in procuring the recommended drugs for detoxification and maintenance therapy in opioid dependence give reasons to consider treatment alternatives for the same. This case series aims to address the need and effectiveness of evidence-based treatment in opioid dependence.

Anti-nociceptive and anti-inflammatory activities of the essential oil isolated from Cupressus arizonica Greene fruits.

BackgroundCupressus arizonica Greene is a coniferous tree with great importance in fragrance and pharmaceutical industries. Essential oils from C. arizonica (EC) have shown potential antioxidant, and anti-microbial activities. This study aimed at investigating the anti-nociceptive and anti-inflammatory effects/mechanisms of EC.MethodsThe EC was evaluated for anti-nociceptive and anti-inflammatory activities on male Wistar rats using a formalin test and carrageenan-induced paw edema, respectively. Also, we pre-treated some of the animals with naloxone and flumazenil in the formalin test to find out the possible contributions of opioid and benzodiazepine receptors to EC anti-nociceptive effects. Finally, gas chromatography/mass spectrometry (GC/MS) analysis was used to identify the EC’s constituents.ResultsEC in intraperitoneal doses of 0.5 and 1 g/kg significantly decrease the nociceptive responses in both early and late phases of the formalin test. From a mechanistic point of view, flumazenil administration 20 minutes before the most effective dose of EC (1 g/kg) showed a meaningful reduction in the associated anti-nociceptive responses during the early and late phases of the formalin test. Naloxone also reduced the anti-nociceptive role of EC in the late phase. Furthermore, EC at the doses of 1, 0.5, and 0.25 g/kg significantly reduced paw edema from 0.5 hours after carrageenan injection to 4 hours. GC/MS analysis showed that isolated EC is a monoterpene-rich oil with the major presence of α-pinene (71.92%), myrcene (6.37%), δ-3-carene (4.68%), β-pinene (3.71%), and limonene (3.34%).ConclusionsEC showed potent anti-nociceptive and anti-inflammatory activities with the relative involvement of opioid and benzodiazepine receptors.

Understanding the Mechanism of Action of NAI-112, a Lanthipeptide with Potent Antinociceptive Activity

NAI-112, a glycosylated, labionine-containing lanthipeptide with weak antibacterial activity, has demonstrated analgesic activity in relevant mouse models of nociceptive and neuropathic pain. However, the mechanism(s) through which NAI-112 exerts its analgesic and antibacterial activities is not known. In this study, we analyzed changes in the spinal cord lipidome resulting from treatment with NAI-112 of naive and in-pain mice. Notably, NAI-112 led to an increase in phosphatidic acid levels in both no-pain and pain models and to a decrease in lysophosphatidic acid levels in the pain model only. We also showed that NAI-112 can form complexes with dipalmitoyl-phosphatidic acid and that Staphylococcus aureus can become resistant to NAI-112 through serial passages at sub-inhibitory concentrations of the compound. The resulting resistant mutants were phenotypically and genotypically related to vancomycin-insensitive S. aureus strains, suggesting that NAI-112 binds to the peptidoglycan intermediate lipid II. Altogether, our results suggest that NAI-112 binds to phosphate-containing lipids and blocks pain sensation by decreasing levels of lysophosphatidic acid in the TRPV1 pathway.

Anti-oedematous and antinociceptive activities assessment of stem bark aqueous extract of Ficus exasperata Vahl. (Moraceae) in rat and mice.

Background: Ficus exasperata Vahl. (Moraceae) is widely used in African traditional medicine for the treatment of various diseases. The present study is undertaken to assess the anti-oedematous and antinociceptive activities of the stem bark aqueous extract of Ficus exasperata in mice and rats. Methods: The anti-oedematous activity was investigated following carrageenan or histamine-induced rat paw oedema models. Antinociceptive activity was evaluated using acetic acid induced writhing test (1 %, 10 ml/kg), capsaicin-induced neurogenic pain (32 µg/mL, 30 µL) and formalin-induced test (1%, 20 µL). Extract was administrated orally at 37.5, 75 and 150 mg/kg. Results: Pre-treatment of rats with Ficus exasperata stem bark aqueous extract exhibited significant inhibition of paw oedema during all the phases of both carrageenan and histamine induced edema in rat. The maximum inhibition percentages were 94.75 % (3 h) and 30.64 % after one hour at the dose of 37.5 mg/kg, respectively, in carrageenan or histamine models. Antinociceptive activity showed that aqueous extract reduced significantly (p &lt; 0.001) the pain induced by acetic acid with an inhibition percentage of 70.8% (150 mg/kg). In the formalin-induced test, the extract also reduced significantly (p &lt; 0.001) licking time during neurogenic phase and inflammatory phase with inhibition percentages of 44.75% and 52.78% respectively at the dose of 75 and 150 mg/kg. In addition, aqueous extract of F. exasperata reduced significantly (p &lt; 0.001) neurogenic pain induced by capsaïcin by 71.28 % at the highest dose (150 mg/kg). Conclusion: This finding suggests that the stem bark aqueous extract of Ficus exasperata possess potent anti-oedematous and antinociceptive activities.

Dieckol attenuates the nociception and inflammatory responses in different nociceptive and inflammatory induced mice model

Pain is the common indicator of inflammatory ailments and traumatic tissue injuries. The dieckol is an important therapeutic compound, which present in many seaweeds. The present research work was planned to assess the anti-inflammatory and anti-nociceptive actions of dieckol by using animal model. The anti-nociceptive action of dieckol was investigated by acetic acid triggered writhing, formalin provoked nociception, tail immersion test, hot-plate methods and the anti-inflammatory effects was explored by carrageenan triggered paw edema method. In the present investigation the administration of dieckol was remarkably suppressed and inhibited the acetic acid-provoked writhing, formalin-triggered nociception, tail immersion test, hot plate-provoked nociception in the experimental animals. The dieckol was significantly (p < 0.05) inhibited the carrageenan-triggered inflammation, leukocyte infiltration and diminished the formation of pro-inflammatory regulators in the experimental animals. Altogether, the dieckol was showed a potent anti-nociceptive and anti-inflammatory activity.

Synthetic efforts toward the bicyclo[3.2.1]octane fragment of rhodojaponin III

Rhodojaponin III is a grayanane-type diterpenoid natural product with a novel chemical scaffold. It shows potent antinociceptive activity and may represent a new class of natural non-opioid analgesics with a novel mode of action. We explored the Au(I)-catalyzed Conia-ene cyclization and the Mn(III)-mediated radical cyclization of alkynyl ketones for the synthesis of the bicyclo[3.2.1]octane fragment of rhodojaponin III. These strategies will be applicable in the synthesis of rhodojaponin III and analogs for future biological studies.