Capsaicin-induced Nociception Research Articles

Anti-Inflammatory, Antinociceptive, and LC-MS Metabolic Profile from Pseudotrimezia juncifolia (Klatt) Lovo & A. Gil.

Pseudotrimezia juncifolia (Klatt) Lovo & A. Gil (Iridaceae) is a popularly known species with primarily ornamental economic interest. It has traditional uses as purgative, in conditions related to the menstrual cycle, for blood purification, as wound healing, and as anti-inflammatory. The anti-inflammatory and antinociceptive activities of the decoction from its aerial stems, corms, and stamens are described here with dereplication studies on LC-MS/MS supported by the GNPS platform, where phenolic compounds were annotated and correlated with its biological activity. The decoction was evaluated in chemical (formalin and capsaicin) and thermal (hot plate) induced nociception or carrageenan-induced inflammation in mice. Decoction (at 10, 30, or 100 mg/kg doses) significantly reduced formalin- or capsaicin-induced nociception. All doses also demonstrated an antinociceptive effect in the hot plate model increasing the time the animal spent in responding to thermal signal. Naloxone partially reversed the antinociceptive effect. An anti-inflammatory effect was observed since a reduction in cell migration, protein extravasation interleukin-1, and tumor necrosis factor production induced by carrageenan in the subcutaneous air pouch was quantified. Metabolomic analyses showed a predominance of phenolic substances, mainly flavonoids and chlorogenic acids. The literature showed that these two groups have significant anti-inflammatory and analgesic activity, and chemical data corroborate the pharmacological results observed.

5-Alkoxy-1-aryl-3-polyfluoroalkylpyrazoles with Antinociceptive Activity: Partial Agonists of TRPV1 Ion Channels.

Chemoselective O-alkylation of 1-aryl-3-polyfluoroalkylpyrazol-5-oles under basic conditions resulted in a series of 5-alkoxypyrazoles (26 derivatives). They showed an acceptable ADME profile (in silico) and can be considered as drug-like. In experiments in vivo (CD-1 mice), it was found that the obtained compounds do not have toxic properties at a dose of more than 150 mg/kg (for most compounds at a dose of >300 mg/kg, and for lead compounds - >600 mg/kg). 22 Compounds from this series demonstrated from moderate to high analgesic effects (28-104 % at 1 h and 37-109 % at 2 h after administration) in vivo in the hot plate test (SD rats, 15 mg/kg, intraperitoneal (ip)). The lead compound was 4-([1-phenyl-3-(trifluoromethyl)pyrazol-5-yl]oxy)butan-1-ol, which not only increased the latent period in the hot plate test by 103 % at both measurement points but also showed a pronounced analgesic effect under conditions of capsaicin-induced nociception (CD-1 mice, 15 mg/kg, ip). According to molecular modeling, all synthesized compounds can interact with the TRPV1 ion channel. This biological target was confirmed in in vitro experiments on Chinese hamster ovary cells expressing rTRPV1. 5-Alkoxypyrazoles were partial agonists of the TRPV1 ion channel in various degree, and the most active was the same pyrazole as in in vivo tests.

Antinociceptive and anti-inflammatory effect of a standardized fraction of Oenothera rosea L'Hér. ex Aiton and its possible mechanism of action in mice.

Objective:This study was conducted to investigate the antinociceptive and anti-inflammatory effect of ethyl acetate fraction of Oenothera rosea (EAOr) and the mechanism involved, in mice.Materials and Methods:The antinociceptive activity was tested using chemical- and heat-induced nociception models. The anti-inflammatory activity was tested using carrageenan-induced edema and inflammatory cytokines were measured.Results:EAOr reduced the licking time on the second phase of the formalin test (100 and 177 mg/kg). The antinociception of EAOr was prevented by L-NAME (10 mg/kg), 1H-[1, 2, 4]-oxadiazolo [4, 3-a]-quinoxalin-1-one (ODQ, 0.1 mg/kg), glibenclamide (10 mg/kg) and bicuculline (1 mg/kg), but not by naloxone (2 mg/kg). Also, EAOr decreased licking time in capsaicin induced-nociception. EAOr did not have effect on withdrawal latency in tail-flick test. Carrageenan-induced paw edema was reduced by EAOr, and TNF-α and IL-1β levels were reduced in mice treated with EAOr by 72.2 and 32.8%, respectively. Furthermore, EAOr did not present side effects as sedation nor gastric injury. Chemical analysis of this fraction showed the presence of glycosylated quercetin derivatives such as quercetin glucoside and quercetin rhamnoside in a 2.5% concentration.Conclusion:This study demonstrates antinociceptive and anti-inflammatory effect of an organic fraction of O. rosea and its possible interaction with the NO-cGMP-K+ channels and GABAergic system and thus, it could be considered a therapeutic alternative.

Evaluation of the systemic and spinal antinociceptive effect of a new hybrid NSAID tetrahydropyran derivative.

Pain is responsible for inducing physical and mental stress, interfering negatively in patients' quality of life. Classic analgesic drugs, such as opioids and non-steroidal anti-inflammatory drugs, are known for their wide range of adverse effects, making it important to develop new drugs. Thus, this study aimed to analyse the action of the hybrid compound cis- (±) -acetate of 4-chloro-6- (naphthalene-1-yl) -tetrahydro-2h-pyran -2-yl) methyl2- (2- [2,6-dichlorophenylamine] phenyl (LS19) under acute nociceptive conditions, and deepened the understanding of the responsible mechanisms. Male Swiss mice were evaluated in the acetic acid-induced abdominal writhing, formalin, tail flick, capsaicin- and glutamate-induced nociception, thermal stimulation in animals injected with capsaicin and rotarod tests besides the acute and subchronic toxicological evaluation. The compound showed effect on the acetic acid-induced abdominal writhing, formalin (both phases), tail flick, thermal stimulation in animals injected with capsaicin and capsaicin-induced nociception tests. In the study of the mechanism of action was observed reversion of the antihyperalgesic effect of the compound from the previous intraperitoneal and intrathecal administration of naloxone, nor-binaltorphimine, naltrindole, methylnaltrexone, 7-nitroindazole, L-NAME, ODQ, glibenclamide on the tail flick test. In the thermal stimulation in animals injected with capsaicin, the compound showed antinociceptive effect by oral and intraplantar routes, besides to reducing the levels of TNF-α, IL-1β and PGE2 in the paws previously administered with capsaicin. There were no signs of acute and subchronic intoxication with the compound. In summary, the compound LS19 presented spinal and local antihyperalgesic effect, demonstrating participation of the opioid/NO/cGMP/K+ ATP pathway and TRPV1 receptors and it demonstrated safety in its use in mice.

Mechanisms involved in the antinociceptive and anti-inflammatory effects of a new triazole derivative: 5-[1-(4-fluorophenyl)-1H-1,2,3-triazol-4-yl]-1H-tetrazole (LQFM-096).

The aim of this study was to design, synthesize and evaluate the potential analgesic and anti-inflammatory effects of 5-[1-(4-fluorphenyl)-1H-1,2,3-triazol-4-yl]-1H-tetrazole-(LQFM-096: a new triazole compound) as well as to elucidate its possible mechanisms of action. The oral administration of LQFM-096 (10, 20 or 40mg/kg) decreased the number of writhing in mice. At the dose of 20mg/kg, LQFM-096 reduced the licking time at both neurogenic and inflammatory phases of the formalin test. Pretreatment with naloxone (3mg/kg) and glibenclamide (3mg/kg) attenuated the antinociceptive effect of LQFM-096 in the first phase of the formalin test. At the dose of 20mg/kg, LQFM-096 also decreased the licking time in the acidified saline-induced and capsaicin-induced nociception. This effect was blocked by naloxone (3mg/kg) pretreatment prior to the administration of LQFM-096. In addition, LQFM-096 inhibited hyperalgesia induced by carrageenan and PGE2. Naloxone (3mg/kg) attenuated the effect of LQFM-096 through disinhibition of PGE2-induced hyperalgesia. The anti-inflammatory effect of LQFM-096 was demonstrated in carrageenan-induced oedema or pleurisy as well as CFA-induced arthritis. The hyperalgesia and cellular migration in CFA-induced arthritis were reduced significantly. Altogether, these findings suggest antinociceptive effect of LQFM-096 and implicate the modulation of ASICs/TRPV1 channels by opioid/KATP pathway. The anti-inflammatory effect of LQFM-096 was mediated by a reduction in oedema, leukocytes migration, TNF-α, PGE2 levels and myeloperoxidase activity.

Stephalagine, an aporphine alkaloid from Annona crassiflora fruit peel, induces antinociceptive effects by TRPA1 and TRPV1 channels modulation in mice

Pain relief represents a critical unresolved medical need. Consequently, the search for new analgesic agents is intensively studied. Annona crassiflora, a native species of the Brazilian Savanna, represents a potential source for painful treatment. This study aimed to investigate the antinociceptive potential of A. crassiflora fruit peel, focusing on its major alkaloid, stephalagine, in animal models of pain evoked by the activation of transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) channels. Male C57BL/6/J mice were submitted to formalin-, cinnamaldehyde-, and capsaicin-induced nociception tests to assess nociceptive behavior, and to the open-field and rotarod tests for motor performance analyses. Moreover, the stephalagine's effect was tested on capsaicin- and cinnamaldehyde-induced Ca2+ influx in spinal cord synaptosomes. In silico assessments of the absorption, distribution, metabolism and central nervous system permeability of stephalagine were carried out. The ethanol extract and alkaloidal fraction reduced the nociception induced by formalin. When administered by oral route (1mg/kg), stephalagine reduced the spontaneous nociception and paw edema induced by TRPV1 agonist, capsaicin, and by TRPA1 agonists, cinnamaldehyde- and formalin, without altering the animals' locomotor activity. The prediction of in silico pharmacokinetic properties of stephalagine suggests its capacity to cross the blood-brain barrier. Furthermore, this alkaloid reduces the capsaicin- and cinnamaldehyde-mediated Ca2+ influx, indicating a possible modulation of TRPV1 and TRPA1 channels, respectively. Together, our results support the antinociceptive and anti-edematogenic effects of the A. crassiflora fruit peel and suggest that these effects are triggered, at least in part, by TRPV1 and TRPA1 modulation by stephalagine.

Early Phase of Type 1 Diabetes Decreases the Responsiveness of C-Fiber Nociceptors in the Temporomandibular Joint of Rats

Diabetes is a chronic degenerative disease that represent a major threat to public health worldwide. Once the disease is established, one of the major concerns about the diabetes complications is the development of neuropathy. This study established an experimental model that evaluates the effect of type 1 diabetes on nociceptive challenges in the temporomandibular joint (TMJ). Streptozotocin-induced type 1 (STZ 75 mg/Kg) diabetes inhibited the responsiveness of C-fibers nociceptors located in the TMJ of Wistar rats since seventh day after the disease induction. Diabetes-induced hyporesponsiveness of C-fibers nociceptors was associated with significantly reduction of protein level of neuropeptides Substance P and Calcitonin Gene Related Peptide. Diabetic animals pre-treated with Protein Kinase C (PKC)-α and -β inhibitor (GO6976) or PKC-β inhibitor (LY333531) significantly increased capsaicin-induced nociception in the TMJ higher protein levels of Na+/K+-ATPase pump in the trigeminal ganglia. On the other hand, although diabetes inhibits formalin-induced nociception higher protein levels of pro-inflammatory cytokine IL1-β and chemokine CINC-1/CXCL-1 were observed. Overall, the results of the present work suggest that diabetes causes a hyporesponsiveness of C-fiber and a potentialization of the inflammatory response which may result in the degenerative process of periarticular tissues without pain perception.

The effect of central administration of alpha-pinene on capsaicin-induced dental pulp nociception.

To assess the effects of central administration of α-pinene alone and in combination with either bicuculline or naloxone, as GABAA and μ-opioid receptor antagonists, respectively, on capsaicin-induced dental pulp stimulation in rats. Forty-eight adult male Wistar rats aged 2months (230-270g) were cannulated via their lateral ventricles for the central administration of the drugs. α-Pinene was injected at 0.1, 0.2 and 0.4μmolL-1 . Then, dental pulp stimulation was induced by intradental application of capsaicin solution (100μg), and nociceptive scores were recorded for up to 40min. For investigation of the anti-inflammatory effects of α-pinene, expression of COX-2 in the subnucleolus caudalis (Vc) of rats was determined using immunofluorescence staining. Nonparametric repeated measure Friedman and Kruskal-Wallis tests as well as parametric one-way analysis of variance were used for the statistical analysis. α-Pinene at 0.2 and 0.4μmolL-1 was able to decrease capsaicin-induced nociception. Moreover, there was a significant increase in the expression of COX-2-positive cells in the Vc of capsaicin-treated rats (P<0.01). This effect was prohibited by α-pinene (0.4μmolL-1 ). Co-administration of bicuculline (1μg per rat) or naloxone (6μg per rat) with α-pinene (0.4μmolL-1 ), however, prevented the inhibitory effects of α-pinene on both capsaicin-induced pulp nociception and COX-2 over-expression. Pinene exhibited significant curable effects on capsaicin-induced pulpal nociception and inflammation mainly via pharmacological interfacing with GABAA and μ-opioid receptors.

Evaluation of the antinociceptive and anti-inflammatory activities of piperic acid: Involvement of the cholinergic and vanilloid systems

Piperin is the active compound of black pepper (Piper nigrum). From the piperine was obtained the molecule of the piperic acid (PAC). The objective of this study was to evaluate the antinociceptive and anti-inflammatory of the compound. The antinociceptive effects of PAC were evaluated by abdominal writhing, formalin, capsaicin and tail-flick tests; while the anti-inflammatory effects were evaluated by paw oedema and air pouch tests, and in vitro COX inhibition assay. The possible action mechanism of PAC was evaluated using naloxone, L-NAME, glibenclamide and atropine in tail flick test and by Cholinesterase activity assay and production of TNF-α and IL-1β. PAC significantly reduced the nociceptive effects induced by acetic acid or formalin in mice. PAC also demonstrated an antinociceptive effect in the tail-flick model. The muscarinic receptor antagonist, atropine reduced the antinociceptive effect of PAC in the tail-flick model. PAC was able to inhibit capsaicin-induced nociception, showing involvement of TRPV1. The compound did not alter the motor capacity of the animals, not interfering in the nociceptive response. PAC also showed anti- inflammatory activity by inhibiting the formation of carrageenan-induced paw oedema, leukocyte migration, and cytokine production / release. Atropine reduced the activity of PAC on leukocyte migration, and cytokine production. The compound showed to be able to reduce the cytokine production stimulated by capsaicin. PAC inhibited the COX activity. The results presented suggest that the possible cholinomimetic action and vanilloid agonist of the piperic acid may be responsible by antinociceptive and anti- inflammatory effects; these effects are devoid of toxicity.

Inflammation induces Epac-protein kinase C alpha and epsilon signaling in TRPV1-mediated hyperalgesia.

The exchange proteins activated by cAMP (Epacs) have been shown to play important roles in producing inflammation-induced nociception. Transient receptor potential vanilloid type 1 (TRPV1) is a major receptor processing thermal and chemosensitive nociceptive information. The role of Epacs in modulating the activity of TRPV1 has yet to be determined. Studying the effect of complete Freund adjuvant (CFA)-induced inflammation on capsaicin-activated TRPV1 nociceptive responses in dorsal root ganglia (DRG), we found that CFA produced a large increase in capsaicin-induced responses. The increase was inhibited by Epac1 and Epac2 antagonists. Thus, activation of Epacs is critical in producing enhancement in TRPV1-mediated responses under inflammatory conditions. In addition, the inflammation-induced enhancement of TRPV1 responses was blocked by PKCα and PKCε inhibitors, suggesting the essential roles of these PKCs in enhancing TRPV1 responses. To determine the mechanism underlying the Epac actions on TRPV1, we studied the effects of the Epac activator, 8-(4-chlorophenylthio)-2-O-methyl-cAMP (CPT), on capsaicin-induced nociceptive behavioral responses, capsaicin-activated currents, expression and membrane trafficking of PKC and TRPV1 in DRG. CPT was found to enhance capsaicin-induced nociception and ionic currents. The enhancement was inhibited by PKCα and PKCε inhibitors. In addition, CPT increased the expression of phosphorylated PKCα (pPKCα) and membrane TRPV1 expression in DRG. Studying the colocalization of TRPV1 and pPKCα or pPKCε in DRG slices prepared from CFA-treated rats, we found that pPKCα or pPKCε expressed with TRPV1 in different-sized neurons to exert differential influences on TRPV1 activity. Thus, Epac-PKC signaling is critically important in producing inflammation-induced potentiation of TRPV1 functions.

Oxytocin Modulates Nociception as an Agonist of Pain-Sensing TRPV1

Oxytocin is a hormone with various actions. Oxytocin-containing parvocellular neurons project to the brainstem and spinal cord. Oxytocin release from these neurons suppresses nociception of inflammatory pain, the molecular mechanism of which remains unclear. Here, we report that the noxious stimulus receptor TRPV1 is an ionotropic oxytocin receptor. Oxytocin elicits TRPV1 activity in native and heterologous expression systems, regardless of the presence of the classical oxytocin receptor. In TRPV1 knockout mice, DRG neurons exhibit reduced oxytocin sensitivity relative to controls, and oxytocin injections significantly attenuate capsaicin-induced nociception in invivo experiments. Furthermore, oxytocin potentiates TRPV1 in planar lipid bilayers, supporting a direct agonistic action. Molecular modeling and simulation experiments provide insight into oxytocin-TRPV1 interactions, which resemble DkTx. Together, our findings suggest the existence of endogenous regulatory pathways that modulate nociception via direct action of oxytocin on TRPV1, implying its analgesic effect via channel desensitization.

D-limonene exhibits superior antihyperalgesic effects in a β-cyclodextrin-complexed form in chronic musculoskeletal pain reducing Fos protein expression on spinal cord in mice

Chronic musculoskeletal pain is one of the main symptoms found in Fibromyalgia with unclear etiology and limited pharmacological treatment. The aim of this study was to complex LIM in β-cyclodextrin (LIM-βCD) and then evaluate its antihyperalgesic effect in an animal model of chronic musculoskeletal pain. Differential scanning calorimetry and scanning electron microscopy was used for the characterization of the inclusion complex. Male Swiss mice were used for experimental procedures where mechanical hyperalgesia, thermal hyperalgesia, muscular strength, Fos immunofluorescence was studied after induction of hyperalgesia. Mechanism of action was also investigated through tail flick test and capsaicin-induced nociception. Endothermic events and morphological changes showed that the slurry complex method was the best method for the complexation. After induction of hyperalgesia, the oral administration of LIM-βCD (50mg/kg) significantly increased the paw withdrawal threshold compared to uncomplexed limonene. Fos immunofluorescence showed that both compounds significantly decreased the number of Fos-positive cells in the dorsal horn. In nociceptive tests, FLU was able to reverse the antinociceptive effect of LIM-βCD. After intraplantar administration of capsaicin, LIM was able to significantly decrease time to lick. LIM-βCD has antihyperalgesic action superior to its uncomplexed form, with possible action in the dorsal horn of the spinal cord. These results suggest the possible applicability of LIM, uncomplexed or complexed with βCD, in conditions such as FM and neuropathic pain, for which there are currently only limited pharmacological options.

Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity.

Because of its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors [ Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation . WO 2014201206, 2014 ] of NaV1.7, which demonstrate nanomolar inhibition of NaV1.7 and exhibit high levels of selectivity over other sodium channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound 39 (AM-0466) demonstrated robust pharmacodynamic activity in a NaV1.7-dependent model of histamine-induced pruritus (itch) and additionally in a capsaicin-induced nociception model of pain without any confounding effect in open-field activity.

Anti-nociceptive effect of total alkaloids isolated from the seeds of Areca catechu L (Arecaceae) in mice

Purpose : To investigate the antinociceptive effect of the total alkaloids (TA) isolated from the seeds of Areca catechu L . (SAC) and to elucidate the probable mechanism of action. Methods : TA extraction conditions including concentration of ethanol, extraction temperature, liquid–solid ratio and designed pH were optimized by an orthogonal experiment {L9(3)4} test. The antinociceptive effect of the extract in mice was evaluated by acetic acid writhing reflex test, hot plate test, capsaicin-induced nociception test, tail-flick test and formalin-induced pain test in mice. Furthermore, pretreatment of the animals with naloxone (2 mg/kg) was performed to investigate whether the antinociceptive effect involved the opioid route or not. The locomotor activity of TA in mice were also assessed. Results : The optimum extraction conditions of TA were as follows: solid-liquid ratio of 1: 15 (w/v), ethanol concentration of 80 %, pH of 9.0 and extraction temperature of 70°C. Oral administration of TA produced a marked anti-nociceptive activity in mice, and pretreatment with naloxone did not reverse the anti-nociceptive activity of TA in mice. Also, the locomotor activity of mice was not affected by TA. In addition, TA significantly down-regulated the expression levels of COX-2 in the dorsal root of mice spinal cord at 100, 200 and 400 mg/kg doses. Conclusion : The results demonstrate that TA possesses significant anti-nociceptive effects, and the mechanisms are closely related to suppression of COX-2 expression. Overall, the results provided scientific support for the use of TA in treatment of pain. Keywords : Areca catechu , Total alkaloids, Anti-nociceptive, Formalin-induced pain, Naloxone

Mother root of Aconitum carmichaelii Debeaux exerts antinociceptive effect in Complet Freund's Adjuvant-induced mice: roles of dynorpin/kappa-opioid system and transient receptor potential vanilloid type-1 ion channel.

BackgroundProcessed Chuanwu (PCW), the mother root of Aconitum carmichaeliiDebeauxv, has been widely used as a classic Traditional Chinese Medicine for pain relieve for over two millennia clinically. However, its action on chronic inflammatory pain has not been clarified. Here, we investigated the antinociceptive effect of PCW in complete freund’s adjuvant (CFA)-induced mice and its possible mechanisms associated with opioid system and TRPV1 ion channel.MethodsMale ICR mice were intraplantarly injected with CFA. PCW (0.34, 0.68 and 1.35 g/kg) was orally given to mice once a day for 7 days. Von frey hairs and planter test were assessed to evaluate the antinociceptive effect of PCW. To investigate the participation of dynorphin/opioid system in PCW antinociception, subtype-specific opioid receptor antagonists or anti-dynorphin A antiserum were used. To eliminate other central mechanisms that contribute to PCW antinociception, hot plate (50 °C) test were performed. Further, involvements of TRPV1 in PCW antinociception were evaluated in CFA-induced TRPV1−/− and TRPV1+/+ C57BL/6 male mice, and in capsaicin-induced nociception ICR naive mice pretreated with nor-BNI. Meanwhile, calcium imaging was performed in HEK293T-TRPV1 cells. Finally, rotarod, open-field tests and body temperature measurement were carried out to assess side effects of PCW.ResultsPCW dose-dependently attenuated mechanical and heat hypersensitivities with no tolerance, which could be partially attenuated by coadministration of k-opioid receptor antagonist nor-binaltorphimine (nor-BNI) or anti-dynorphin A (1–13) antiserum. And PCW antinociception was totally erased by pretreatment with nor-BNI in the hot plate test. In addition, PCW antinociception was decreased in TRPV1−/− mice compared to TRPV1+/+ group. And PCW still manifested inhibitory effects in capsaicin-induced nociception with nor-BNI pretreatment. PCW significantly inhibited capsaicin-induced calcium influx in HEK293T-TRPV1 cells. Finally, no detectable side effects were found in naive mice treated with PCW.ConclusionsThis study shows PCW’s potent antinociceptive effect in inflammatory conditions without obvious side effects. This effect may result from the activation of κ-opioid receptor via dynorpin release and the inhibition of TRPV1. These findings indicate that PCW might be a potential agent for the management of chronic inflammatory pain.

TRPV1 channel inhibition contributes to the antinociceptive effects of Croton macrostachyus extract in mice.

BackgroundPrevious study showed that extracts from Croton macrostachyus (Euphorbiaceae) exhibit analgesic effects in acute pain models. The present study evaluates the antinociceptive properties of the methanol/methylene chloride extract (MECM) of the stem bark of this plant using mice models of persistent inflammatory and neuropathic pain, and assesses its mechanism of action.MethodsMECM was tested on Complete Freund adjuvant (CFA)-induced persistent thermal and mechanical pain, neuropathic pain induced by partial sciatic nerve ligation (PSNL), prostaglandin E2 (PGE2)-induced acute mechanical hyperalgesia, as well as on nociception induced by capsaicin in mice. Mechanical hyperalgesia was assessed using von Frey hair in awake mice. The mechanism of action of MECM was evaluated by using glibenclamide on PGE2-induced hyperalgesia or rimonabant on capsaicin-induced pain.ResultsMECM administered orally at the doses of 250 and 500 mg/kg, induced long lasting and significant antihyperalgesic effects on CFA-inflammatory and PSNL-induced neuropathic pain. MECM significantly reduced the mechanical hyperalgesia induced by PGE2 either when administered preventively or therapeutically. MECM also significantly and time dependently inhibited the capsaicin-induced nociception. These effects were not affected by glibenclamide or by rimonabant.ConclusionsThe present results demonstrate that the oral administration of MECM to mice resulted in long lasting antihyperalgesic activity in inflammatory and neuropathic pain as well as in acute and persistent pain. The mechanism underlying the long lasting MECM antihyperalgesic effect is currently unknown, but might be mediated, at least partially, through the modulation of TRPV1 receptors.

Evaluation of Anti‐inflammatory and Analgesic Effects of Synthesized Derivatives of Ibuprofen

Inflammatory and pain are major areas for drug discovery. Current analgesic drugs often cause a number of side-effects. In the present study, we modified carboxylic acid group of ibuprofen, one of non-steroidal anti-inflammatory drugs, based on the common structure of transient receptor potential vanilloid type 1 antagonists which are considered as new candidates for analgesic drugs, and synthesized several derivatives of ibuprofen. Comprehensive evaluations of the pharmacological properties of these compounds were investigated. Compound 17 showed weak cyclooxygenase inhibition and exhibited strong transient receptor potential vanilloid type 1 antagonistic activity. It was found to be capable of blocking noxious thermal nociception and capsaicin-induced nociception in mice. Besides, 17 showed less ulcerogenic action than ibuprofen did and had no hyperthermia side-effect compared with common transient receptor potential vanilloid type 1 antagonists. Therefore, it suggested that 17 could be used as a safe alternative analgesic candidate for pain treatment.

Inhibitory Effects of Capsaicin on Voltage-Gated Potassium Channels by TRPV1-Independent Pathway

Previously we observed that capsaicin, a transient receptor potential vanilloid 1 (TRPV1) receptor activator, inhibited transient potassium current (IA) in capsaicin-sensitive and capsaicin-insensitive trigeminal ganglion (TG) neurons from rats. It suggested that the inhibitory effects of capsaicin on IA have two different mechanisms: TRPV1-dependent and TRPV1-independent pathways. The main purpose of this study is to further investigate the TRPV1-independent effects of capsaicin on voltage-gated potassium channels (VGPCs). Whole cell patch-clamp technique was used to record IA and sustained potassium current (IK) in cultured TG neurons from trpv1 knockout (TRPV1(-/-)) mice. We found that capsaicin reversibly inhibited IA and IK in a dose-dependent manner. Capsaicin (30 μM) did not alter the activation curve of IA and IK but shifted the inactivation-voltage curve to hyperpolarizing direction, thereby increasing the number of inactivated VGPCs at the resting potential. Administrations of high concentrations capsaicin, no use-dependent block, and delay of recovery time course were found on IK and IA. Moreover, forskolin, an adenylate cyclase agonist, selectively decreased the inhibitory effects of IK by capsaicin, whereas none influenced the inhibitions of IA. These results suggest that capsaicin inhibits the VGPCs through TRPV1-independent and PKA-dependent mechanisms, which may contribute to the capsaicin-induced nociception.

Antioedematous and Analgesic Properties of Fertile Fronds of Drynaria quercifolia

Inflammation is a complex biological response of tissue cells to harmful stimuli including trauma, tissue necrosis, and infections which plays a key role in the pathophysiology of many deadly diseases. In ethnomedicine Drynaria quercifolia fronds are used to treat inflammation as poultice on swellings and as antibacterial, hepatoprotective, and antipyretic agent. Herein, we have evaluated the antioedematous, antiproliferative, and analgesic properties of the ethanolic extract of fertile fronds of D. quercifolia (FF) by standard procedures. Oral administration of FF produced significant inhibition of carrageenan and histamine induced paw oedema in Wistar rats. FF significantly reduced both wet weight and dry weight of granuloma tissue which shows the inhibitory effect on exudative and proliferative phases of inflammation. FF significantly attenuated acute and delayed phases of formalin induced pain, acetic acid-induced writhing, capsaicin-induced nociception, and hot plate test in mice. Phytochemical analysis revealed the presence of coumarins, flavonoids, glycosides, phenolics, saponins, steroids, tannins, and terpenoids. Total phenolic content was 186 mg/g equivalent of gallic acid. The HPLC estimation showed flavanone glycoside naringin (1.2%) and its aglycone naringenin (0.02%). The presence of potent anti-inflammatory and analgesic principles in FF and their synergistic action may be the reason for the proposed therapeutic effects.

Evidence for the Analgesic Activity of Resveratrol in Acute Models of Nociception in Mice

The effects of trans-resveratrol (1) were evaluated in acute nociception models induced by capsaicin or glutamate in mice, in an attempt to further characterize its mechanism of action. The oral administration of 1 (50 and 100 mg/kg) reduced significantly the licking behavior elicited by capsaicin (1.6 μg/paw) or glutamate (10 μmol/paw). The co-administration of 1 into the mouse paw (200 μg/site) markedly prevented glutamate-induced licking, without affecting capsaicin responses. In addition, the intrathecal (it) injection of 1 (150 to 600 μg/site) greatly reduced the licking behavior caused by capsaicin, but not glutamate. Similarly, the intracerebroventricular injection of 1 (300 μg/site) caused a potent inhibition of capsaicin-induced nociception, while the glutamate responses remained unaffected. However, the co-administration of 1 (300 μg/site) reduced the biting behavior induced by spinal injection of glutamate (30 μg/site, it), leaving capsaicin (6.4 μg/site)-induced biting unaltered. Notably, the oral administration of 1 (100 mg/kg) inhibited significantly the capsaicin-induced increase of c-Fos and COX-2 labeling in the spinal cord and COX-2 expression in the cortex, but failed to affect c-Fos and COX-2 expression in the glutamate model. This study has explored the effects of 1 in both the capsaicin and glutamate models, extending current knowledge on the analgesic effects of trans-resveratrol.