oxadiazoles has been researched along with Pain* in 43 studies
2 trial(s) available for oxadiazoles and Pain
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Opicapone versus placebo in the treatment of Parkinson's disease patients with end-of-dose motor fluctuation-associated pain: rationale and design of the randomised, double-blind OCEAN (OpiCapone Effect on motor fluctuations and pAiN) trial.
Optimisation of dopaminergic therapy may alleviate fluctuation-related pain in Parkinson's disease (PD). Opicapone (OPC) is a third-generation, once-daily catechol-O-methyltransferase inhibitor shown to be generally well tolerated and efficacious in reducing OFF-time in two pivotal trials in patients with PD and end-of-dose motor fluctuations. The OpiCapone Effect on motor fluctuations and pAiN (OCEAN) trial aims to investigate the efficacy of OPC 50 mg in PD patients with end-of-dose motor fluctuations and associated pain, when administered as adjunctive therapy to existing treatment with levodopa/dopa decarboxylase inhibitor (DDCi).. OCEAN is a Phase IV, international, multicentre, randomised, double-blind, placebo-controlled, parallel-group, interventional trial in PD patients with end-of-dose motor fluctuations and associated pain. It consists of a 1-week screening period, 24-week double-blind treatment period and 2-week follow-up period. Eligible patients will be randomised 1:1 to OPC 50 mg or placebo once daily while continuing current treatment with levodopa/DDCi and other chronic, stable anti-PD and/or analgesic treatments. The primary efficacy endpoint is change from baseline in Domain 3 (fluctuation-related pain) of the King's Parkinson's disease Pain Scale (KPPS). The key secondary efficacy endpoint is change from baseline in Domain B (anxiety) of the Movement Disorder Society-sponsored Non-Motor rating Scale (MDS-NMS). Additional secondary efficacy assessments include other domains and total scores of the KPPS and MDS-NMS, the Parkinson's Disease Questionnaire (PDQ-8), the MDS-sponsored Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts III and IV, Clinical and Patient's Global Impressions of Change, and change in functional status via Hauser's diary. Safety assessments include the incidence of treatment-emergent adverse events. The study will be conducted in approximately 140 patients from 50 clinical sites in Germany, Italy, Portugal, Spain and the United Kingdom. Recruitment started in February 2021 and the last patient is expected to complete the study by late 2022.. The OCEAN trial will help determine whether the use of adjunctive OPC 50 mg treatment can improve fluctuation-associated pain in PD patients with end-of-dose motor fluctuations. The robust design of OCEAN will address the current lack of reliable evidence for dopaminergic-based therapy in the treatment of PD-associated pain.. EudraCT number 2020-001175-32 ; registered on 2020-08-07. Topics: Antiparkinson Agents; Catechol O-Methyltransferase; Humans; Oxadiazoles; Pain; Parkinson Disease | 2022 |
Evaluation of the effects of a metabotropic glutamate receptor 5-antagonist on electrically induced pain and central sensitization in healthy human volunteers.
This study aimed to investigate the effect of a single dose of the mGluR5-antagonist AZD9272 on electrically induced pain, central sensitization and axon reflex flare.. This was a randomized, double-blind, placebo-controlled crossover study. Twenty-five healthy male volunteers received a single oral dose of AZD9272 or placebo on two occasions separated by 10-20 days. Electrical stimulation with a constant current for 100 min delivered through intracutaneous electrodes inserted on the forearm was used to induce a stable level of pain (6 of 10 on a 0-10 numerical rating scale; NRS). Pain intensity was assessed every 10 min during stimulation. The area of punctate hyperalgesia, area of dynamic mechanical allodynia, and area and intensity of flare reaction were measured every 20 min during stimulation. The stimulation procedure, current intensity and measurements were identical at both treatment visits. The AUC0-100 min (area under curve, 100 min stimulation) was calculated for each variable. The AUC0-100 min for pain NRS and hyperalgesia area were defined as primary variables. Linear mixed effects models were used for the statistical analysis.. Twenty-one subjects completed the study per protocol. No significant differences were found between AZD9272 and placebo regarding any of the AUC0-100 min variables for pain NRS, hyperalgesia area, allodynia area, flare area or flare intensity. The plasma levels of AZD9272 were maximal during the pain measurements and corresponded to >50% brain mGluR5 receptor occupancy.. Single doses of the centrally acting mGluR5-antagonist AZD9272 did not reduce C-fibre evoked pain, central sensitization or flare reaction. Topics: Adult; Central Nervous System Sensitization; Double-Blind Method; Evoked Potentials; Healthy Volunteers; Humans; Hyperalgesia; Oxadiazoles; Pain; Pain Measurement; Pain Threshold; Pyridines; Receptor, Metabotropic Glutamate 5; Skin; Young Adult | 2013 |
41 other study(ies) available for oxadiazoles and Pain
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Design, synthesis and molecular docking of benzophenone conjugated with oxadiazole sulphur bridge pyrazole pharmacophores as anti inflammatory and analgesic agents.
The prostaglandins (PG) a group of physiologically active lipid compounds having diverse hormone like effects are important mediators of the body's response to pain and inflammation, and are formed from essential fatty acids found in cell membranes. This reaction is catalyzed by cyclooxygenase, a membrane associated enzyme occurring in two isoforms, COX-1 and COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting the activity of COX. In view of this, a series of novel benzophenones conjugated with oxadiazole sulphur bridge pyrazole moiety 8a-l were designed, synthesized, characterized and subsequently evaluated for anti-inflammatory and analgesic property. The investigation of novel analogues 8a-l for potential anti-inflammatory activity showed high levels of COX-1 and COX-2 inhibitory activity. Among the series, compound 8i with electron withdrawing fluoro group at the para position of the benzoyl ring of benzophenone was characterized by highest IC Topics: Acetic Acid; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzophenones; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Edema; Formaldehyde; Humans; Mice; Molecular Docking Simulation; Molecular Structure; Oxadiazoles; Pain; Pain Measurement; Pyrazoles; Rats; Structure-Activity Relationship | 2019 |
Anti-inflammatory, anti-rheumatic and analgesic activities of 2-(5-mercapto-1,3,4-oxadiazol-2-yl)-N-propylbenzenesulphonamide (MOPBS) in rodents.
Chronic inflammation is pathologically associated with various clinical conditions such as rheumatoid arthritis. Several anti-inflammatory and analgesic drugs currently available in market presents a wide range of problems. Therefore, the current study was aimed to evaluate anti-inflammatory and analgesic activities of newly synthesized compound 2-(5-mercapto-1,3,4-oxadiazol-2-yl)-N-propylbenzenesulphonamide (MOPBS). Carrageenan and CFA-induced models were developed for evaluation of anti-inflammatory and analgesic activity. Quantitative real-time PCR (qRT-PCR) was performed to determine the mRNA expression levels of inflammatory mediators. Pain behaviours were evaluated by performing Von Frey, Randall Selitto, cold acetone and hot plate test respectively. X-ray imaging and haematoxylin and eosin (H&E) staining were performed for examination of soft tissues of treated mice paw. Additionally, Kodzeila's screen test and weight test were performed for determination of any side effects on motor function and muscle strength. Acute pretreatment of animals with MOPBS (1, 10, 50 and 100 mg/kg, i.p.) produced a significant reduction of paw oedema against carrageenan-induced acute inflammation as well as notable inhibition of mechanical hyperalgesia, allodynia and thermal hyperalgesia. Similarly, in chronic inflammation model, administration of MOPBS (50 mg/kg, i.p.) produced a remarkable reduction of paw oedema. Additionally, MOPBS pretreatment showed a significant inhibition of thermal hyperalgesia, mechanical allodynia, and mechanical hyperalgesia in chronic arthritis model. Several pro-inflammatory mediators such as nitric oxide (NO), vascular endothelial growth factor (VEGF), interleukins (IL-1β, IL-6) and tumor necrosis factor-α (TNF-α) were inhibited by MOPBS treatment in blood plasma and paw tissues, respectively. MOPBS also enhanced the mRNA expression levels of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), superoxide dismutase (SOD2) and heme oxygenase (HO-1) and in turn reduced arthritis severity and inflammation. Furthermore, anti-inflammatory data were confirmed by X-rays and histological analysis. MOPBS pretreatment did not produce any apparent toxic effect on gastric, kidney and liver function and on muscle strength and motor function. Hence, the present data suggest that MOPBS might be a candidate for several chronic inflammatory diseases such RA and other auto-immune diseases. Topics: Analgesics; Animals; Anti-Inflammatory Agents; Antirheumatic Agents; Arthritis, Experimental; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Hyperalgesia; Inflammation; Male; Mice; Oxadiazoles; Pain; Real-Time Polymerase Chain Reaction; Sulfonamides | 2018 |
A novel P2X4 receptor-selective antagonist produces anti-allodynic effect in a mouse model of herpetic pain.
Accumulating evidence indicates that purinergic P2X4 receptors (P2X4R: cation channels activated by extracellular ATP) expressed in spinal microglia are crucial for pathological chronic pain caused by nerve damage, suggesting a potential target for drug discovery. We identified NP-1815-PX (5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1, 2-b][1,4]diazepine-2,4(3H,5H)-dione) as a novel antagonist selective for P2X4R with high potency and selectivity compared with other P2XR subtypes. In in vivo assay for acute and chronic pain, intrathecal administration of NP-1815-PX produced an anti-allodynic effect in mice with traumatic nerve damage without affecting acute nociceptive pain and motor function (although its oral administration did not produce the effect). Furthermore, in a mouse model of herpetic pain, P2X4R upregulation in the spinal cord exclusively occurred in microglia, and intrathecal NP-1815-PX suppressed induction of mechanical allodynia. This model also showed K(+)/Cl(-) cotransporter 2 (KCC2) downregulation, which is implicated in dorsal horn neuron hyperexcitability; this downregulation was restored by intrathecal treatment with NP-1815-PX or by interfering with brain-derived neurotrophic factor (BDNF) signaling, a P2X4R-activated microglial factor implicated in KCC2 downregulation. Taken together, the newly developed P2X4R antagonist NP-1815-PX produces anti-allodynic effects in chronic pain models without altering acute pain sensitivity, suggesting that microglial P2X4R could be an attractive target for treating chronic pain. Topics: Animals; Azepines; Disease Models, Animal; Humans; Hyperalgesia; Mice; Microglia; Oxadiazoles; Pain; Posterior Horn Cells; Purinergic P2X Receptor Antagonists; Receptors, Purinergic P2X4; Spinal Cord | 2016 |
Design, synthesis and QSAR studies on a series of 2, 5-disubstituted- 1,3,4-oxadiazole derivatives of diclofenac and naproxen for analgesic and anti-inflammatory activity.
A series of twenty molecules belonging to 2,5-disubstituted-1,3,4-oxadiazole derivatives of Diclofenac and Naproxen were designed, synthesized and their structures were confirmed by spectroscopy. The target compounds were evaluated for anti-inflammatory and analgesic activity. The result indicates that the compounds 12, 4, 6, 7 and 15 were found to have good analgesic and anti-inflammatory activities, while the compounds 12 and 14 were found to have good analgesic and the compound 22 were found to have good anti-inflammatory activities. HQSAR and Topomer QSAR studies were performed to get insights in the structures contributing for biological activity. The compounds bearing mono-substitution such as Cl, OCH3 and NO2 in the phenyl ring were found to have maximum analgesic and anti-inflammatory activities. Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Drug Design; Female; Inflammation; Male; Mice; Molecular Structure; Naproxen; Oxadiazoles; Pain; Pain Measurement; Quantitative Structure-Activity Relationship; Rats | 2015 |
Synthesis, characterization, evaluation and molecular dynamics studies of 5, 6-diphenyl-1,2,4-triazin-3(2H)-one derivatives bearing 5-substituted 1,3,4-oxadiazole as potential anti-inflammatory and analgesic agents.
A series of triazin-3(2H)-one derivatives bearing 1,3,4-oxadiazole (4a-4o) were synthesized, characterized and evaluated for anti-inflammatory and analgesic activities. Preliminary in vitro anti-inflammatory activity was assessed using an albumin denaturation assay. The promising compounds were further evaluated in acute, sub-chronic and chronic animal models of inflammation. Derivatives 4d, 4e, 4g, 4j and 4l exhibited significant anti-inflammatory activity with reduced ulcerogenic, hepatotoxic and renotoxic liabilities compared to standard indomethacin. These potential derivatives were also evaluated for in vivo analgesic activity using a writhing model and the formalin-induced paw licking response in mice. Compounds 4d, 4e and 4g exhibited comparable analgesic activity, whereas 4j and 4l yielded moderate effects. The specificity of compounds 4d, 4e, 4g, 4j, and 4l to inhibit (cyclooxygenase-1) COX-1 and (cyclooxygenase-2) COX-2 isozymes and their kinetics were also determined via an in vitro COX inhibition assay. In silico docking studies were performed using a molecular dynamics simulation of the most active compound 4d (COX-2 IC50: 3.07 μM) at the COX-2 active site. The outcome of this exercise helped to verify the consensual interaction of these compounds with the enzyme. Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Behavior, Animal; Carrageenan; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Formaldehyde; Kinetics; Mice; Molecular Dynamics Simulation; Molecular Structure; Oxadiazoles; Pain; Rats; Stomach Ulcer; Structure-Activity Relationship; Triazines | 2015 |
Activity of nicorandil, a nicotinamide derivative with a nitrate group, in the experimental model of pain induced by formaldehyde in mice.
Nicorandil (2-nicotinamide ethyl nitrate), an antianginal drug characterized by the coupling of nicotinamide with a nitric oxide (NO) donor, activates guanylyl cyclase and opens ATP-dependent K(+) channels. In the present study, we investigated the effects induced by per os (p.o.) administration of nicorandil (12.5, 25 or 50 mg/kg) or equimolar doses (corresponding to the highest dose of nicorandil) of N-(2-hydroxyethyl) nicotinamide (NHN), its main metabolite, or nicotinamide in the model of nociceptive response induced by formaldehyde in mice. Nicorandil, but not NHN or nicotinamide, inhibited the second phase of the nociceptive response. This activity was observed when nicorandil was administered between 30 and 120 min before the injection of formaldehyde. Ipsilateral intraplantar injection of nicorandil (125, 250 or 500 μg/paw) did not inhibit the nociceptive response. After p.o. administration of nicorandil (50 mg/kg), peak plasma concentrations of this compound and NHN were observed 0.63 and 4 h later, respectively. Nicotinamide concentrations were not increased after administration of nicorandil. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 or 2 mg/kg), a guanylyl cyclase inhibitor, partially attenuated the antinociceptive activity of nicorandil. However, this activity was not changed by glibenclamide (30 or 60 mg/kg), an inhibitor of ATP-dependent K(+) channels. In conclusion, we demonstrated the antinociceptive activity of nicorandil in a model of pain that exhibits both a nociceptive and an inflammatory profile. This activity is not mediated by nicotinamide or NHN. The coupling of an NO-donor to nicotinamide results in a compound with an increased potency. The NO-cGMP pathway, but not ATP-dependent K(+) channels, partially mediates the antinociceptive activity of nicorandil. Topics: Analgesics; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Formaldehyde; Glyburide; Male; Mice; Nicorandil; Oxadiazoles; Pain | 2013 |
Synthesis and pharmacological evaluation of some novel thebaine derivatives: N-(tetrazol-1H-5-yl)-6,14-endoethenotetrahydrothebaine incorporating the 1,3,4-oxadiazole or the 1,3,4-thiadiazole moiety.
In this study, we synthesized some novel N-(tetrazol-1H-5-yl)-6,14-endoethenotetrahydrothebaine 7α-substituted 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as potential analgesic agents. The structures of the compounds were established on the basis of their IR, ¹H NMR, ¹³C NMR, 2D NMR, and high-resolution mass spectral data. The analgesic activity was evaluated by a rat-hot plate test model and a rat tail-flick model. Compound 12 showed analgesic activity higher than that of morphine. In addition to a histopathological and biochemical evaluation, the LD₅₀ dose for the most active compound 12 was determined. Topics: Analgesics; Animals; Disease Models, Animal; Lethal Dose 50; Magnetic Resonance Spectroscopy; Male; Morphine; Oxadiazoles; Pain; Rats; Rats, Wistar; Thebaine; Thiadiazoles | 2013 |
Design and synthesis of 3,5-disubstituted-1,2,4-oxadiazoles as potent inhibitors of phosphodiesterase4b2.
A series of 3,5-disubstituted-1,2,4-oxadiazoles has been prepared and evaluated for phosphodiesterase inhibition (PDE4B2). Among the prepared 3,5-disubstituted-1,2,4-oxadiazoles, compound 9a is the most potent inhibitor (PDE4B2 IC(50) = 5.28 μm). Structure-activity relationship studies of 3,5-disubstituted-1,2,4-oxadiazoles revealed that substituents 3-cyclopentyloxy-4-methoxyphenyl group at 3-position and cyclic ring bearing heteroatoms at 5-position are important for activity. Molecular modeling study of the 3,5-disubstituted-1,2,4-oxadiazoles with PDE4B has shown similar interactions of 3-cyclopentyloxy-4-methoxyphenyl group; however, heteroatom ring is slightly deviating when compared to Piclamilast. 3-(3-Cyclopentyloxy-4-methoxyphenyl)-5-(piperidin-4-yl)-1,2,4-oxadiazole (9a) exhibited good analgesic and antiinflammatory activities in formalin-induced pain in mice and carrageenan-induced paw edema model in rat. Topics: Analgesics; Animals; Anti-Inflammatory Agents; Cyclic Nucleotide Phosphodiesterases, Type 4; Drug Design; Edema; Female; Humans; Male; Mice; Models, Molecular; Oxadiazoles; Pain; Phosphodiesterase 4 Inhibitors; Rats; Rats, Wistar | 2012 |
Discovery of new orally effective analgesic and anti-inflammatory hybrid furoxanyl N-acylhydrazone derivatives.
We report the design, the synthesis and the biological evaluation of the analgesic and anti-inflammatory activities of furoxanyl N-acylhydrazones (furoxanyl-NAH) by applying molecular hybridization approach. Hybrid compounds with IL-8-release inhibition capabilities were identified. Among them, furoxanyl-NAH, 17, and benzofuroxanyl-derivative, 24, together with furoxanyl-NAH derivative, 31, without IL-8 inhibition displayed both orally analgesic and anti-inflammatory activities. These hybrid derivatives do not have additional LOX- or COX-inhibition activities. For instance, LOX-inhibition by furoxanyl-NAH derivative, 42, emerged as a structural lead to develop new inhibitors. The lack of mutagenicity of the active derivatives 17, 31, and 42, allow us to propose them as candidates for further clinical studies. These results confirmed the success in the exploitation of hybridization strategy for identification of novel N-acylhydrazones (NAH) with optimized activities. Topics: Analgesics; Animals; Anti-Inflammatory Agents; Cell Line; Cyclooxygenase Inhibitors; Drug Design; Female; Humans; Hydrazones; Inflammation; Interleukin-8; Lipoxygenase Inhibitors; Male; Mice; Oxadiazoles; Pain; Rats | 2012 |
Positive allosteric modulation of α4β2 nAChR agonist induced behaviour.
Neuronal cholinergic transmission is a prerequisite for proper CNS function. Consequently, disturbance of this system is associated with a number of pathophysiological conditions such as Parkinson's disease, Alzheimer's disease, schizophrenia and ADHD. Consequently, drug discovery efforts have spurred considerable research endeavours into identifying specific compounds for this system. Nicotinic acetylcholine receptors (nAChR) are ligand gated ion channels involved in cholinergic transmission. nAChRs are homo- or heteromeric pentamers with α4β2 receptors being the most abundant heteromer. The stoichiometry of α4β2 receptors can be either (α4)(3)(β2)(2) or (α4)(2)(β2)(3) representing channels with low (LS) or high (HS) sensitivity, respectively, to endogenous ligands. In the present study we applied the partial nAChR α4β2 LS and HS agonist NS3956 and the LS selective positive allosteric modulator NS9283 to investigate the role of α4β2 in Parkinson and pain models. In 6-OHDA lesioned rats, NS3956 increased rotational behaviour when rats were co-treated with nomifensine. This effect was absent in the presence of mecamylamine. In contrast, co-treatment with NS3956 and NS9283 reduced rotational behaviour in the animals. In a rat formalin pain model NS3956 induced an analgesic response that was strongly potentiated by NS9283. Finally in vitro experiments were applied to determine dopamine release from striatal minces. NS3956 induced a concentration dependent release while NS9283 was unable to potentiate agonist induced release. Together these results emphasize involvement of α4β2 nAChR in rotational and analgesic responses and confirm striatal α4β2 receptors to be of the HS form. Topics: Allosteric Regulation; Animals; Azepines; Corpus Striatum; Female; Male; Nicotinic Agonists; Oxadiazoles; Oxidopamine; Pain; Pain Measurement; Parkinsonian Disorders; Pyridines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Nicotinic; Rotation | 2012 |
Potentiation of analgesic efficacy but not side effects: co-administration of an α4β2 neuronal nicotinic acetylcholine receptor agonist and its positive allosteric modulator in experimental models of pain in rats.
Positive modulation of the neuronal nicotinic acetylcholine receptor (nAChR) α4β2 subtype by selective positive allosteric modulator NS-9283 has shown to potentiate the nAChR agonist ABT-594-induced anti-allodynic activity in preclinical neuropathic pain. To determine whether this benefit can be extended beyond neuropathic pain, the present study examined the analgesic activity and adverse effect profile of co-administered NS-9283 and ABT-594 in a variety of preclinical models in rats. The effect of the combined therapy on drug-induced brain activities was also determined using pharmacological magnetic resonance imaging. In carrageenan-induced thermal hyperalgesia, co-administration of NS-9283 (3.5 μmol/kg, i.p.) induced a 6-fold leftward shift of the dose-response of ABT-594 (ED(50)=26 vs. 160 nmol/kg, i.p.). In the paw skin incision model of post-operative pain, co-administration of NS-9283 similarly induced a 6-fold leftward shift of ABT-594 (ED(50)=26 vs. 153 nmol/kg). In monoiodo-acetate induced knee joint pain, co-administration of NS-9283 enhanced the potency of ABT-594 by 5-fold (ED(50)=1.0 vs. 4.6 nmol/kg). In pharmacological MRI, co-administration of NS-9283 was shown to lead to a leftward shift of ABT-594 dose-response for cortical activation. ABT-594 induced CNS-related adverse effects were not exacerbated in presence of an efficacious dose of NS-9283 (3.5 μmol/kg). Acute challenge of NS-9283 produced no cross sensitization in nicotine-conditioned animals. These results demonstrate that selective positive allosteric modulation at the α4β2 nAChR potentiates nAChR agonist-induced analgesic activity across neuropathic and nociceptive preclinical pain models without potentiating ABT-594-mediated adverse effects, suggesting that selective positive modulation of α4β2 nAChR by PAM may represent a novel analgesic approach. Topics: Allosteric Regulation; Analgesics; Animals; Azetidines; Behavior, Animal; Body Temperature; Brain; Disease Models, Animal; Drug Therapy, Combination; Magnetic Resonance Imaging; Male; Nicotinic Agonists; Osteoarthritis; Oxadiazoles; Pain; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic | 2011 |
Ketamine activates the L-arginine/Nitric oxide/cyclic guanosine monophosphate pathway to induce peripheral antinociception in rats.
The involvement of the L-arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway in antinociception has been implicated as a molecular mechanism of antinociception produced by several antinociceptive agents, including μ-, κ-, or δ-opioid receptor agonists, nonsteroidal analgesics, cholinergic agonist, and α2C adrenoceptor agonist. In this study, we investigated whether ketamine, a dissociative anesthetic N-methyl-D-aspartate receptor antagonist, was also capable of activating the L-arginine/NO/cGMP pathway and eliciting peripheral antinociception.. The rat paw pressure test was used, with hyperalgesia induced by intraplantar injection of prostaglandin E2. All drugs were locally administered into the right hindpaw of male Wistar rats.. Ketamine (10, 20, 40, 80 μg/paw) elicited a local antinociceptive effect that was antagonized by the nonselective NOS inhibitor L-NOARG (12, 18, and 24 μg/paw) and by the selective neuronal NOS inhibitor L-NPA (12, 18, and 24 μg/paw). In another experiment, we used the inhibitors L-NIO and L-NIL (24 μg/paw) to selectively inhibit endothelial and inducible NOS, respectively. These 2 drugs were ineffective at blocking the effects of the peripheral ketamine injection. In addition, the level of nitrite in the homogenized paw indicated that exogenous ketamine is able to induce NO release. The soluble guanylyl cyclase inhibitor ODQ (25, 50, and 100 μg/paw) blocked the action of ketamine, and the cGMP-phosphodiesterase inhibitor zaprinast (50 μg/paw) enhanced the antinociceptive effects of low-dose ketamine (10 μg/paw).. Our results suggest that ketamine stimulates the L-arginine/NO/cyclic GMP pathway via neuronal NO synthase to induce peripheral antinociceptive effects. Topics: Analgesia; Anesthetics, Dissociative; Animals; Arginine; Cyclic AMP; Dinoprostone; Drug Synergism; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Guanylate Cyclase; Hyperalgesia; Ketamine; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Oxadiazoles; Pain; Peripheral Nervous System Diseases; Quinoxalines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Signal Transduction | 2011 |
Synthesis and biological property of some novel 1,3,4-oxadiazoles.
A series of biphenyl-1,3,4-oxadiazoles namely 5-[substituted-(1,1'-biphenyl)-3-yl]-1,3,4-oxadiazole-2(3H)-thiones and its S-alkyl derivatives have been synthesized by multi step organic synthesis involving Suzuki-Miyaura coupling using palladium catalyst. The synthesized compounds were characterized by (1)H NMR, (13)C NMR, (19)F NMR, IR and LCMS spectroscopic properties. They were tested for their antimicrobial and analgesic activities. Some of them showed significant activity. Topics: Analgesics; Animals; Anti-Infective Agents; Bacteria; Female; Fungi; Male; Mice; Microbial Sensitivity Tests; Oxadiazoles; Pain; Pain Measurement; Structure-Activity Relationship | 2010 |
Synthesis, analgesic and anti-inflammatory activities of novel 3-(4-acetamido-benzyl)-5-substituted-1,2,4-oxadiazoles.
A series of 3-(4-acetamido-benzyl)-5-substituted-1,2,4-oxadiazoles (7a-7n) were synthesized and screened for analgesic and in vivo anti-inflammatory activities using acetic acid writhing in mice model and carrageenan-induced paw oedema method in mice, respectively. The analgesic activity of compounds 7i and 7m is superior while that of 7d, 7c, 7f and 7j is equal to the reference standard, diclofenac sodium. The anti-inflammatory activity of compounds 6, 7c, 7e, 7f, 7i, 7l, 7m and 7n is found to be superior than that of diclofenac sodium which is used as a reference, while compounds 7d and 7g are found to be equipotent with the reference compound. Topics: Analgesics; Animals; Anti-Inflammatory Agents; Drug Evaluation, Preclinical; Edema; Mice; Oxadiazoles; Pain; Structure-Activity Relationship | 2009 |
Synthesis of novel 1,3,4-oxadiazole derivatives and their biological properties.
A novel series of 2-[3-(4-bromophenyl)propan-3-one]-5-(substituted phenyl)-1,3,4-oxadiazoles (4a-n) have been synthesized from 3-(4-bromobenzoyl)propionic acid (3) with the aim to get better anti-inflammatory and analgesic agents with minimum or without side effects (ulcerogenicity). Compound 3 was reacted with several aryl acid hydrazides (2a-n) in phosphorous oxychloride to obtain the title compounds. Structures of the synthesized compounds were supported by means of IR, 1H NMR and mass spectroscopy. Title compounds were evaluated for their anti-inflammatory, analgesic, ulcerogenic and antibacterial activities. Antibacterial activity was expressed as the corresponding minimum inhibitory concentration (MIC). A fair number of compounds were found to have significant anti-inflammatory and analgesic activities, while a few compounds showed appreciable antibacterial activity. The newly synthesized compounds showed very low ulcerogenic action. The findings of the present study indicate that cyclization of the carboxylic group of 3 into novel 1,3,4-oxadiazole nucleus resulted in increased anti-inflammatory and analgesic activities with a significant decrease of ulcerogenic activity. Topics: Acetic Acid; Analgesics; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Carrageenan; Disease Models, Animal; Drug Design; Escherichia coli; Female; Inflammation; Male; Mice; Microbial Sensitivity Tests; Molecular Structure; Oxadiazoles; Pain; Rats; Rats, Wistar; Staphylococcus aureus; Stomach Ulcer; Structure-Activity Relationship | 2009 |
Gonadal hormones decrease temporomandibular joint kappa-mediated antinociception through a down-regulation in the expression of kappa opioid receptors in the trigeminal ganglia.
We have previously demonstrated that activation of kappa-opioid receptor located in the temporomandibular joint (TMJ) of rats induces a significantly greater TMJ antinociception in diestrus females than in proestrus females (higher estradiol serum levels than diestrus) and males. These findings indicate that gonadal hormones decrease TMJ kappa-mediated antinociception. The aim of this study was to investigate some of the mechanisms by which gonadal hormones decrease TMJ kappa-mediated antinociception. Western blot analysis demonstrated a significantly lower kappa-opioid receptor expression in the trigeminal ganglia of intact males than in intact and ovariechtomized (OVX) females and orchidectomized (ORX) males. In females, kappa-opioid receptor expression in the trigeminal ganglia was significantly lower in proestrus than in diestrus and OVX females. Taken together these findings suggest that gonadal hormones, especially male gonadal hormones, down-regulate kappa-opioid receptor expression. Co-application of the NOS inhibitor L-NMMA or the NO-sensitive guanylyl cyclase inhibitor ODQ with the kappa-opioid receptor agonist U50,488 blocked TMJ kappa-mediated antinociception in males and females. These findings suggest that antinociception induced by activation of kappa opioid receptors in the TMJ region is mediated by the L-arginine/NO/cGMP pathway in both sexes. Despite the involvement of the L-arginine/NO/cGMP pathway in TMJ kappa-mediated antinociception in both sexes, gonadal hormones do not diminish the activity of this pathway to decrease TMJ kappa-mediated antinociception. Alternatively, they significantly reduce kappa-opioid receptor expression in the trigeminal ganglia. Topics: Analgesics; Animals; Arginine; Cyclic GMP; Down-Regulation; Female; Gonadal Hormones; Humans; Male; Nitric Oxide; omega-N-Methylarginine; Oxadiazoles; Pain; Quinoxalines; Rats; Rats, Wistar; Receptors, Opioid, kappa; Sex Characteristics; Signal Transduction; Temporomandibular Joint; Trigeminal Ganglion | 2009 |
Teleantagonism: A pharmacodynamic property of the primary nociceptive neuron.
Previous work from our group showed that intrathecal (i.t.) administration of substances such as glutamate, NMDA, or PGE(2) induced sensitization of the primary nociceptive neuron (PNN hypernociception) that was inhibited by a distal intraplantar (i.pl.) injection of either morphine or dipyrone. This pharmacodynamic phenomenon is referred to in the present work as "teleantagonism". We previously observed that the antinociceptive effect of i.t. morphine could be blocked by injecting inhibitors of the NO signaling pathway in the paw (i.pl.), and this effect was used to explain the mechanism of opioid-induced peripheral analgesia by i.t. administration. The objective of the present investigation was to determine whether this teleantagonism phenomenon was specific to this biochemical pathway (NO) or was a general property of the PNNs. Teleantagonism was investigated by administering test substances to the two ends of the PNN (i.e., to distal and proximal terminals; i.pl. plus i.t. or i.t. plus i.pl. injections). We found teleantagonism when: (i) inhibitors of the NO signaling pathway were injected distally during the antinociception induced by opioid agonists; (ii) a nonselective COX inhibitor was tested against PNN sensitization by IL-1beta; (iii) selective opioid-receptor antagonists tested against antinociception induced by corresponding selective agonists. Although the dorsal root ganglion seems to be an important site for drug interactions, the teleantagonism phenomenon suggests that, in PNNs, a local sensitization spreads to the entire cell and constitutes an intriguing and not yet completely understood pharmacodynamic property of this group of neurons. Topics: Analgesics, Opioid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dinoprostone; Dopamine; Drug Interactions; Enzyme Inhibitors; Indomethacin; Interleukin-1beta; Male; Morphine; Naloxone; Narcotic Antagonists; Nitric Oxide; Nociceptors; omega-N-Methylarginine; Oxadiazoles; Pain; Pyrrolidines; Quinoxalines; Rats; Rats, Wistar; Sensory Receptor Cells; Signal Transduction | 2008 |
Role of NO/cGMP/KATP pathway in antinociceptive effect of sildenafil in zymosan writhing response in mice.
Previous studies have found that sildenafil produces antinociception in experimental models. This work was undertaken to determine the participation of the NO/cGMP/K(ATP) pathway in the antinociception induced by sildenafil.. The antinociceptive effect of sildenafil was determined in the zymosan-induced writhing response in mice. Sildenafil (1-30 mg/kg; i. p.), given 30 min before zymosan (1 mg/animal; i. p.), inhibited the writhing response (5.0 +/- 1.3 versus 26.6 +/- 2.7; p < 0.001) in a dose-dependent manner. L-NAME (30 mg/kg; s. c.) significantly (p < 0.05) reversed this effect (16.6 +/- 3.1 versus 6.4 +/- 1.6) and L-arginine (200 mg/kg; i. p.) prevented the L-NAME effect (6.8 +/- 0.8 versus 16.6 +/- 3.1; p < 0.05). ODQ (0,3-1 mg/kg; i. p.) and glybenclamide (0.3-1 mg/kg; p. o.) pre-treatment significantly (p < 0.01) inhibited the antinociceptive effect of sildenafil (18.0 +/- 1.7 versus 2.1 +/- 1.0 and 5.5 +/- 0.7 versus 1.6+0.7, respectively). Diazoxide (10 mg/kg; s. c) significantly (p < 0.001) abolished the glybenclamide effect (1.6 +/- 0.8 versus 14 +/- 1.2).. The data indicate that the antinociceptive effect of sildenafil is dependent on the activation of the NO/cGMP/ K(ATP) pathway. Topics: Analgesics; Animals; Behavior, Animal; Cyclic GMP; Dose-Response Relationship, Drug; Male; Mice; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxadiazoles; Pain; Piperazines; Potassium Channels; Purines; Quinoxalines; Signal Transduction; Sildenafil Citrate; Sulfones; Zymosan | 2007 |
Non-carboxylic analogues of naproxen: design, synthesis, and pharmacological evaluation of some 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole derivatives.
A series of substituted 1,3,4-oxadiazole (2-7 and 14-19), 1,2,4-triazole (20-25), and 1,3,4-thiadiazole (26-31) derivatives of naproxen have been synthesized by cyclization of 2-(6-methoxy-2-naphthyl)propanoic acid hydrazide 1 and N(1)[2-(6-methoxy-2-naphthyl) propanoyl]-N(4)-alkyl/aryl-thiosemicarbazides (8-13) under various reaction conditions. All the compounds were screened for their anti-inflammatory activity by carrageenan-induced rat paw edema test method. Compounds showing high anti-inflammatory activity were also tested for their analgesic, ulcerogenic, and lipid peroxidation. Few of the synthesized compounds showed significant anti-inflammatory and analgesic activities along with reduced ulcerogenic effect and lipid peroxidation. Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Chemical and Drug Induced Liver Injury; Drug Design; Edema; Liver; Liver Function Tests; Male; Mice; Molecular Structure; Naproxen; Oxadiazoles; Pain; Rats; Stomach Ulcer; Thiadiazoles; Triazoles | 2007 |
The nitric oxide-cyclic GMP-protein kinase G-K+ channel pathway participates in the antiallodynic effect of spinal gabapentin.
The possible participation of the nitric oxide (NO)-cyclic GMP-protein kinase G (PKG) pathway on gabapentin-induced spinal antiallodynic activity was assessed in spinal nerve injured rats. Intrathecal gabapentin, diazoxide or pinacidil reduced tactile allodynia in a dose-dependent manner. Pretreatment with NG-L-nitro-arginine methyl ester (L-NAME, non-specific inhibitor of NO synthase NOS), 7-nitroindazole (neuronal NO synthase inhibitor), 1H-[1,2,4] -oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor) or (9S, 10R, 12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo-[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT-5823, specific PKG inhibitor), but not NG-D-nitro-arginine methyl ester (D-NAME) or okadaic acid (protein phosphatase 1 and 2 inhibitor) prevented gabapentin-induced antiallodynia. Pinacidil activity was not blocked by L-NAME, D-NAME, 7-nitroindazole, ODQ, KT-5823 or okadaic acid. Moreover, KT-5823, glibenclamide (ATP-sensitive K+ channel blocker), apamin and charybdotoxin (small- and large-conductance Ca2+-activated K+ channel blockers, respectively), but not margatoxin (voltage-gated K+ channel blocker), L-NAME, 7-nitroindazole, ODQ or okadaic acid, reduced diazoxide-induced antiallodynia. Data suggest that gabapentin-induced spinal antiallodynia could be due to activation of the NO-cyclic GMP-PKG-K+ channel pathway. Topics: Amines; Analgesics; Animals; Apamin; Carbazoles; Charybdotoxin; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclohexanecarboxylic Acids; Diazoxide; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Gabapentin; gamma-Aminobutyric Acid; Glyburide; Indazoles; Indoles; Injections, Spinal; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Okadaic Acid; Oxadiazoles; Pain; Pinacidil; Potassium Channel Blockers; Potassium Channels; Protein Kinase Inhibitors; Quinoxalines; Rats; Rats, Wistar; Signal Transduction; Spinal Nerves; Stereoisomerism; Time Factors; Vasodilator Agents | 2006 |
Peripheral antinociceptive effect of pertussis toxin: activation of the arginine/NO/cGMP/PKG/ ATP-sensitive K channel pathway.
The aim of the present study was to determine the effect of pertussis toxin (PTX) on inflammatory hypernociception measured by the rat paw pressure test and to elucidate the mechanism involved in this effect. In this test, prostaglandin E(2) (PGE(2)) administered subcutaneously induces hypernociception via a mechanism associated with neuronal cAMP increase. Local intraplantar pre-treatment (30 min before), and post-treatment (5 min after) with PTX (600 ng/paw1, in 100 microL) reduced hypernociception induced by prostaglandin E(2) (100 ng/paw, in 100 microL, intraplantar). Furthermore, local intraplantar pre-treatment (30 min before) with PTX (600 ng/paw, in 100 microL) reduced hypernociception induced by DbcAMP, a stable analogue of cAMP (100 microg/paw, in 100 microL, intraplantar), which indicates that PTX may have an effect other than just G(i)/G(0) inhibition. PTX-induced analgesia was blocked by selective inhibitors of nitric oxide synthase (L-NMMA), guanylyl cyclase (ODQ), protein kinase G (KT5823) and ATP-sensitive K(+) channel (Kir6) blockers (glybenclamide and tolbutamide). In addition, PTX was shown to induce nitric oxide (NO) production in cultured neurons of the dorsal root ganglia. In conclusion, this study shows a peripheral antinociceptive effect of pertussis toxin, resulting from the activation of the arginine/NO/cGMP/PKG/ATP-sensitive K(+) channel pathway. Topics: Adenosine Triphosphate; Analgesia; Analgesics; Animals; Arginine; Bucladesine; Carbazoles; Cells, Cultured; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Dinoprostone; Enzyme Inhibitors; Ganglia, Spinal; Glyburide; Indoles; KATP Channels; Male; Neurons; Nitric Oxide; omega-N-Methylarginine; Oxadiazoles; Pain; Pain Measurement; Pertussis Toxin; Potassium Channels, Inwardly Rectifying; Quinoxalines; Rats; Rats, Wistar; Signal Transduction; Tolbutamide | 2006 |
Analysis of the mechanism underlying the peripheral antinociceptive action of sildenafil in the formalin test.
The mechanism of the antinociceptive action of the phosphodiesterase 5 inhibitor, sildenafil, was assessed in the formalin test. Local peripheral ipsilateral, but not contralateral, administration of sildenafil (50-200 microg/paw) produced a dose-related antinociception during both phases of the formalin test. The local peripheral pretreatment with protein kinase G inhibitor peptide (PKG inhibitor, 0.01-1 microg/paw), charybdotoxin (large- and intermediate-conductance Ca2+-activated K+ channel blocker, 0.01-1 microg/paw), apamin (small-conductance Ca2+-activated K+ channel blocker, 0.1-2 microg/paw), tolbutamide (ATP-sensitive K+ channel blocker, 12.5-50 microg/paw), and tetraethylammonium (non-selective voltage-dependent K+ channel blocker, 12.5-50 microg/paw), but not 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, inhibitor of guanylyl cyclase, 12.5-50 microg/paw) or saline, significantly diminished in a dose-dependent manner sildenafil-induced local peripheral antinociception. Given alone, local peripheral administration of inhibitors did not modify formalin-induced nociceptive behavior. Results suggest that sildenafil produces its local peripheral antinociceptive effect via activation of the cyclic GMP-PKG-K+ channel pathway. Topics: Analgesics; Animals; Apamin; Charybdotoxin; Cyclic GMP-Dependent Protein Kinases; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Formaldehyde; Guanylate Cyclase; Injections, Subcutaneous; Oxadiazoles; Pain; Pain Measurement; Piperazines; Potassium Channel Blockers; Purines; Quinoxalines; Rats; Rats, Wistar; Sildenafil Citrate; Sulfones; Tetraethylammonium; Time Factors; Tolbutamide | 2005 |
Peripheral and spinal mechanisms of antinociceptive action of lumiracoxib.
The possible participation of the nitric oxide (NO)-cyclic GMP-K(+) channel pathway, serotonergic or opioidergic system on lumiracoxib-induced local or intrathecal antinociception was assessed in the formalin test. Local or intrathecal administration of lumiracoxib dose-dependently produced antinociception in the second phase of the test. Moreover, local or intrathecal pretreatment with N(G)-L-nitro-arginine methyl ester (L-NAME, NO synthesis inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor), glibenclamide (ATP-sensitive K(+) channel blocker), charybdotoxin and apamin (large- and small-conductance Ca(2+)-activated-K(+) channel blockers, respectively) or margatoxin (voltage-dependent K(+) channel blocker), but not N(G)-D-nitro-arginine methyl ester (D-NAME) or vehicle, significantly prevented lumiracoxib-induced antinociception. The intrathecal injection of methiothepin (serotonin receptor antagonist) reduced lumiracoxib-induced intrathecal antinociception. Local peripheral or intrathecal naloxone did not modify either local or intrathecal lumiracoxib-induced antinociception. Results suggest that lumiracoxib activates the NO-cyclic GMP-K(+) channels to produce local and intrathecal antinociception. Data also suggest that lumiracoxib activates the intrathecal serotonergic system, but not opioid receptors either at peripheral or spinal sites. Topics: Analgesics; Animals; Apamin; Behavior, Animal; Charybdotoxin; Diclofenac; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Formaldehyde; Glyburide; Guanylate Cyclase; Hindlimb; Injections, Spinal; Injections, Subcutaneous; Methiothepin; Naloxone; Neurotoxins; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Organic Chemicals; Oxadiazoles; Pain; Pain Measurement; Quinoxalines; Rats; Rats, Wistar; Scorpion Venoms | 2005 |
Synthesis of some new 2-(6-methoxy-2-naphthyl)- 5-aryl-1,3,4-oxadiazoles as possible non-steroidal anti-inflammatory and analgesic agents.
The synthesis of some new 2-(6-methoxy-2-naphthyl)-5-aryl-1,3,4-oxadiazoles (4a-k) has been described. Ethyl-6-methoxy-2-naphthoate (1) yielded on treatment with hydrazine hydrate to 6-methoxy-2-naphthoic acid hydrazide (2). Compound 2 reacted with substituted aromatic carboxylic acids (3a-k) in phosphorus oxychloride yielded 2-(6-methoxy-2-naphthyl)-5-aryl-1,3,4-oxadiazoles (4a-k). Newly synthesized compounds were characterized by IR, (1)H-NMR and mass spectral data. All the compounds were screened for their anti-inflammatory and analgesic activity. Compound 4j exhibited promising anti-inflammatory and analgesic activities. Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Edema; Mice; Molecular Structure; Oxadiazoles; Pain; Pain Measurement; Rats; Structure-Activity Relationship | 2005 |
Possible involvement of the spinal nitric oxide/cGMP pathway in vincristine-induced painful neuropathy in mice.
The mechanisms that underlie the development of vincristine-induced painful neuropathy are poorly understood. The nitric oxide (NO)-cGMP pathway has been reported to be involved in the spinal transmission of nociceptive information. In the present study, we examined whether alterations in spinal nociceptive processing via the NO-cGMP pathway contribute to vincristine-induced painful neuropathy in mice. Mice were intraperitoneally treated with vincristine at a dose of 0.05 mg/kg 1 day after the measurement of pre-drug latency in the tail-flick test, and then treated with a dose of 0.125 mg/kg twice a week for 6 weeks. In vincristine-treated mice, a significant decrease in tail-flick latencies developed at 4 weeks after treatment. Pretreatment with L-arginine (30-300 mg/kg, s.c.), a substrate of NO synthase (NOS), dose-dependently increased the tail-flick latencies in vincristine-treated mice. The L-arginine-induced increase in tail-flick latencies in vincristine-treated mice was completely reversed by i.t. pretreatment with NG-nitro-L-arginine methyl ester (L-NAME, 3-30 nmol), a NOS inhibitor. Furthermore, i.t. pretreatment with 8-bromoguanosine 3', 5'-cyclic monophosphate (8-Br-cGMP, 0.3-3.0 nmol), a membrane-permeable cGMP analog, dose-dependently increased the tail-flick latencies in vincristine-treated mice. The contents of NO metabolites, cGMP and protein levels of neuronal NOS in the spinal cord in vincristine-treated mice were significantly reduced compared to those in vehicle-treated naive mice. These results indicate that dysfunction of the L-arginine/NO/cGMP cascade in the spinal cord may trigger vincristine-induced thermal hyperalgesia in mice. Topics: Analysis of Variance; Animals; Arginine; Blotting, Western; Cyclic GMP; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors; Injections, Spinal; Male; Mice; Mice, Inbred ICR; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxadiazoles; Pain; Pain Measurement; Quinoxalines; Reaction Time; Spinal Cord; Time Factors; Vincristine | 2005 |
Peripheral participation of the phosphodiesterase 3 on formalin-evoked nociception.
The local peripheral (subcutaneous) injection of phosphodiesterase 3 inhibitor trequinsin dose-dependently enhanced formalin-evoked flinching during late second phase of this test. Treatment with the nitric oxide synthase inhibitor N-L-nitro-arginine methyl ester or guanylyl cyclase inhibitor 1-H-[1,2,4,]oxadiazolo[4,3-a]quinoxalin-1-one significantly reversed trequinsin-induced pronociceptive effect. Results suggest that the peripheral phosphodiesterase 3 may play an important physiologic role on inflammatory pain by controlling cyclic AMP levels and therefore the nociceptor threshold. Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Cyclic Nucleotide Phosphodiesterases, Type 3; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Formaldehyde; Guanylate Cyclase; Injections, Subcutaneous; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Oxadiazoles; Pain; Pain Measurement; Quinoxalines; Rats; Rats, Wistar; Tetrahydroisoquinolines; Time Factors | 2005 |
Lack of the nitric oxide-cyclic GMP-potassium channel pathway for the antinociceptive effect of intrathecal zaprinast in a rat formalin test.
Zaprinast is a phosphodiesterase inhibitor that is active in various models of pain when administered locally. In addition, the antinociception of zaprinast is involved in the nitric oxide (NO)-cGMP pathway. However, the effect of zaprinast administered spinally has not been examined. Therefore, this study examined the effect of zaprinast on the formalin-induced nociception at the spinal level. Next, the role of the NO-cGMP-potassium channel pathway on the effect of zaprinast was further clarified. Catheters were inserted into the intrathecal space of male Sprague-Dawley (SD) rats. Pain was induced by applying 50 microl of a 5% formalin solution to the hindpaw. The change in the zaprinast-induced effect was examined after an intrathecal pretreatment with a NO synthase inhibitor (l-NMMA), a guanylyl cyclase inhibitor (ODQ) or a potassium channel blocker (glibenclamide). Zaprinast produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. Intrathecal l-NMMA, ODQ and glibenclamide did not reverse the antinociception of zaprinast in either phase of the formalin test. These results suggest that zaprinast is effective against both acute pain and the facilitated pain state at the spinal level. However, the NO-sensitive cGMP-potassium channel pathway is not contributable to the antinociceptive mechanism of zaprinast in the spinal cord. Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Analgesics; Animals; Cyclic GMP; Formaldehyde; Glyburide; Injections, Spinal; Male; Nitric Oxide; omega-N-Methylarginine; Oxadiazoles; Pain; Pain Measurement; Phosphodiesterase Inhibitors; Potassium Channels; Purinones; Quinoxalines; Rats; Rats, Sprague-Dawley; Signal Transduction | 2005 |
Effect of diabetes on the mechanisms of intrathecal antinociception of sildenafil in rats.
The mechanism of intrathecal antinociceptive action of the phosphodiesterase 5 inhibitor sildenafil was assessed in diabetic rats using the formalin test. Intrathecal administration of sildenafil (12.5-50 microg) produced a dose-related antinociception during both phases of the formalin test in non-diabetic and diabetic rats. Intrathecal pretreatment with N-L-nitro-arginine methyl ester (L-NAME, nitric oxide (NO) synthase inhibitor, 1-50 microg), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor, 1-10 microg), KT5823 (protein kinase G (PKG) inhibitor, 5-500 ng), charybdotoxin (large-conductance Ca2+-activated K+ channel blocker, 0.01-1 ng), apamin (small-conductance Ca2+-activated K+ channel blocker, 0.1-3 ng) and glibenclamide (ATP-sensitive K+ channel blocker, 12.5-50 microg), but not N-D-nitro-arginine methyl ester (D-NAME, 50 microg) or saline, significantly diminished sildenafil (50 microg)-induced antinociception in non-diabetic rats. Intrathecal administration of ODQ, KT5823, apamin and glibenclamide, but not L-NAME nor charybdotoxin, reversed intrathecal antinociception induced by sildenafil in diabetic rats. Results suggest that sildenafil produces its intrathecal antinociceptive effect via activation of NO-cyclic GMP-PKG-K+ channels pathway in non-diabetic rats. Data suggest that diabetes leads to a dysfunction in NO and large-conductance Ca2+-activated K+ channels. Sildenafil could have a role in the pharmacotherapy of diabetes-associated pain. Topics: Analgesia; Animals; Blood Glucose; Body Weight; Carbazoles; Cyclic GMP-Dependent Protein Kinases; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Formaldehyde; Guanylate Cyclase; Indoles; Injections, Spinal; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Oxadiazoles; Pain; Pain Measurement; Phosphodiesterase Inhibitors; Piperazines; Potassium Channel Blockers; Purines; Quinoxalines; Rats; Rats, Wistar; Sildenafil Citrate; Streptozocin; Sulfones; Time Factors | 2005 |
Participation of the NO-cyclic GMP pathway in rofecoxib-induced antinociception.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arginine; Cyclic GMP; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Guanylate Cyclase; Isoenzymes; Lactones; Molsidomine; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Oxadiazoles; Pain; Prostaglandin-Endoperoxide Synthases; Quinoxalines; Rats; Rats, Wistar; Sulfones; Uric Acid | 2003 |
Participation of the nitric oxide-cyclic GMP-ATP-sensitive K(+) channel pathway in the antinociceptive action of ketorolac.
The involvement of nitric oxide (NO), cyclic GMP and ATP-sensitive K(+) channels in the antinociceptive effect of ketorolac was assessed using the formalin test in the rat. Local administration of ketorolac in a formalin-injured paw produced a dose-dependent antinociceptive effect due to a local action, as drug administration in the contralateral paw was ineffective. Pretreatment of the injured paw with N(G)-L-nitro-arginine methyl ester (L-NAME, an NO synthesis inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, a soluble guanylyl cyclase inhibitor) or glibenclamide (an ATP-sensitive K(+) channel blocker) prevented ketorolac-induced antinociception. However, pretreatment with saline or N(G)-D-nitro-arginine methyl ester (D-NAME) did not block antinociception. Local administration of S-nitroso-N-acetylpenicillamine (SNAP, an NO donor) was inactive by itself, but increased the effect of ketorolac. The present results suggest that the antinociceptive effect of ketorolac involves activation of the NO-cyclic GMP pathway, followed by an opening of ATP-sensitive K(+) channels at the peripheral level. Topics: Adenosine Triphosphate; Analgesics; Animals; Behavior, Animal; Cyclic AMP; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Glyburide; Guanylate Cyclase; Ketorolac; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Oxadiazoles; Pain; Pain Measurement; Penicillamine; Potassium Channels; Quinoxalines; Rats; Rats, Wistar; Signal Transduction | 2001 |
Evidence for the participation of the nitric oxide-cyclic GMP pathway in the antinociceptive action of meloxicam in the formalin test.
The involvement of the nitric oxide-cyclic GMP pathway in the antinociceptive action of the cyclooxygenase-2 preferential inhibitor meloxicam was assessed in the rat formalin test. Rats received local pretreatment with saline or meloxicam and then 50 microl of dilute formalin (1%). Local administration of meloxicam produced a dose-dependent antinociception in the second phase of the formalin test. The antinociception produced by meloxicam was due to a local action as its administration in the contralateral paw was ineffective. Local pretreatment of the paws with saline or N(G)-D-nitro-arginine methyl ester (D-NAME) did not affect the antinociception produced by meloxicam. However, N(G)-L-nitro-arginine methyl ester (L-NAME, a NO synthesis inhibitor) or 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, a soluble guanylyl cyclase inhibitor) blocked in a dose-dependent way the effect of meloxicam. It is concluded that the peripheral antinociceptive effect of meloxicam involves a local NO-cyclic GMP pathway. Topics: Analgesics, Non-Narcotic; Animals; Cyclic GMP; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Formaldehyde; Guanylate Cyclase; Meloxicam; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxadiazoles; Pain; Pain Measurement; Quinoxalines; Rats; Rats, Wistar; Thiazines; Thiazoles | 2000 |
Yohimbine produces antinociception in the formalin test in rats: involvement of serotonin(1A) receptors.
Previous studies have suggested that the alpha2-adrenergic receptor antagonist yohimbine produced antinociceptive effects in the formalin test in rats. However, yohimbine is also an agonist at serotonin (5-HT)1A receptors, suggesting the possibility that the antinociceptive effects of yohimbine might be mediated via these receptors.. The purpose of the present studies was to evaluate the potential role of 5-HT(1A) receptors in mediating the antinociceptive effects of yohimbine.. The antinociceptive effects of yohimbine were evaluated using the formalin test in rats.. Yohimbine (2.5-10 mg/kg s.c.) produced dose-related antinociception during both phase I and phase II of the formalin test, and was approximately equipotent and equiefficacious to morphine. The selective 5-HT(1A) receptor antagonist WAY 100,635 (0.03-3.0 mg/kg s.c.) produced a partial reversal of yohimbine. In comparison, the selective 5-HT(1A) receptor agonist (+/-)8-hydroxy-dipropylaminotetralin HBr (8OH-DPAT; 1.0 mg/kg s.c.) also produced a dose-related antinociception in the formalin test, although 8OH-DPAT was completely reversed by WAY 100,635 (3.0 mg/kg s.c.). The antinociceptive effects of yohimbine were not antagonized by the 5-HT(1B/1D) antagonist GR 127935 (1.0 mg/kg and 3.0 mg/kg s.c.), the 5-HT2 antagonist LY53857 (1.0 mg/kg s.c.), or the 5-HT3 antagonist zatosetron (3.0 mg/kg s.c.).. The present results demonstrate that yohimbine produces a dose-related antinociception in the formalin test in rats which is mediated in part by the agonistic actions at 5-HT(1A) receptors. Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Adrenergic alpha-Antagonists; Animals; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Ergolines; Formaldehyde; Male; Nociceptors; Oxadiazoles; Pain; Pain Measurement; Piperazines; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Antagonists; Serotonin Receptor Agonists; Time Factors; Yohimbine | 2000 |
Effects of a selective 5-HT(1B/1D) receptor agonist on spinal and trigeminal reflexes in the anaesthetized rabbit.
The effects of the 5-HT(1B/1D) receptor agonist L-741,604 on a trigeminally-mediated (jaw depressor) reflex and a spinally-mediated (flexion withdrawal) reflex have been compared between spinalized and intact, anaesthetized rabbits. L-741,604 depressed the jaw depressor reflex dose-dependently in all animals, to a median of 5% (inter-quartile range, IQR, 3 - 28%, n=18) of pre-drug levels after a cumulative dose of 3.1 micromol kg(-1) i.v. This effect was reversed by the 5-HT(1B/1D) antagonist GR 127,935 (1 - 2 micromol kg(-1) i.v.). The flexion withdrawal reflex was depressed by L-741, 604 in non-spinalized animals, to a median of 22% (IQR 10 - 36%, n=10) of pre-drug levels after the highest dose, an action that was reversed by GR 127,935. In spinalized rabbits, L-741,604 up to 0.3 micromol kg(-1) i.v. cumulative increased the flexion reflex to a median of 189% (IQR 169 - 198%, n=8) of pre-drug controls. With higher doses the reflex decreased, so that after 3.1 micromol kg(-1) it was 75% (IQR 55 - 96%) of pre-drug levels. Subsequent GR 127,935 increased reflexes to a median of 180% (IQR 136 - 219%) of controls. L-741,604 increased arterial blood pressure and decreased heart rate in both preparations, effects that were reversed by GR 127,935. Thus, when the spinal cord was intact L-741,604 inhibited spinal and trigeminal reflexes in the same way. Although spinalization enabled a non-5-HT(1B/1D)-mediated excitatory effect of L-741,604 on spinal reflexes, there was a clear inhibitory effect of the drug at high doses. These data suggest that L-741,604 inhibits spinal reflexes by increasing descending inhibition and by a direct action in the cord. The same processes could apply to inhibition of trigeminally-mediated events. Topics: Animals; Blood Pressure; Dose-Response Relationship, Drug; Female; Heart Rate; Male; Oxadiazoles; Pain; Piperazines; Rabbits; Receptor, Serotonin, 5-HT1B; Receptor, Serotonin, 5-HT1D; Receptors, Serotonin; Reflex; Serotonin Receptor Agonists; Spinal Cord; Trigeminal Caudal Nucleus | 2000 |
Activation of spinal N-methyl-D-aspartate receptors stimulates a nitric oxide/cyclic guanosine 3,5-monophosphate/glutamate release cascade in nociceptive signaling.
Increasing evidence has suggested the possibility that the activation of N-methyl-D-aspartate (NMDA) receptors modulates spinal nociceptive transmission via a nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate (cGMP) pathway. However, the existence and the role of an NO/cGMP pathway in the modulation of spinal nociceptive transmission has been unclear. The authors hypothesized that the activation of NMDA receptors stimulates an NO/cGMP pathway, and this pathway evokes glutamate release within the spinal cord, modulating spinal nociceptive transmission.. The authors have examined the effects of an NO synthase inhibitor and a soluble guanylate cyclase inhibitor on the concentrations of NO metabolites (NO2-/NO3-) and glutamate in the cerebrospinal fluid after intrathecal perfusion of NMDA, concomitantly observing pain-related behavior (scratching, biting, and vocalization) in unanesthetized, free-moving rats using an intrathecal microdialysis method. The contents of cGMP in the dorsal horn were also measured using enzyme immunoassay method.. Intrathecal perfusion of NMDA produced pain-related behavior and increased glutamate and NO2-/NO3-concentrations in a dose-dependent manner. A competitive NMDA receptor antagonist, D,L-2-amino-5-phosphonovaleric acid, completely blocked the NMDA-induced responses. An NO synthase inhibitor, N(G)-monomethyl-L-arginine acetate, at a dose that completely blocked the increase in NO2-/NO3-, inhibited both the NMDA-induced pain-related behavior and the increase in glutamate concentration. In addition, a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazole[4,3-a]quinoxaline-1-one, also inhibited significantly NMDA-induced pain-related behavior and the increase in glutamate concentration. NMDA induced an increase in cGMP in the dorsal half of the spinal cord, which was blocked by N(G)-monomethyl-L-arginine acetate.. The results of this study support the hypothesis that the activation of NMDA receptors modulated pain-related behavior via an NO/cGMP/glutamate release cascade within the spinal cord. Topics: 2-Amino-5-phosphonovalerate; Animals; Behavior, Animal; Cyclic GMP; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Glutamic Acid; Guanylate Cyclase; Male; Microdialysis; Nitric Oxide; Nociceptors; omega-N-Methylarginine; Oxadiazoles; Pain; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Spinal Cord; Synaptic Transmission | 1999 |
Nitric oxide signaling in pain and nociceptor sensitization in the rat.
We investigated the role of nitric oxide (NO) in inflammatory hyperalgesia. Coinjection of prostaglandin E2 (PGE2) with the nitric oxide synthase (NOS) inhibitor NG-methyl-L-arginine (L-NMA) inhibited PGE2-induced hyperalgesia. L-NMA was also able to reverse that hyperalgesia. This suggests that NO contributes to the maintenance of, as well as to the induction of, PGE2-induced hyperalgesia. Consistent with the hypothesis that the NO that contributes to PGE2-induced sensitization of primary afferents is generated in the dorsal root ganglion (DRG) neurons themselves, L-NMA also inhibited the PGE2-induced increase in tetrodotoxin-resistant sodium current in patch-clamp electrophysiological studies of small diameter DRG neurons in vitro. Although NO, the product of NOS, often activates guanylyl cyclase, we found that PGE2-induced hyperalgesia was not inhibited by coinjection of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a guanylyl cyclase inhibitor. We then tested whether the effect of NO depended on interaction with the adenylyl cyclase-protein kinase A (PKA) pathway, which is known to mediate PGE2-induced hyperalgesia. L-NMA inhibited hyperalgesia produced by 8-bromo-cAMP (a stable membrane permeable analog of cAMP) or by forskolin (an adenylyl cyclase activator). However, L-NMA did not inhibit hyperalgesia produced by injection of the catalytic subunit of PKA. Therefore, the contribution of NO to PGE2-induced hyperalgesia may occur in the cAMP second messenger pathway at a point before the action of PKA. We next performed experiments to test whether administration of exogenous NO precursor or donor could mimic the hyperalgesic effect of endogenous NO. Intradermal injection of either the NOS substrate L-arginine or the NO donor 3-(4-morphinolinyl)-sydnonimine hydrochloride (SIN-1) produced hyperalgesia. However, this hyperalgesia differed from PGE2-induced hyperalgesia, because it was independent of the cAMP second messenger system and blocked by the guanylyl cyclase inhibitor ODQ. Therefore, although exogenous NO induces hyperalgesia, it acts by a mechanism different from that by which endogenous NO facilitates PGE2-induced hyperalgesia. Consistent with the hypothesis that these mechanisms are distinct, we found that inhibition of PGE2-induced hyperalgesia caused by L-NMA could be reversed by a low dose of the NO donor SIN-1. The following facts suggest that this dose of SIN-1 mimics a permissive effect of basal levels of NO with regard to PGE2-ind Topics: Animals; Dinoprostone; Enzyme Inhibitors; Guanylate Cyclase; Hyperalgesia; Male; Nitric Oxide; Nitric Oxide Synthase; Nociceptors; omega-N-Methylarginine; Oxadiazoles; Pain; Quinoxalines; Rats; Rats, Sprague-Dawley; Serotonin Receptor Agonists; Signal Transduction; Tetrodotoxin | 1998 |
Analgesic and anti-inflammatory effects of 3-[3-(phenyl)-1,2,4-oxadiazol-5-yl] propionic acid.
Significant local analgesic and anti-inflammatory activity has been observed after oral administration of 3-[3-(phenyl)-1,2,4-oxadiazol-5-yl] propionic acid (POPA). Doses of 150 and 300 mg/kg body weight administered orally by gavage to adult (25-35 g) albino mice of both sexes can inhibit acetic acid-induced writhing by 31.0% and 49.5%, respectively (mean +/- SEM writhing numbers during 20 min were 52.0 +/- 6.0 and 38.3 +/- 7.2 vs 75.8 +/- 6.6 for control group which received saline; N = 6). Carrageenin-induced inflammation in the female Wistar rat (200-250 g) can be reduced by 43.3% and 42.2% 3 h after oral administration (gavage) of 75 and 150 mg/kg of POPA (mean +/- SEM, 30.0 +/- 1.3% and 30.6 +/- 2.4% vs 52.9 +/- 3.7% for control group which received saline; N = 5). In the hot plate test on adult albino mice (25-35 g) of both sexes, POPA (150 and 300 mg/kg, po) was totally ineffective (N = 10). Our results indicate that POPA appears to offer potential safety and efficacy as a local analgesic and anti-inflammatory agent with no central nervous system involvement Topics: Administration, Oral; Analgesics; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Female; Inflammation; Male; Mice; Oxadiazoles; Pain; Rats; Rats, Wistar; Time Factors | 1994 |
The NMDA receptor: central role in pain inhibition in rat periaqueductal gray.
An injection of the excitatory amino acid analogue, N-methyl-D-aspartate (NMDA), in the rat periaqueductal gray resulted in potent analgesia. A prior injection of the NMDA antagonist, (-)-2-amino-7-phosphonoheptanoate (D-AP7), antagonized this action, indicating a receptor-mediated action. NMDA given with morphine potentiated the morphine analgesia while D-AP7 blocked morphine analgesia. These results delineate for the first time a functional role for the NMDA receptor in the control of pain in the mammalian central nervous system. Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Analgesia; Animals; Aspartic Acid; Kainic Acid; Male; Morphine; N-Methylaspartate; Oxadiazoles; Pain; Periaqueductal Gray; Quisqualic Acid; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter | 1988 |
Nociceptive action of excitatory amino acids in the mouse: effects of spinally administered opioids, phencyclidine and sigma agonists.
Intrathecal administration of the excitatory amino acid (EAA) agonists, N-methyl-D-aspartate (NMDA), quisqualate (Quis) or kainic acid (KA), in the spinal subarachnoid space of mice produced a dose-related biting and scratching behavior. Higher doses appeared aversive, suggesting a nociceptive action for EAAs in the spinal cord. Intrathecally administered NMDA, but not Quis or KA, produced a hyperalgesic effect in the tail-flick and hot-plate tests. To test the hypothesis that EAA agonists are involved in transmission of nociceptive information in the spinal cord, we tested the effect of various opioid, sigma and phencyclidine compounds on the action of NMDA in the tail-flick, hot-plate and biting and scratching nociceptive tests. Our results indicated that the involvement of mu, sigma and phencyclidine receptors was predominant in blockade of the behavioral and hyperalgesic effects of intrathecally administered NMDA. Delta receptors appeared less involved, and involvement of kappa receptors was not detectable in blockade of the behavioral and hyperalgesic effects of intrathecally administered NMDA. Quis and KA effects were not altered by any of these agonists. Agonist doses required to inhibit NMDA-induced hyperalgesia in the tail-flick and hot-plate tests were significantly less than those needed to inhibit biting and scratching behavior. The adrenergic agonist norepinephrine inhibited NMDA- but not Quis- or KA-induced biting and scratching behavior. This action appeared to be alpha-1 mediated because it was reversed by phentolamine but not by yohimbine. These results suggest that the actions of EAAs in the spinal cord are differentially affected by various opioid phencyclidine, sigma and adrenergic receptor agonists and support the hypothesis that EAAs are involved in the transmission of nociceptive information in the spinal cord. Topics: Animals; Aspartic Acid; Enkephalins; Hot Temperature; Kainic Acid; Male; Mice; N-Methylaspartate; Narcotics; Nociceptors; Oxadiazoles; Pain; Phencyclidine; Phentolamine; Quisqualic Acid; Receptors, Opioid; Receptors, sigma; Spinal Cord | 1987 |
[Effect of sidnocarb on learning and memory].
It has been established that in well-trained rats sydnocarb (mesocarb) does not exert a considerable effect on the generation of conditioned reflex of passive avoidance (CRPA). On the contrary, in poorly-trained animals sydnocarb significantly improves CRPA indexes at all three stages of its generation. Sydnocarb proved most effective, when injected before training (on day I). The absence of sydnocarb-induced pain threshold decrease in response to electrical pain stimulation suggests a direct drug effect on memory processes. Topics: Animals; Conditioning, Classical; Escape Reaction; Learning; Male; Memory; Oxadiazoles; Pain; Psychotropic Drugs; Rats; Reinforcement, Psychology; Sensory Thresholds; Sydnones | 1987 |
[Duodenal mechanogram during treatment of visceral algospastic states with propaxoline].
Topics: Duodenum; Gastrointestinal Diseases; Gastrointestinal Motility; Humans; Oxadiazoles; Pain; Spasm | 1967 |
[Clinical experience with a new spasmolithic: propaxoline].
Topics: Adult; Aged; Anti-Inflammatory Agents; Female; Humans; Male; Middle Aged; Muscles; Oxadiazoles; Pain | 1967 |