Search

Objectives: Safe and effective drugs are still lacking for many pain therapies. In recent years, growing interest has been devoted thus on herbal drugs as an option to identify new pain killers. Based on this, extensive researches are carried out on Verbascum L. genus due to its therapeutic potency on pain and inflammation therapy. In this study, among Verbascum species, the antinociceptive effect of Verbascum exuberans Hub.-Mor., and its contributions to nitrergic, serotonergic, or opioidergic pathways as well as its antiinflammatory acitivity were investigated. Materials and Methods: Tail clip, tail flick, and hot plate tests were used to determine the central (spinal and supraspinal) antinociceptive effect, while an acetic acid-induced writhing test was used to measure the peripheral antinociceptive effect of the extract (250 and 500 mg/kg). The extract (250 mg/kg) was then combined with nω-nitro-L-arginine methyl ester, cyproheptadine, and naloxone to evaluate its involvement in nitrergic, serotonergic, or opioidergic pathways, respectively. Carrageenan-induced hind paw edema model was used to determine the antiinflammatory effect of the extract (250 mg/kg). Results: The extract shows central spinal but not central supraspinal antinociceptive effect, and presents peripheral antinociceptive effect. The antinociceptive actions of the extract is largely regulated via targeting the nitrergic pathway, while the opioidergic pathway is partly involved. Further, the extract shows antiinflammatory effect due to the significant inhibitions on the time dependent edema progression and the cytokine (tumor necrosis factor-alfa and interleukin-1beta) productions. [ABSTRACT FROM AUTHOR]

Background: There is a wide range of animal models available today for studying chronic pain associated with a variety of etiologies and an extensive list of clinical manifestations of peripheral neuropathies. Photobiomodulation is a new tool for the treatment of pain in a convenient, noninvasive way. Objective: The aim of this work is to elucidate the effects of infrared light‐emitting diodes (LEDs) on behavioral responses to nociceptive stimuli in chronic pain models. Methods: Forty‐eight Swiss male mice weighing 25 to 35 g were used. Two chronic pain models, ischemia‐reperfusion (IR) and spared spinal nerve injury, were performed and then treated with infrared LED irradiation (390 mW, 890 nm, 17.3 mW/cm2, 20.8 J/cm2, for 20 minutes). The behavioral tests used were a mechanical hypersensitivity test von Frey test) and a cold allodynia test (acetone test). Results: The results showed that, in the IR model, the infrared LED had a significant effect on mechanical stimulation and cold allodynia on every day of treatment. In the spared nerve injury model, an analgesic effect was observed on every treatment day (when started on the 3rd and 7th days after the surgery). In both models, the effect was abolished when the treatment was interrupted. Conclusions: These findings suggest that photobiomodulation therapy may be a useful adjunct treatment for chronic pain. [ABSTRACT FROM AUTHOR]

Clinically, neuropathic pain treatment remains a challenging issue because the major therapy, centred around pharmacological intervention, is not satisfactory enough to patient by reason of low effectiveness and more adverse reaction. Therefore, it is still necessary to find more effective and safe therapy to ameliorate neuropathic pain. The purpose of this study was to explore the antinociceptive effect of Echinacoside (ECH), an active compound of Cistanche deserticola Ma, on peripheral neuropathic pain induced by chronic constriction injury (CCI) in mice, and to demonstrate its potential mechanism in vivo and vitro. In the present study, results showed that intraperitoneal administration of ECH (50, 100, and 200 mg/kg) could alleviate mechanical allodynia, cold allodynia and thermal hyperalgesia via behavioural test. Moreover, the structure and function of injured sciatic nerve by CCI were taken a turn for the better to a certain extent after ECH treatment using histopathological and electrophysiological test. Furthermore, ECH repressed the expression of the P2X7R and FKN and reduced the expression and release of the IL-1β, IL-6 and TNF-α. Besides, ECH could decrease Ca2+ influx and Cats efflux and inhibit phosphorylation of p38MAPK. To sum up, the present study illustrated that ECH could alleviate peripheral neuropathic pain by inhibiting microglia overactivation and inflammation through P2X7R/FKN/CX3CR1 signalling pathway in spinal cord. This study would provide a new perspective and strategy for the pharmacological treatment on neuropathic pain. [Display omitted] • Echinacoside ameliorated CCI-induced neuropathic pain in mice. • Echinacoside alleviated peripheral neuropathic pain through inhibiting P2X7R/FKN/CX3CR1 pathway in spinal cord. • Echinacoside may have potential as therapeutic agent for neuropathic pain. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Schinopsis brasiliensis is a native plant from Brazil, popularly used in folk medicine to relieve pain and treat inflammation. This study evaluated the antinociceptive and anti-inflammatory activities and antioxidant properties of the hydroethanol extract (HEE) and ethyl acetate fraction (EAF) obtained from S. brasiliensis bark. Materials and methods The HEE and EAF of S. brasiliensis bark (10, 30 and 100 mg/kg, p.o.) were evaluated using models of analgaesia (formalin-induced licking and hot-plate models) or inflammation (licking response by formalin-induced and carrageenan-induced cell migration into the subcutaneous air pouch). The antioxidant activities of HEE and EAF (50, 100 and 200 µg/ml) were evaluated using the lipoperoxidation method induced in egg yolk by 2′-azobis(2-amidinopropane) dihydrochloride (AAPH) and FeSO 4 . Results HEE and EAF presented a central antinociceptive effect (at 100 mg/kg dose), increasing the baseline and area under the curve in the hot plate model. EAF (100 mg/kg) significantly reduced (p< 0.005) the pain response in the first (45%) and second (35%) phases of the formalin-induced licking model, while HEE (100 mg/kg) reduced (38%) only the pain response in the second phase. Regarding anti-inflammatory activity, EAF (100 mg/kg) also inhibited the inflammatory process induced by subcutaneous carrageenan injection in the SAP model, reducing the amount of the cytokine TNF-α produced. Conclusion HEE and EAF from S. brasiliensis bark show pharmacological interest because they were able to inhibit the peripheral and central transmission of pain. Our data also suggest that the anti-inflammatory activity caused by EAF exposure occurs through the inhibition of the pro-inflammatory cytokine TNF-α, also reducing the spreading of the inflammatory processes by neutralizing reactive oxygen species, which are by-products in the biosynthesis of pain mediators. [ABSTRACT FROM AUTHOR]

Peripheral painful neuropathy is one of the most common complications in diabetes and necessitates improved treatment. Fisetin, a naturally occurring flavonoid, has been reported to exert antidepressant-like effect in previous studies. As antidepressant drugs are employed clinically to treat neuropathic pain, this work aimed to investigate whether fisetin posses beneficial effect on diabetic neuropathic pain and explore the mechanism(s). We subjected mice to diabetes by a single intraperitoneal (i.p.) injection of streptozotocin (200 mg/kg), and von Frey test or Hargreaves test was used to assess mechanical allodynia or thermal hyperalgesia, respectively. Chronic treatment of diabetic mice with fisetin not only ameliorated the established symptoms of thermal hyperalgesia and mechanical allodynia, but also arrested the development of neuropathic pain when given at low doses. Although chronic fisetin administration did not impact on the symptom of hyperglycemia in diabetic mice, it reduced exacerbated oxidative stress in tissues of spinal cord, dorsal root ganglion (DRG) and sciatic verve. Furthermore, the analgesic actions of fisetin were abolished by repetitive co-treatment with the reactive oxygen species (ROS) donor tert -butyl hydroperoxide ( t -BOOH), but potentiated by the ROS scavenger phenyl- N - tert -butylnitrone (PBN). Finally, acute blockade of spinal GABA A receptors by bicuculline totally counteracted such fisetin analgesia. These findings indicate that chronic fisetin treatment can delay or correct neuropathic hyperalgesia and allodynia in mice with type 1 diabetes. Mechanistically, the present fisetin analgesia may be associated with its antioxidant activity, and spinal GABA A receptors are likely rendered as downstream targets. [ABSTRACT FROM AUTHOR]

Experimental research followed by clinical studies have demonstrated the existence of several types of pain, thus the pain classification according to the mediation has widely extended. In addition, the study of the interactions with pharmacodynamic mechanism expanded very much during the last years; therefore in the new theories appear significant changes concerning synergism, addition and subadditivity in binary combinations. The investigations in this paper were aimed the demonstration of the antinociceptive of some drugs with anticonvulsant action and the analysis of their binary combinations with tramadol, using isobolar analysis. As model of nociception has been used the test of abdominal constrictive response in mouse induced by Zymosan A. the test substances were administered orally alone or in fixed proportion combinations. The data obtained were subjected to isobolar analysis. According to the statistical analysis the following have been observed: the binary combination tramadol-VA has proven to be synergistic (Zmix ⋋ Zadd, f = 0,5, p1 = 677, Tc =3.936, Tt = 3,529, c = 12.78, Ft = 4.46, p ⋋ 0.05), while the binary combination tramadol-CBZ has proven to be borderline additive (Z mix ⋋ Zadd). [ABSTRACT FROM AUTHOR]

Introduction: One of the most important priorities in therapy is pain control. Therefore, many different groups of drugs are being used for this purpose, primarily opioid analgesics and non-steroidal anti-inflammatory drugs (NSAIDs). Opioid analgesic tramadol, by binding to specific receptors, modulates the perception and response to painful stimuli and inhibits transmitting and further processing of pain impulses. Lornoxicam, which belongs to the oxicam class of NSAIDs, is a non-selective cyclooxygenase inhibitor with strong analgesic and anti-inflammatory effects, and better tolerance profile. Preliminary research, which requires further verification, suggests that lornoxicam may be a better alternative or adjunctive therapy to opioid analgesics in the treatment of moderate to severe pain. The aim of this study was to investigate antinociceptive effects of lornoxicam, as well as the combination of lornoxicam with tramadol. Methods: Analgesic effect of combination of lornoxicam and tramadol or lornoxicam applied alone was examined on female albino mice, using a hot plate method. Measurements were made 30, 60, 90 and 120 minutes after intraperitoneal and subcutaneous administration, in dose of 10 mg/kg. Results: Combination of lornoxicam and tramadol, applied intraperitoneally, increases the threshold of sensitivity to painful stimuli, which was not the case with subcutaneous administration. Conclusions: Lornoxicam significantly increases analgesic effect when applied intraperitoneally in combination with tramadol. On the other hand, lornoxicam in combination with tramadol, did not increase the threshold of sensitivity to painful stimuli with significant difference, after subcutaneous administration. [ABSTRACT FROM AUTHOR]

Abstract: Drug combinations have been used in clinical practice for the main purpose of increasing therapeutic effect efficacy. The aim of this study was to determine the antinociceptive effect of tramadol and caffeine administered separately or in combination, as well as their synergistic interaction. The formalin test was used. Nociceptive behavior was evaluated by flinching response of the formalin-treated paw. Rats were divided into five groups and received tramadol alone (4.9–49.6mg/kg, s.c.), caffeine alone (1–17.8mg/kg, p.o.), or combinations of tramadol (4.9, 8.8, 15.6 and 20.8mg/kg, s.c.) and caffeine (1, 3.16 and 10mg/kg, p.o.). Tramadol showed dose-dependent antinociceptive effect in both phases of the formalin test. Caffeine only presented antinociceptive effect in the second phase and this effect was also dose-dependent. In Phase 1, combinations of tramadol and caffeine showed antinociceptive effect similar to that of tramadol alone. In Phase 2, the dose–response curve shifted to the left with the combination of tramadol and each dose of caffeine. Synergism analysis resulted in synergistic effect in ten combinations and antagonism in two combinations. In conclusion, the synergism observed in the majority of tramadol and caffeine combinations used in this study suggests that this drug combination is useful in the treatment of pain. [ABSTRACT FROM AUTHOR]

Aim of the study: Zanthoxylum rhoifolium Lam. (Rutaceae) is locally known as “mamica de cadela”, and its bark is popularly used for toothache and earache. The objective of this study was to investigate the antinociceptive effect of the ethanolic extract from this species’ stem bark (EtOH), its fractions of partition (hexane—HEX, ethyl acetate—AcOEt, aqueous—AQ) and lupeol (a triterpene obtained from HEX) in models of acute pain. Materials and methods: Male and female Swiss mice (25–35g, n =6–12 animals/group) were used to assess acute toxicity and nociception (Animal Ethics Committee/UFPI, No. 09/2008). Acute toxicity was studied up to 2g/kg p.o. of EtOH. In the formalin test (2%, 20μL/paw), the licking time of the stimulated paw was quantified during the first 5min (first phase) and at 15–30min (second phase), 1h after oral treatment with EtOH, HEX, AcOEt or saline, and 30min after use of morphine—MOR (5mg/kg i.p.). The same response evoked by capsaicin (2μg/20μL/paw) was quantified during 5min, after administration of EtOH, HEX, AcOEt, AQ, saline and MOR. The licking time of the paw that was stimulated with glutamate (10μmol/20μL) was measured (15min) after treatment with EtOH, HEX, AcOEt, AQ, lupeol, saline or MK801 (0.03mg/kg, i.p.). Mice were submitted to the rota-rod task and open-field test in order to assess any non-specific muscle-relaxant or sedative effects of EtOH (250mg/kg p.o.) and HEX (500mg/kg p.o.). Results: The animals did not exhibit any acute toxicity to EtOH (up to 2g/kg p.o.), so it was not possible to calculate the LD50. EtOH, HEX and AcOEt (62.5–250mg/kg) produced a significant antinociceptive effect in the formalin and capsaicin tests. However, AQ was ineffective. EtOH, HEX, AcOEt and lupeol reduced the glutamate-evoked nociceptive response, but AQ had no effect. EtOH and HEX did not alter the locomotion of animals in the open-field or rota-rod tests, which suggest a lack of a central depressant effect. Conclusion: The results confirm the popular use of Zanthoxylum rhoifolium as an analgesic, and contribute to the pharmacological knowledge of this species because it was shown that EtOH and its less polar partition fractions (HEX, AcOEt) have an antinociceptive effect in models of chemical nociception, and that lupeol appears to be one of the constituents responsible for this effect. [Copyright &y& Elsevier]

Abstract: A polysaccharide (M w 2.39×104 g/mol) was extracted with cold water from the basidiomycete Pleurotus pulmonarius, and its antinociceptive and anti-inflammatory properties were evaluated. It was a mannogalactan (MG), whose structure was characterized using mono- and two-dimensional NMR spectroscopy, methylation analysis, and a controlled Smith degradation. It had a main chain of (1→6)-linked α-d-galactopyranosyl and 3-O-methyl-α-d-galactopyranosyl units, both of which are partially substituted at O-2 by β-d-mannopyranosyl non-reducing ends. The MG was tested for its effects on the acetic acid-induced writhing reaction in mice, a typical model for inflammatory pain, causing a marked and dose-dependent inhibition of the nociceptive response, with ID50 of 16.2 (14.7–17.7)mg/kg and inhibition of 93±3% at a dose of 30mg/kg. An inflammatory response was not inhibited. [Copyright &y& Elsevier]

The infusion of Brugmansia suaveolens, popularly known as trombeteira or cartucheira, has been used to treat pain in Brazil. The present study was conducted to test for its antinociceptive effects using the abdominal-writhing, formalin, tail-flick, and hot-plate tests in mice. The aqueous extract from B. suaveolens flowers administered intraperitoneally at doses of 100 and 300 mg/kg body weight significantly inhibited acetic acid-induced abdominal constrictions. An increase in hot-plate latency was also observed in animals receiving both doses (100 and 300 mg/kg). In the formalin test, both doses from the aqueous extract inhibited the first (0-5 min) and second phase (20-25 min). Tail-flick assays demonstrated that treatment of animals with plant extract induced attenuation of the response. These results suggest that the aqueous extract from B. suaveolens flowers produced antinociceptive effects, as demonstrated in the experimental models of nociception in mice. This supports popular medicinal uses of this plant as an analgesic. [ABSTRACT FROM AUTHOR]

Abstract: (±)-Pentazocine is widely used clinically to treat mild to moderate pain as a racemic compound. Although it is known that (−)-pentazocine acts as a kappa opioid receptor agonist to exhibit analgesic actions and (+)-pentazocine acts as a sigma receptor agonist without analgesic effects, their combined effect on memory has not been investigated in detail. In this study, the effect of (+)- and/or (−)-pentazocine on scopolamine-induced memory impairment in mice was investigated using spontaneous alternation performance in a Y-maze. (+)-Pentazocine (0.35 μmol/kg, s.c.) administered 30 min before behavioral testing significantly improved the impairment of spontaneous alternation induced by scopolamine. A higher dose of (−)-pentazocine (3.50 μmol/kg, s.c.) also reversed the scopolamine-induced impairment of alternation performance. Interestingly, the ameliorating effects of not only (+)-pentazocine, but also (−)-pentazocine were antagonized by a selective sigma receptor antagonist, N,N-dipropyl-2-[4-methoxy-3-(2-phenylenoxy)-phenyl]-ethylamine monohydrochloride (NE-100) (2.6 μmol/kg, i.p.). However, those effects were not antagonized by a selective kappa opioid receptor antagonist, nor-binaltorphimine (4.9 nmol/mouse, i.c.v.). Coadministration of (+)- and (−)-pentazocine (0.35 or 3.50 μmol/kg each) did not have any additive or antagonizing effects on the percent alternation. An antinociceptive effect was observed only with (−)-pentazocine (3.50 μmol/kg, s.c.), and was antagonized by nor-binaltorphimine (4.9 nmol/mouse, i.c.v.), but not by NE-100 (2.6 μmol/kg, i.p.). These results suggest that although the analgesic effect of pentazocine was mediated via kappa opioid receptors, the ameliorating effect on scopolamine-induced impairment of spontaneous alternation was mediated via sigma receptors, not via kappa opioid receptors. [Copyright &y& Elsevier]

Abstract: The antinociceptive effects of crude Fuzei, the root of Aconitum carmichaeli and of Fuzei processed by three different methods were determined in mice and rats using the light tail-flick assay. A dose-dependent and significant increase in pain threshold was found at 60min post treatment, with doses of 20–60mg/kg crude Fuzei. The analgesic effects of processed Fuzei (20–60mg/kg) exhibited a dose-dependent inhibition of tail-flick, but the effects were lower than those produced by crude Fuzei in the same tests. The analgesic effect of Yan-Fuzei, the salt baking product, was the most potent of the processed products and was nearly that provided by crude Fuzei. Although the concentrations of aconitine were significantly lower in the processed Fuzei than in the crude Fuzei, a higher oral LD50 was found for all of the processed Fuzei formulations. Moreover, antinociception of crude Fuzei and its processed products was attenuated but not totally blocked by naloxone at doses sufficient to block opioid μ-receptors. Furthermore, the analgesic effect of crude Fuzei and its processed products was decreased in opioid μ-receptor knockout mice, but the effect remained unaltered in mice with opioid μ-receptors, indicating that the analgesic effect of Fuzei is centrally mediated. These results demonstrate that Fuzei processed by salt baking possesses analgesic effects within a large therapeutic range, probably via a mechanism involving central opioid receptors that mediate the antinociception. [Copyright &y& Elsevier]

Due to their small size, lipid nanocapsules (LNC) might be promising for an injectable as well as for an oral drug delivery system, providing both sufficient drug solubility avoiding vessel embolisation for the intravenous injection and a positive effect of drug absorption after oral administration. Biocompatible ibuprofen LNC were developed in a size range of around 50 nm with a new preparation method. Drug incorporation into LNC was successful to a high degree in all formulations tested (94–98%) and the in vitro drug release in phosphate buffer occurred within 24 h. Pharmacokinetic data were recorded in vivo from rats after intravenous or oral administration, while the antinociceptive efficiency of the LNC formulation was compared with ibuprofen solution by the tail flick test. The AUC and half-life of intravenously injected ibuprofen LNC were found to be 16 and 19%, respectively, higher than a simple drug solution, while the mean residence time was not changed. Oral administration of LNC showed an 18% increase of AUC and a 27% higher mean residence time. The antinociceptive effect was similar for oral administration, drug solution, and LNC at 30 min after administration, and was prolonged up to 4 h in the LNC group. The pain relief after intravenous administration was prolonged when administering LNC formulation for at least 2 h. A drug delivery system for intravenous administration of ibuprofen has been developed which exhibits sustained release properties by either oral or intravenous route and may be interesting in the treatment of postoperative pain. [Copyright &y& Elsevier]

Objective. It has been hypothesized that serotonin reuptake inhibitor antidepressants (ADs) are only weakly antinociceptive but augment noradrenergic (NA) antinociception. Thus, ADs with combined serotonergic (SN) and NA activity, (i.e., the serotonergic/noradrenergic (SN/NA) ADs) should have greater antinociceptive activity versus the NA ADs, which in turn should have more antinociceptive activity than the SN ADs. The objective of this structured review was to test this hypothesis by reviewing relevant basic science literature on the treatment of experimental pain with the above different types of ADs. Design, Setting, Participants, Outcome, Measures. Animal or human experimental AD pain treatment studies were located by the usual search methods. For animal studies only placebo-controlled studies were included for review. For human studies only double blind placebo-controlled studies were selected for review. The animal and human studies were then sorted according to the pain model represented, e.g., neuropathic pain model. Studies were then characterized according to the type of AD utilized, and the antinociceptive outcome of the AD trial. Results. Twenty-two animal studies and 5 human studies fulfilled the inclusion criteria of this structured review. Within the animal nonspecific pain model there were 10 SN/NA AD trials, 9 NA AD trials and 7 SN AD trials. Of these trials 100%, 88.9%, and 14.3% respectfully demonstrated a positive AD antinociceptive effect. Overall, for all the animal models there were 25 SN/NA, 9 NA, and 8 SN trials. Of these trials 92%, 88.9%, and 25% respectfully demonstrated a positive AD antinociceptive effect. For the human pain models, only the SN/NA ADs had been utilized in 7 trials. Here in 42.8% of the trials there was a reported antinociceptive effect. Conclusions. Overall, the results of this structured review support the above hypothesis. [ABSTRACT FROM AUTHOR]

This study offers a novel oral pregabalin (PG)-loaded drug delivery system based on chitosan and hypromellose phthalate-based polymeric nanocomposite in order to treat neuropathic pain (PG-PN). PG-PN has a particle size of 432 ± 20 nm, a polydispersity index of 0.238 ± 0.001, a zeta potential of +19.0 ± 0.9 mV, a pH of 5.7 ± 0.06, and a spherical shape. Thermal and infrared spectroscopy confirmed nanocomposite generation. PG-PN pharmacokinetics was studied after a single oral dose in male Wistar rats. PG-PN showed greater distribution and clearance than free PG. The antinociceptive effect of PG-PN in neuropathic pain rats was tested by using the chronic constriction injury model. The parameter investigated was the mechanical nociceptive threshold measured by the von Frey filaments test; PG-PN showed a longer antinociceptive effect than free PG. The rota-rod and barbiturate sleep induction procedures were used to determine adverse effects; the criteria included motor deficit and sedative effects. PG-PN and free PG had plenty of motors. PG-PN exhibited a less sedative effect than free PG. By prolonging the antinociceptive effect and decreasing the unfavorable effects, polymeric nanocomposites with pregabalin have shown promise in treating neuropathic pain. [ABSTRACT FROM AUTHOR]

Cecropia Loefl. species (Urticaceae) are widely spread across the rainforest in tropical and subtropical regions of Central and South America. Inhabitants of different regions of Brazil employ leaves, fruits and sprouts of Cecropia hololeuca Miq. mainly as anti-inflammatory, anti-asthmatic, expectorant, fever suppressant, and against cough. To evaluate the antinociceptive and anti-inflammatory activities of an aqueous leaf extract of C. hololeuca in a murine model of zymosan-induced arthritis (ZIA) and characterize compounds contributing to these effects. The crude aqueous extract of C. hololeuca (CAE) was obtained by infusion, screened for antinociceptive and anti-inflammatory activities, and fractionated (solvent partition; RP-2 and Sephadex G-25 column chromatography), yielding fractions that were chemically and pharmacologically investigated. TLC, HPLC-DAD, HPLC-DAD-ESI-MS/MS and NMR analyses were peformed. The antinociceptive activity was assessed by means of acetic acid-induced writhing, hot-plate and rota-rod tests. ZIA was used to evaluate the anti-arthritic activity of oral treatment with CAE, butanolic (BF) and aqueous fraction (AF), as well as the fractions obtained from BF (F2, F2-A and F2–B). Rutin, a flavonoid found in C. hololeuca , was also tested. Mechanical hypernociception, joint edema, local neutrophil recruitment and articular TNF-α quantification were performed to measure the severity of arthritis and identify the anti-inflammatory potential of C. hololeuca. CAE (0.03–1 g/kg, p. o.) showed a dose-related inhibitory effect on acetic acid-induced writhing test, but did not change the pain latency in the hotplate test, nor the first fall time on the rota-rod test. In addition, CAE (1 g/kg, p. o.) inhibited by 65% the mechanical hypernociception, 46% the joint edema, 54% the neutrophil recruitment and 53% the articular TNF-α concentration levels in ZIA. BF (0.4 g/kg, p. o.), AF (0.6 g/kg), F2 (0.1 g/kg) and F2-A (0.045 g/kg), but not F2-B (0.055 g/kg), inhibited the mechanical hypernociception, joint edema and neutrophil recruitment in ZIA. Rutin (0.001–0.03 g/kg, p. o.) produced dose-related inhibitory effects in the mechanical hypernociception, joint edema and neutrophil recruitment, and at 0.03 g/kg also inhibited articular TNF-α synthesis after intra-articular zymosan injection. Isoorientin, isovitexin, rutin and isoquercitrin were identified in the most active fraction (F2-A), along with luteolin and apigenin derivatives, tentatively identified as isoorientin-2″- O -glucoside and isovitexin-2″- O -glucoside. This study corroborates the popular use by oral route of aqueous preparations of C. hololeuca against joint inflammatory disorders, such as rheumatoid arthritis. Our results demonstrated for the first time that oral administration of rutin shows antinociceptive and anti-inflammatory effects in ZIA, indicating that this flavonoid is one of the immunomodulatory compounds involved in the anti-arthritic activity of C. hololeuca. Image 1 [ABSTRACT FROM AUTHOR]

"Curcumae Radix", the dried rhizomes of Curcuma kwangsiensis documented in Chinese pharmacopoeia, has been traditionally used for the treatment of inflammatory and pain diseases, such as jaundice and red urine, cleaning the heart-fire and depression, arthralgia, and dysmenorrhea. However, according to literature surveys, anti-inflammatory and antinociceptive studies of C. kwangsiensis have been seldom reported so far. The current study focuses on the anti-inflammatory and antinociceptive effects of C. kwangsiensis and discovering the bioactive compounds for its traditional usages both in vivo and in vitro , which could provide scientific justification about its traditional use. The anti-inflammatory and antinociceptive assays of various layers (ME, EA, AQS) from C. kwangsiensis were achieved by carrageenan-induced paw edema and acetic acid-induced writhing animal models, respectively. The most bioactive part, EA layer was further phytochemically investigated by multiple step chromatography techniques. The structures of these isolates were unambiguously elucidated by means of extensive spectroscopic and chemical methods, and comparison with corresponding data of the reported literature. Four major sesquiterpenoids (4 , 6 , 14 , and 15) were achieved for their anti-inflammatory and antinociceptive assays by the two aforementioned animal models in vivo. All the isolated compounds were evaluated for their anti-inflammatory effects via detecting inflammatory mediator releases (COX-2, IL-1 β , and TNF- α) in RAW 264.7 macrophage cells induced by LPS. The ME and EA layers significantly alleviated the paw edema caused by carrageenan and decreased the number of writhes induced by acetic acid at the dose of 200 and/or 100 mg/kg in comparison to the control group (p < 0.01 / 0.05), and the EA layer exhibited better activity than that of ME layer. Subsequent phytochemical investigation on EA layer of C. kwangsiensis exhibited that three new terpenoid compounds (1 – 3), identified as (12 Z ,14 R)-7 β -hydroxylabda-8(17),12-diene-14,15,16-triol (1), (12 Z ,14 S)- 7 β -hydroxlabda-8(17),12-diene-14,15,16-triol (2), and (4 S)-hydroxy-(8)-methoxy-(5 S)-(H)-guaia1(10),7(11)-dien-12,8-olide (3), together with twenty-two known analogs were isolated. Furthermore, four major sesquiterpenoids (4 , 6 , 14 , and 15) significantly relieved the paw edema and number of writhes at 100 and/or 50 mg/kg (p < 0.05/0.01). Likewise, the majority of sesqui- and diterpenoids isolated could remarkably inhibited the secretion of inflammatory mediators (COX-2, IL-1 β , and TNF- α) in LPS-stimulated RAW 264.7 macrophages cells at the concentration of 20 μ g/mL, comparable to DXM used as the positive control. All the results suggested that EA layer from C. kwangsiensis possessed the anti-inflammatory and antinociceptive activities, and these sesqui- and diterpenoids could be the effective constituents responsible for relieving inflammation. The present studies undoubtedly determined the anti-inflammatory and antinociceptive material basis of C. kwangsiensis , including the EA layer and its precise components, which presented equivalent or better anti-inflammatory effects than that of positive control (ASP/DXM) in vivo and in vitro. These results not only would account for scientific knowledge for traditional use of C. kwangsiensis , but also provide credible theoretical foundation for the further development of anti-inflammatory and antinociceptive agents. Image 1 [ABSTRACT FROM AUTHOR]