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Dipyrone (DIP), also known as metamizole, is an over-the-counter analgesic used in Europe and Latin America. Evidence suggesting that inflammatory pain attenuation by DIP is associated with a direct impact on peripheral primary nociceptive neurons through the stimulation of nitric oxide signaling pathway. However, the molecular mechanism by which DIP activates this pathway remains unknown. The PI3Kγ/AKT signaling cascade activation is one of the well-known molecular mechanisms that promote nitric oxide production in sensory neurons. Herein, we investigated the role of the PI3Kγ/AKT signaling cascade in the context of peripheral analgesic effect of DIP. DIP was administered into PGE2 pre-sensitized paws of rats and mechanical hyperalgesia was determined using electronic von Frey test after 1 h. Nonselective or selective pharmacological inhibitors of PI3Kγ and AKT were also administered in DIP-treated rats under paws sensitized with PGE2. Intraplantar injection of DIP attenuated PGE2-induced hyperalgesia in a dose-dependent manner. Treatment with nonselective (wortmannin or LY294002) or selective (AS605240) pharmacological inhibitors of PI3Kγ reduced the peripheral antihypernociceptive effect of DIP. Consistently, AKT selective inhibitor also reversed analgesic DIP effects. Corroborating these data, we found that DIP induced AKT phosphorylation in cultured dorsal root ganglion neurons, which was prevented in the presence of PI3Kγ selective inhibitor. Taken together, these findings provide evidence that peripheral analgesic effect of DIP is dependent on the activation of PI3Kγ/AKT signaling pathway., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Pain is a classical sign of inflammation, and sensitization of primary sensory neurons (PSN) is the most important mediating mechanism. This mechanism involves direct action of inflammatory mediators such as prostaglandins and sympathetic amines. Pharmacologic control of inflammatory pain is based on two principal strategies: (i) non-steroidal anti-inflammatory drugs targeting inhibition of prostaglandin production by cyclooxygenases and preventing nociceptor sensitization in humans and animals; (ii) opioids and dipyrone that directly block nociceptor sensitization via activation of the NO signaling pathway. This review summarizes basic concepts of inflammatory pain that are necessary to understand the mechanisms of peripheral NO signaling that promote peripheral analgesia; we also discuss therapeutic perspectives based on the modulation of the NO pathway., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Tagetes lucida Cav. (Asteraceae) is an ancient medicinal plant commonly used to alleviate pain. Nevertheless, scientific studies validating this property are lacking in the literature. Animal models of pain were used to evaluate the antinociceptive and anti-inflammatory activities of T. lucida essential oil (TLEO) and a bioactive metabolite. The chemical constitution and possible toxicity of the extract and the mechanism of action of β-caryophyllene were also explored. Temporal course curves and dose-response graphics were generated using TLEO (0.1-10 mg/kg or 3.16-31.62 mg/kg) and β-caryophyllene (3.16-10 mg/kg). Metamizole (80 mg/kg) and indomethacin (20 mg/kg) were used as reference drugs in the formalin assay and writhing test in rats and mice, respectively. The β-caryophyllene mechanism of action was explored in the presence of naloxone (1 mg/kg), flumazenil (10 mg/kg), WAY100635 (0.16 mg/kg), or nitro-l-arginine methyl ester (L-NAME) (20 mg/kg) in the formalin test in rats. GC/MS analysis demonstrated the presence of geranyl acetate (49.89%), geraniol (7.92%), and β-caryophyllene (6.27%). Significant and dose-dependent antinociceptive response was produced by TLEO and β-caryophyllene without the presence of gastric damage. In conclusion, β-caryophyllene was confirmed as a bioactive compound in the T. lucida analgesic properties by involving the participation of receptors like opioids, benzodiazepines, and Serotonin 1A receptor (5-HT 1A ), as well as nitric oxide.

Objective: To investigate the relationship between metamizol pharmacokinetics and the antinociceptive effect produced after subcutaneous administration of metamizol (177.8 mg/kg) alone or in combination with morphine (3.2 mg/kg), under acute and chronic treatments., Methods: Antinociception was assessed using the pain-induced functional impairment model in rat (PIFIR). Serial blood samples were collected from the same animals to study the pharmacokinetics of metamizol., Key Findings: The co-administration of the drugs in single dose, confirmed the potentiation of their individual antinociceptive effects. When the drugs were administered alone following the chronic schedule, a pronounced tolerance development to their antinociceptive effects was found, whereas it was significantly attenuated when they were administered together. Metamizol pharmacokinetics was unaltered by the presence of morphine. Plasma concentrations of 4-methylaminoantipyrine, an active metabolite markedly decreased under chronic administration., Conclusions: The mechanism involved in the potentiation of the antinociceptive effect produced by the combination, cannot be explained by the interaction of morphine on metamizol pharmacokinetics. Other pharmacokinetic interactions along with known pharmacodynamic interactions in which metamizol active metabolites contribute, should be considered. The frequency of administration enhances tolerance development and induces metamizol elimination process., (© 2017 Royal Pharmaceutical Society.)

Background and Purpose: Although still used by hundreds of millions of people worldwide, the mechanism of the analgesic action of the pyrazolone derivatives (PDs), dipyrone, propyphenazone and antipyrine remains unknown. The transient receptor potential ankyrin 1 (TRPA1) channel, expressed by nociceptors, is emerging as a major pain transduction pathway. We hypothesized that PDs target the TRPA1 channel and by this mechanism produce their analgesic effect., Experimental Approach: Calcium responses and currents were studied in cultured TRPA1-expressing rodent dorsal root ganglion neurons and human cells. Acute nociception and mechanical hypersensitivity were investigated in naïve and genetically manipulated mice., Key Results: Pyrazolone and PDs selectively inhibited calcium responses and currents in TRPA1-expressing cells and acute nocifensor responses in mice evoked by reactive channel agonists (allyl isothiocyanate, acrolein and H2 O2 ). In line with recent results obtained with TRPA1 antagonists and TRPA1 gene deletion, the two most largely used PDs, dipyrone and propyphenazone, attenuated TRPA1-mediated nociception and mechanical allodynia in models of inflammatory and neuropathic pain (formalin, carrageenan, partial sciatic nerve ligation and the chemotherapeutic drug, bortezomib). Notably, dipyrone and propyphenazone attenuated carrageenan-evoked mechanical allodynia, without affecting PGE2 levels. The main metabolites of PDs did not target TRPA1 and did not affect TRPA1-dependent nociception and allodynia., Conclusions and Implications: Evidence that in rodents the nociceptive/hyperalgesic effect produced by TRPA1 activation is blocked by PDs suggests that a similar pathway is attenuated by PDs in humans and that TRPA1 antagonists could be novel analgesics, devoid of the adverse haematological effects of PDs., (© 2015 The British Pharmacological Society.)

Experiments on rats divided into two groups (with high and low pain sensitivity) were used to assess the effect of tropalgin, a new derivative of tropine, in thermal pain tests (tail-flick and hot plate). Tropalgin was found to possess an analgesic effect comparable to that of reference sodium metamizole. ED50 of tropalgin was 2 mg/kg for intraperitoneal administration. The duration of the analgesic effect of tropalgin in rats low pain sensitivity was longer than in animals highly sensitive to pain. It is suggested that the analgesic effect of tropalgin can be related to the adenosine liberating action of this drug.

We compared analgesic activities of individual alkaloids extracted from Baikal aconite (Aconitum baikalensis): napelline, hypaconitine, songorine, mesaconitine, 12-epinapelline N-oxide. The detected analgesic activity was comparable to that of sodium metamizole. The mechanisms of analgesia were different in diterpene alkaloids of different structure. The antinociceptive effect of atisine alkaloids (12-epinapelline N-oxide, songorine) was naloxonedependent and realized via opioid receptor modulation.

Cannabinoid CB1 receptors have been implicated in the antinociceptive effect of paracetamol. In the current study, we examined whether blockade of CB1 receptors prevent the analgesic activity of dipyrone, in a similar way to paracetamol. Hot-plate and tail-flick tests were used to assess the antinociceptive activity in mice. Dipyrone and WIN 55,212-2, a cannabinoid agonist, exerted significant antinociceptive effects in both hot-plate and tail flick tests. The CB1 receptor antagonist, AM-251 (3 mg/kg), at a dose which had no effect when used alone, did not alter the antinociceptive effect of dipyrone, whereas completely prevented the antinociceptive activity of WIN 55,212-2 in both thermal antinociceptive tests. Our findings suggest that, unlike paracetamol, cannabinoid CB1 receptors do not participate in the antinociceptive action of dipyrone when acute pain tests used.

Salicylaldehyde 2-chlorobenzoyl hydrazone (H(2)LASSBio-466), salicylaldehyde 4-chlorobenzoyl hydrazone (H(2)LASSBio-1064) and their complexes [Zn(LASSBio-466)H(2)O](2) (1) and [Zn(HLASSBio-1064)Cl](2) (2) were evaluated in animal models of peripheral and central nociception, and acute inflammation. All studied compounds significantly inhibited acetic acid-induced writhing response. Upon coordination the anti-nociceptive activity was favored in the complex 1. H(2)LASSBio-466 inhibited only the first phase of the formalin test, while 1 was active in the second phase, like indomethacin, indicating its ability to inhibit nociception associated with the inflammatory response. Hence coordination to zinc(II) altered the pharmacological profile of H(2)LASSBio-466. H(2)LASSBio-1064 inhibited both phases but this effect was not improved by coordination. The studied compounds did not increase the latency of response in the hot plate model, indicating their lack of central anti-nociceptive activity. All compounds showed levels of inhibition of zymosan-induced peritonitis comparable or superior to indomethacin, indicating an expressive anti-inflammatory profile.

Context: Capparis ovata Desf. (Capparaceae) grows widely in Turkey. Flower buds and fruits of the plant are used in folk medicine for their analgesic, antirheumatismal, and diuretic effects., Objective: This study evaluated the possible antinociceptive effect of the methanol extract of C. ovata (CME) in mice., Materials: The antinociceptive effect of methanol extract, prepared with the C. ovata flower buds, was studied at the doses of 50, 100, and 200 mg/kg (i.p.) using tail-immersion, hot-plate, and writhing tests in mice. Morphine sulfate (5 mg/kg; i.p.) and dipyrone (100 mg/kg; i.p.) were used as reference analgesic agents. Naloxone (5 mg/kg; i.p.) was also tested., Results: It was observed that the C. ovata extract had a significant antinociceptive effect in these tests. In the hot-plate and tail-immersion test results, the doses of 50, 100, and 200 mg/kg increased the percentage of the maximum possible effect (MPE%) value for nociception significantly according to the control value (P < 0.001). All doses of the extract decreased the number of acetic acid-induced abdominal constrictions in mice when compared with control group (P < 0.001). These effects were inhibited by pretreatment with naloxone., Discussion and Conclusion: Based on the results obtained, it can be concluded that CME is a potentially antinociceptive agent which acts as both at the peripheral and central levels.

Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly used for treatment of arthritis. However, their long-term use has been associated with considerable morbidity, limiting their application. Thus, there remains a need to develop new drugs for the effective and safe relief of chronic inflammatory pain. In this context, the present study was designed to evaluate the antinociceptive and antiedematogenic effects of the 5-trifluoromethyl-4,5-dihydro-1H-pyrazole derivatives EPFCA3 and MPFCA4 after acute (1-1000 micromol/kg) and chronic (100 micromol/kg for 15 days) administration in rats submitted to a model of adjuvant-induced arthritis. We also analyzed some biochemical indicators of toxicity (alanine aminotransferase, aspartate aminotransferase, urea and creatinine levels) after prolonged administration of these compounds. We found that acute and chronic subcutaneuous administration of EPFCA3 and MPFCA4 produces an antinociceptive, but not antiedematogenic, effect on the arthritis animal model induced by complete Freund's adjuvant (CFA). No signs of toxicity were observed in the animals chronically treated with EPFCA3 or MPFCA4. Dipyrone (1-1000 micromol/kg) was used as the positive control and its effect was similar to that of the novel pyrazoles. The activity of tissue myeloperoxidase, the tissue TNF-alpha level and the serum haptoglobin level was increased by intraplantar CFA injection. However, chronic administration of EPFCA3, MPFCA4 or dipyrone was not able to alter the relation between these parameters and inflammation. Our results suggest that EPFCA3 and MPFCA4 are good candidates for the development of new drugs for pain treatment.

Opiate analgesia can be hampered by a reduction in pharmacological effectiveness (tolerance), and this crucially depends on the periaqueductal gray matter (PAG). Non-opioids like metamizol (dipyrone) or aspirin also induce PAG-dependent analgesia and tolerance, but the neuronal bases of this tolerance are unknown. Metamizol is a pyrazolon derivative and cyclooxygenase inhibitor with widespread use as an analgesic in Europe and Latin America. Metamizol was microinjected into the PAG of awake male rats, and antinociception was assessed by the tail flick (TF) and hot plate (HP) tests. Microinjection twice daily for 2.5 days caused tolerance to metamizol. The rats were then anesthetized and recordings from pain-facilitating on-cells and pain-inhibiting off-cells of the rostral ventromedial medulla (RVM) were performed. PAG microinjection of morphine or metamizol depresses on-cells, activates off-cells and thus inhibits nociception, including TF and HP. In metamizol-tolerant rats, however, PAG microinjection of metamizol failed to affect on- or off-cells, and this is interpreted as the reason for tolerance. In metamizol-tolerant rats morphine microinjection into PAG also failed to affect RVM neurons or nociception (cross-tolerance). In naïve, non-tolerant rats the antinociceptive effect of PAG-microinjected metamizol or morphine was blocked when CTOP, a mu-opioid antagonist, was previously microinjected into the same PAG site. These results emphasize a close relationship between opioid and non-opioid analgesic mechanisms in the PAG and show that, like morphine, tolerance to metamizol involves a failure of on- and off-cells to, respectively, disfacilitate and inhibit nociception. Cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting.

The aim of this study was to improve the mustard oil (MO) induced temporomandibular joint (TMJ) nociception model and to investigate the potential analgesic activity of systemic dipyrone and tramadol on the nociceptive behavioral responses induced by injection of low concentrations of the MO into the rat TMJ region. TMJ injection of 2.5% MO produced a significant nociceptive behavior expressed by head flinching and orofacial rubbing. This activity was related to the MO injection since mineral oil (vehicle) did not elicit response. Local application of the lidocaine N-ethyl bromide quaternary salt, QX-314 (2%) and systemic administration of morphine (4 mg/kg) significantly reduced the MO-induced nociceptive responses, validating the nociceptive character of the behaviors. The pretreatment with systemic dipyrone (19, 57 or 95 mg/kg) as well as tramadol (5, 7.5 or 10 mg/kg) was effective in decreasing the nociceptive behavioral responses induced by the injection of MO into the rat TMJ. In conclusion, TMJ injection of low concentrations of MO in rats produces well defined and quantifiable nociceptive behaviors constituting a reliable behavioral model for studying TMJ pain mechanisms and testing analgesic drugs. The results also suggest that dipyrone and tramadol could be effective analgesic options in the management of TMJ pain.

Aims: The aim of the present study was to evaluate the antinociceptive effect of the novel pyrazoline methyl ester: 4-methyl-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazole methyl ester (MPF4)., Main Methods: The effect of MPF4 was assessed in two models of pain: arthritic pain caused by Complete Freund's Adjuvant (CFA) and postoperative pain caused by surgical incision in mice., Key Findings: MPF4 given intraperitoneally (1.0 mmol/kg, i.p.) produced marked antinociception in inflammatory allodynia caused by CFA. The antinociceptive effect produced by MPF4 was reversed with the pre-treatment of animals with naloxone or naltrindole. Oral administration of MPF4 (1.0 mmol/kg, p.o), dipyrone (1.0 mmol/kg, p.o.) and morphine (0.026 mmol/kg, p.o.) also produced an anti-allodynic effect. However, none of the compounds evaluated reversed the paw edema produced by CFA. Moreover, MPF4, dipyrone and morphine also produced an anti-allodynic effect in the surgical incisional pain model. The maximal inhibitions obtained with preemptive drug treatment were 66+/-7%, 73+/-9% and 88+/-8% for MPF4 (1.0 mmol/kg, p.o.), dipyrone (1.0 mmol/kg, p.o.) and morphine (0.026 mmol/kg, p.o.), respectively. The maximal inhibitions obtained with curative drug treatment were 53+/-9%, 83+/-7% and 84+/-7%, for MPF4, dipyrone and morphine, respectively. Unlike indomethacin, MPF4 did not induce gastric lesions at the dose that caused the highest antinociception (1.0 mmol/kg, p.o). The anti-allodynic action of MPF4, dipyrone and morphine was not associated with impairment of motor activity., Significance: The results of the present study suggest that MPF4 represents a potential target for the development of new drugs to treat persistent inflammatory pain.

Background and Purpose: The analgesics, paracetamol and dipyrone are weak inhibitors of the cyclooxygenase isoforms 1 or 2 (COX-1, COX-2) but more potent on COX-3. Both are also weak anti-inflammatory agents, relative to their analgesic and antipyretic activities. In a model of inflammatory pain mediated by prostaglandins, both compounds were analgesic. We have analysed this shared effect further in order to elucidate the underlying mechanisms., Experimental Approach: Inflammation was induced in one hind paw of rats by intraplantar injection of 250 microg lambda-carrageenan (CG) and the contralateral paw injected with saline. Nociceptive thresholds to mechanical stimulation were measured immediately before and for 6 h after, injection of CG. The analgesics were s.c. or locally (intraplantar) injected either 30 min before or 2 h after CG. In some groups, naltrexone was injected (s.c. or intraplantar), 1 h before CG., Key Results: Pretreatment with paracetamol or dipyrone (60-360 mg kg(-1)) reversed hyperalgesia induced by CG and increased nociceptive threshold in the inflamed paw above the basal level (hypoalgesia). Paracetamol, but not dipyrone, also raised nociceptive thresholds in the non-inflamed paw. Subcutaneous, but not local, administration of naltrexone, a specific opioid antagonist, reversed the hypoalgesia induced by paracetamol, but similar naltrexone treatment had no effect on dipyrone-induced analgesia., Conclusions and Implications: Although both paracetamol and dipyrone are inhibitors of COX isoforms and thus of prostaglandin biosynthesis and were analgesic in our model, their analgesic actions were functionally and mechanistically different. Satisfactory mechanisms of action for these analgesics still remain to be established.

Introduction: Adjunct nonopioid analgesics may improve pain control in patients with cancer needing morphine or its derivates. Dipyrone is a cheap nonopioid analgesic widely used in many countries., Objective: The objective of the study was to evaluate, whenever morphine was started, if associating dipyrone with it would improve pain control and if this effect was time dependent., Materials and Methods: This is a double-blind placebo-controlled randomized crossover study. Thirty-four ambulatory cancer patients experiencing cancer-related pain for which oral morphine was to be started at the dose of 10 mg orally (PO) every 4 h were randomized to take either dipyrone 500 mg PO every 6 h or placebo. After 48 h, patients would be switched from dipyrone to placebo and vice versa. Pain was the primary outcome and was measured using a visual analogue scale before starting medications, at 48 and 96 h., Results: We randomized 16 patients to start with placebo (group 1) and 18 with dipyrone (group 2). Pain scores for groups 1 and 2 were at baseline: 7.31 +/- 0.29 vs 6.88 +/- 0.28 (p = 0.3), at 48 h: 7.06 +/- 0.32 vs 5.5 +/- 0.31 (p = 0.001), and at 96 h: 3.18 +/- 0.39 vs 1.94 +/- 0.37 (p = 0.03). Both groups had significant improvements in pain scores after introducing dipyrone (p < 0.001, for both). Main toxicities were nausea, vomiting, epigastric pain, and myalgias. Twenty-eight patients chose dipyrone, four placebo, and two were indifferent., Conclusions: We conclude that dipyrone adds significantly to the analgesic effect of morphine and, when given at the time of starting morphine, results in better pain scores even after dipyrone is discontinued.

The influence of tiagabine at a dose of 3.2 mg/kg (single administration) and at a dose of 1.2 mg/kg (multiple administration - 10 days) on the antinociceptive effect of morphine (10 mg/kg), metamizole (500 mg/kg) and indomethacin (10 mg/kg - single dose and 1.4 mg/kg - multiple doses) was investigated in mice using the hot-plate and tail-flick tests. All drugs were injected intraperitoneally. Tiagabine was administered to mice 30 min before the analgesic drugs. Measurement of the reaction to a noxious stimulus was performed 60, 90 and 120 min after administration of tiagabine. The study was further conducted for 10 days with repeated drug doses. Tiagabine and morphine administered in single doses demonstrate an additive antinociceptive effect in the hot-plate test and a slightly synergistic effect in the tail-flick test. A single administration of tiagabine slightly increased the antinoceptive action of metamizole and indomethacin in both tests, but that effect is less pronounced than the antinociceptive action of tiagabine alone. Repeated administration of tiagabine with morphine abolishes the tolerance to morphine analgesia. Both single and repeated administration of tiagabine alone exerted the antinociceptive effect in the hot-plate test.

Background: While many preclinical models detect the analgesic activity of nonsteroidal antiinflammatory drugs (NSAIDs), the radiant heat tail-flick response has repeatedly been insensitive to this class of drugs. As the tail-flick test involves nociceptive processing at spinal circuits with supraspinal modulation, it seems reasonable to assume that the NSAIDs should not modify strong nociceptive stimuli, since the primary site of action of NSAIDs is likely to be in the periphery., Methods: We injected 3-300 mug of diclofenac, dipyrone, ketorolac, lysine acetyl salicylate, and sodium salicylate intradermally into mice tails and evaluated the tail-flick response to radiant heat. These results were compared with intraperitoneally injected controls. We also evaluated the ability of naloxone to reverse the observed effects., Results: Intradermal injection of each NSAID produced a dose-dependent increase in tail-flick latency. Intraperitoneal NSAIDs injection produced no antinociceptive effects. Naloxone pretreatment had no effect on the antinociceptive effects of intradermal diclofenac, ketorolac, lysine acetyl salicylate, and sodium salicylate. Naloxone completely blocked the antinociceptive effects of intradermal dipyrone., Conclusions: Local, but not systemic, administration of NSAIDs produced antinociception in the tail-flick thermal assay. The endogenous opioid system contributes to the peripheral antinociceptive effects of dipyrone, but not to that of diclofenac, ketorolac, lysine acetyl salicylate, or sodium salicylate, suggesting differences in the mechanisms of action among the NSAIDs.

The combined administration of low doses of opiates with non-steroidal anti-inflammatory drugs can produce additive or supra-additive analgesic effects while reducing unwanted side effects. We have recently reported that co-administration of morphine with dipyrone (metamizol) produces analgesic potentiation both in naïve and in morphine-tolerant rats. The purpose of this work was to determine the role of opioids on the acute potentiation observed between morphine and dipyrone i.v. in the rat tail flick test. To do this, two experiments were done. In the first one, naloxone was administered 10 min before morphine (3.1 mg/kg), dipyrone (600 mg/kg) or their combination at the same doses. Control animals received saline instead of naloxone. In the second experiment, naloxone (or saline) was given 2 min after reaching the maximal peak effect with each individual analgesic treatment. When naloxone was i.v. administered prior to analgesics, it completely blocked morphine effects, partially prevented morphine/dipyrone antinociception and delayed dipyrone-induced nociception. At 3.1 mg/kg, naloxone produced an increased nociception. When naloxone was given after analgesics, it dose-dependently blocked the effects of morphine alone and in combination with dipyrone but with different potency in each case. As to dipyrone, naloxone delayed the time to antinociceptive peak effect. Taken together, these results support the notion that endogenous opioids are involved in the analgesic potentiation observed with the combination of morphine plus dipyrone.

In this study we characterized the nociceptive response and edema induced by the venom of the scorpion Tityus serrulatus in rats and mice and carried out a preliminary pharmacological investigation of the mechanisms involved in these responses. Intraplantar injection of the venom (1 or 10mug) induced edema and a marked ipsilateral nociceptive response, characterized by thermal and mechanical allodynia and paw licking behaviour. The nociceptive response was inhibited by previous intraperitoneal administration of indomethacin (4mg/kg), dipyrone (200mg/kg), cyproheptadine (10mg/kg) or morphine (5 or 10mg/kg), but not by dexamethasone (1 or 4mg/kg) or promethazine (1 or 5mg/kg). The edema was inhibited by previous treatment with promethazine (5 or 10mg/kg) or cyproheptadine (5 or 10mg/kg), but not by indomethacin (2 or 4mg/kg), dexamethasone (1 or 4mg/kg) or cromolyn (40 or 80mg/kg). Some bioactive amines, including histamine and 5-hydroxytryptamine, were found in the venom in low concentrations. In conclusion, the nociceptive response and edema induced by the venom of T. serrulatus may result from the action of multiple mediators including eicosanoids, histamine and 5-hydroxytryptamine. These results may lead to a better understanding of the host response to potent animal toxins and also give insights into a more rational pharmacological approach to alleviate the intense pain associated with the scorpion envenomation.

The antinociceptive activity of (-)-spectaline (1), a piperidine alkaloid isolated from Cassia leptophylla Vog. (Leguminosae), was investigated. We have also studied the acute oral toxicity of 1 in mice and it did not show any signals of toxicity in doses lower than 400 micromol/kg. The antinociceptive effect of 1 was evaluated on chemical (acetic acid, formalin and capsaicin) and thermal (hot plate and tail flick) pain models in mice, using classical standard drugs. Dipyrone ID (50) = 14.68 micromol/kg (4.8 mg/kg), indomethacin ID (50) = 0.78 micromol/kg (0.28 mg/kg) and (-)-spectaline ID (50) = 48.49 micromol/kg (15.75 mg/kg), all produced a significant inhibition of acetic acid-induced abdominal writhing in mice. (-)-Spectaline was inactive in the hyperalgesic model of formalin and did not show any central analgesic activity (hot plate and tail flick models). In the capsaicin-induced neurogenic pain model, (-)-spectaline presented an important inhibitory effect with an ID (50) = 20.81 microg/paw and dipyrone ID (50) = 19.89 microg/paw. The ensemble of results permitted us to identify 1 as an antinociceptive compound. The mechanism underlying this antinociceptive effect of 1 remains unknown, but the results suggest that such an effect could be related to pathways associated to vanilloid receptor systems.

We investigated the scoring properties of the mouse formalin test using the time-sampling method recently developed for infant and adult rats. Formalin was injected under the plantar surface of one rear paw (10 microl, 1-8%), and pain behaviours (paw favouring, lifting and licking) and behavioural state were recorded. Correlational and regression analyses indicated that scores composed of combinations of all three pain behaviours, either summed or weighted, provided less variable indices of pain than licking alone. The maximum percent effect (MPE(50); i.e. pain behaviour 50% of the time) for the log formalin concentration-effect curves was 3-4% in both phases. Habituation to the test environment prior to testing did not alter the MPE(50)s, but slopes were lower in unhabituated mice, dramatically increasing the size of the confidence interval. Formalin dose-dependently reduced locomotion, rearing and sniffing in both the first phase and the early part of the second phase. The combination measures were sensitive to morphine (2-8 mg/kg), amphetamine (1-4 mg/kg), dipyrone (50-200 mg/kg), xylazine (0.25-1 mg/kg), and acepromazine (0.25-1 mg/kg), and resistant to diazepam (0.5-2 mg/kg), pimozide (0.05-0.25 mg/kg), pentobarbital (10 and 15 mg/kg) and indomethacin (2-8 mg/kg). Decreased pain was correlated with increased motor activity for morphine and amphetamine, and with decreased activity for xylazine and acepromazine; dipyrone and indomethacin did not alter activity levels.

Non-opioid analgesics have been shown to elicit antinociception by an action upon central nervous system structures, in addition to their well known action upon peripheral tissues. Microinjection of metamizol (dipyrone), a widely used nonopioid analgesic, into the periaqueductal grey matter (PAG) of rats activates pain-modulating systems in the nucleus raphe magnus and inhibits spinal nociceptive neurons and the tail-flick reflex. Since these effects involve an activation of endogenous opioidergic systems, the possibility that metamizol induces opioid tolerance was investigated. Microinjection of metamizol into the ventrolateral PAG in awake rats induced antinociception, as demonstrated in the heat-elicited tail flick and hot plate tests. When microinjected into the ventrolateral PAG twice daily for 2 days, metamizol induced tolerance, i.e. a progressive loss of its antinociceptive effect. In contrast to rats repeatedly microinjected with saline, metamizol-tolerant rats were also tolerant to morphine microinjection into the same PAG site, and displayed signs of opioid withdrawal upon systemic administration of naloxone. These and other results suggest that metamizol activates endogenous opioid systems and that nonopioid analgesics may, by an action upon the central nervous system, lead to opioid tolerance and the risk of opioid withdrawal.

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

The antinociceptive and rewarding effects of phenacetin, a mild analgesic with abuse liability, were compared with those of acetaminophen, dipyrone and indomethacin in the formalin and conditioned place preference tests. Phenacetin, acetaminophen and dipyrone attenuated the pain response, beginning at 50, 50 and 100 mg/kg, respectively. Systemically active drugs produced weaker antinociception when injected into the paw or intracerebroventricularly at doses approximately 10(3) lower than those required for systemic effects; dose effect relations were bell-shaped by the intracerebroventricular route. By all three routes, there was a clear ceiling to the effects of acetaminophen that is consistent with its clinical efficacy. Systemic phenacetin and acetaminophen produced a conditioned place preference at doses that produced antinociception. Dipyrone produced a place aversion by the systemic route and a place preference intracerebroventricularly. The latter had a bell-shaped dose effect relationship identical to that in the formalin test. Indomethacin was inactive in all tests, except for mild hyperalgesia by the intraventricular route. The results indicate that the antinociceptive effects of phenacetin, acetaminophen and dipyrone reflect a combination of peripheral and central actions, neither of which involves inhibition of cyclooxygenase. The central component of the antinociceptive effects may be related to activation of brain mechanisms that are involved in reinforcement.

In a model of visceral pain consisting of intraperitoneal injection of acetic acid (writhing test), simultaneous administration of subanalgesic doses of metamizol (150 mg/kg) and morphine (0.2 mg/kg) resulted in a potent analgesia (19 +/- 1 vs. 2.3 +/- 0.8 writhes; P < 0.05). While the analgesic effect of morphine (2 mg/kg) was antagonized by naloxone (1 mg/kg), the opioid antagonist did not reverse the analgesia induced by the combination of metamizol and morphine. Potentiation by metamizol was also observed as a bilateral decrease in stimulus-evoked c-Fos induction in superficial laminas (I-II) of the dorsal spinal cord after drug combination compared to single administration (66.5 +/- 2.2 vs. 80.7 +/- 4.2; P < 0.05). Conversely, the number of nuclei immunostained with an antibody that recognizes all proteins of the Fos family was not modified by the same dose combination compared to single treatment (21.1 +/- 1.3 vs. 20.2 +/- 1.2). Furthermore, in a model of somatic pain consisting of peripheral thermal stimulation of the paws, simultaneous administration of metamizol (100-250 mg/kg) and morphine (0.5 mg/kg) failed to modify flexor reflex latency.

The present work describes the antinociceptive effects of some fractions and two pure compounds obtained from the Wedelia paludosa, a Brazilian medicinal plant employed in folk medicine against a variety of diseases, including dolorous pathologies. It was found that such fractions as well as kaurenoic acid and luteolin exhibit marked antinociceptive action in mice using acetic acid-induced writhing. They were more active than some well-known analgesic drugs, such as acetyl salicylic acid, acetaminophen, dipyrone and indomethacin. The results confirm our previous studies conducted with this plant, suggesting that different chemical constituents are responsible for the antinociceptive activity shown by the extracts and fractions prepared from W. paludosa.

A new series of 4,6-diaryl pyridazines substituted in the 3-position by arylpiperazinyl moieties was synthesized and evaluated for analgesic activity. Five out of the nine tested compounds possessed significant antinociceptive effects in the phenylbenzoquinone-induced writhing test (PBQ test) with ED50 values ranging from 26.0 to 37.7 mg/kg ip. The most active derivatives 2a, 2d and 2h had a low toxicity (LD50 > 800 mg/kg ip) but showed some sedative and neurotoxic effects from the dose of 50 mg/kg ip. The three selected pyridazines were devoid of activity in the hot-plate test. However, analgesic activity of 2d and 2h was significantly reversed by naloxone in the PBQ test. Administered at the low dose of 5 mg/kg ip, 2h greatly potentiated the antinociceptive response induced by morphine (0.15 mg/kg sc). In addition, analgesic effects of 2h (2.5 mg/kg ip) were also potentiated by 5-hydroxytryptophan combined with carbidopa. These results suggest that pyridazine 2h induces analgesia, which is mediated via both opioid and serotonergic mechanisms.

The objective of this study was to investigate the site of action of dipyrone in rat paw prostaglandin-induced hyperalgesia. The intracerebroventricular (i.c.v.) injection of dipyrone had no effect on the hyperalgesic response to prostaglandins. In contrast, intraplantar (i.pl.) and intrathecal (i.t.) injections produced dose-dependent analgesic effects. The analgesia observed following the intraperitoneal (i.p.), i.t., i.pl. or combined i.t. and i.pl. administration of dipyrone was abolished by pretreating the paws with L-NMMA (a nitric oxide synthase inhibitor) or methylene blue (MB, an inhibitor of soluble guanylate cyclase). These results support the suggestion that dipyrone-mediated antinociception results from a combined spinal and peripheral effect in the primary peripheral sensory neuron via stimulation of the arginine/cGMP pathway.

In the experiments on Wistar rats with pain syndrome of spinal origin (PSSO) caused by the generator of pathologically enhanced excitation (GPEE) in dorsal horns of the spinal cord lumbosacral segments, it was shown that the intravenous verapamil injection (1.25 mg/kg) undoubtedly decreased behaviour response and improves the state of microcirculation. The compound of 10-fold decreased dose does not affect the behaviour response and microcirculation. When PSSO exists, the intravenous injection of analgin (150 mg/kg) produced an effect on the behaviour response and does not produce any action on microcirculation. When verapamil reaches the dorsal surface of the spinal cord (GPEE area) it decreases the behaviour response and microcirculation disorders created in PSSO. The obtained data make it clear that the GPEE depression caused by the verapamil calcium channel blocker weakens PSSO and normalizes the microcirculation.

Human cerebral evoked potentials can be employed to test the effectiveness of analgesics. In the present study, pain-related cortical responses were elicited by chemical stimulation of the nasal mucosa in combination with electrical stimulation of dental pulp. In alternating sequence, 16 series of 6 chemical and 6 electrical stimuli each were presented. Interstimulus and interseries intervals were 2 s and 50-60 s, respectively. Stimulus intensities were 54% carbon dioxide (v/v) and 4 dB over the electrical current threshold of 21-45 microA for noxious chemical and electrical stimulation, respectively. Four volunteers participated in the study. The EEG was recorded at 8 sites of the international 10-20 system. After each series of stimuli, the test subjects, using visual analogue scales, rated pain intensity relative to a single standard stimulus they had received initially. After running through the procedure once, without their noticing it, the subjects intravenously received 5 ml (2.5 g) metamizol or 5 ml 0.9% NaCl, which were slowly (over a period of 12 min) added to an infusion. The entire stimulation procedure was then repeated 10 min later. Whereas the evoked potentials clearly exhibited habituation effects due to stimulus repetition within a series, the latter were absent in the subjects' pain ratings. Despite the comparatively high i.v. dose of 2.5 g metamizol, pain ratings markedly different from those given under placebo were not observed. In contrast, potential amplitudes after metamizol administration exhibited a clear tendency towards smaller amplitudes in both types of stimulation. In addition, metamizol effects on pain rating could be demonstrated successfully by applying continual chemical stimulation.

The mouse writhing test has been used to evaluate analgesic drugs. In the present work the protective effect of atropine sulfate and eight of its substitutes was studied against acetic acid-induced writhing in mice. This was compared with the protection afforded by noramidopyrine, a non-narcotic analgesic. Both the time of onset of writhing and the number of writhes over a period of 15 min was recorded. The results seem to indicate some correlation between chemical structure and protective effect. Dicyclomine hydrochloride and orphenadrine hydrochloride produced an effect comparable with that of noramidopyrine, while atropine sulphate, oxyphenonium bromide and piperidolate hydrochloride were less potent. Homatropine methylbromide, mepenzolate methylbromide, amprotropine phosphate and penthienate bromide were ineffective.

The pyrazolone derivative, metamizol (dipyrone), possesses analgesic, antipyretic, anti-inflammatory and spasmolytic properties. It is often classified as peripherally acting. To test the possibility that a central action of the drug contributes to its antinociceptive and analgesic effects, experiments were carried out in which the tail-flick response to radiant heat, flexor reflex activity in the tibialis anterior muscle and activity in ascending spinal axons evoked by stimulation of afferent C fibres in the sural nerve, and activity of neurones in the periaqueductal grey matter and the substantia nigra were assessed in rats. Metamizol administered by intraperitoneal (i.p.; 10, 20 and 40 mg/kg) or intrathecal (i.t.; 50 to 400 micrograms) injection to intact rats dose-dependently prolonged the tail-flick latency. Administration by i.t. injection to spinal rats was without effect. Intravenous (i.v.) injection of metamizol (140 mg/kg) reduced flexor reflex activity in intact animals, while an i.t. injection to spinal rats was ineffective at a low dose (100 micrograms) or enhanced the reflex activity at a higher dose (400 micrograms). Activity in ascending axons responding to afferent C fibre stimulation was mostly depressed by i.t. injection of metamizol (40, 80 and 140 mg/kg) in rats with an intact spinal cord. Ascending activity was increased by i.t. injection of the drug (100 and 200 micrograms) to spinal rats. Metamizol (140 mg/kg) i.v. increased the activity of neurones in the PAG and reduced that of neurones in the substantia nigra. Metamizol administered by microinjection into the PAG prolonged the tail-flick latency (15-100 micrograms) and depressed C fibre-evoked activity in ascending axons (100 micrograms). The results suggest that a central action is involved in the analgesic effect of metamizol and that this central action manifests itself by an activation of inhibition originating in the PAG.

The prevention of hyperalgesia by inhibition of prostaglandin synthesis is the most plausible hypothesis on the mechanism of NSAID action. This review also discusses other possibilities of controlling inflammatory hyperalgesia, including the development of peripherally acting opiates. These are obtained by reduction of the opiates' lipophilic properties. The drugs' undesired central effects are thus eliminated, while their peripheral analgesic action is preserved. Moreover, it appears that the adrenergic system is also involved in inflammatory hyperalgesia. This implies that beta-receptor blockers might be useful in eliminating the adrenergic component of inflammatory pain. Metamizol, in contrast to the NSAIDs, is effective even in manifest prostaglandin or sympathetic hyperalgesia.