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The antinociceptive activity of dexketoprofen was studied in mice using the formalin assay for orofacial pain. The interaction between dexketoprofen and co-administered tramadol was studied using isobolographic analysis. The intraperitoneal administration of dexketoprofen or tramadol, showed dose-dependent antinociceptive activity in both phases of the assay. When administered together, the interaction was mildly synergistic during the first phase, and antagonistic in the second phase. Selective opioid receptor antagonists where used in order to measure the analgesic activity of tramadol in other regions of the CNS. The co-administration of dexketoprofen and tramadol, with previous administration of naltrexone, showed high synergistic activity during the first phase, and less but still synergistic during the second. When using naltrindole, the interaction was mildly more synergistic than the mixture dexketoprofen+tramadol during both phases. Using norbinaltorphimine, the interaction was synergistic in both phases, more marked in the second. These results suggest that the opioid activity of tramadol has an inhibiting effect in antinociceptive activity of the interaction between dexketoprofen and tramadol during the inflammatory (late) stages of pain.

Background: Endothelial dysfunction is a key process in atherosclerosis. Hypomethylation is one of the postulated mechanisms involved in atherogenesis and is mainly secondary to a decrease in essential factors such as, folate and vitamin B12 for the biosynthesis of S-adenosylmethionine (SAM), the main methyl-group donor for methylation reactions., Aim: To investigate in an animal model, whether hypomethylation, secondary to folate or vitamin B12 deficiency, affects endothelium-dependent relaxation (EDR) induced by acetylcholine (ACh)., Methods: Adult male Wistar rats were divided into 4 groups of 12 rats each: folate and B12 deficiency (FB12D 0mg folate/kg, 0 microg/kg B12), folate deficiency (FD 0mg folate/kg and 50 microg/kg B12), B12 deficiency (B12D: 8 mg/kg folate and 0 microg/kg B12 and control diet (CD)). After eight weeks the animals were killed and thoracic aorta and liver removed. Serum concentration of homocysteine, folate and vitamin B12 were determined. Hepatic levels of SAM and S-adenosylhomocysteine (SAH) were measured, as indicator of hypomethylation. ACh-induced EDR and sodium nitroprusside (SNP)-induced endothelium-independent relaxation (EIR), in isolated aorta rings were evaluated., Results: Hcy concentrations were significantly increased in the folate and B12 deficient groups. SAM and the SAM/SAH ratio were lower in the FD and FB12D than in the control and B12D group. Folate, B12 deficiency, serum Hcy levels and hepatic SAM/SAH ratio did not affect EDR neither EIR., Conclusions: In adult Wistar rats, chronic folate or folate plus vitamin B12 deficiency generates hypomethylation which is not related to an alteration of endothelial function.

Multiple analgesic-drug combinations are commonly used in the management of acute and chronic pain in humans during multimodal or balanced analgesia. At present, these combinations are used empirically in clinical practice and are considered to be beneficial for the patient. Interactions between two antinociceptive drugs have been thoroughly examined, but the nature of interactions between three analgesics has not been studied. The antinociceptive interaction of ketoprofen (K) with a mixture of morphine (M) and paracetamol (P) was evaluated using a model of visceral acute tonic pain, the acetic-acid writhing test in mice. The i.p. administration of the combination M/P+K resulted in a significant potentiation of the antinociception induced either by K or by the synergic two-drug mixtures M/K, P/K and M/P. The effect of opioid, cholinergic, adrenergic and serotonergic antagonists on the analgesic interaction was assessed. The pretreatment of mice with atropine (1 mg/kg) did not produce any change in the synergistic interaction of the triple combination. The pretreatment with naltrexone (1 mg/kg) or tropisetron (1 mg/kg) reduced the intensity of M/P+K synergic interaction, while prazosin (0.1 mg/kg) significantly potentiated the synergy. The findings of this work suggest that the two major pathways of descending inhibitory systems, noradrenergic and serotonergic are significantly involved in the mechanism of the antinociceptive synergy induced by the triple combination. On the other hand, opioid pathways also seem to participate, since pretreatment with naltrexone reduced the synergy. In conclusion, the triple combination M/P+K induced a strong synergistic antinociceptive effect, which could be of interest for optimal multimodal clinical analgesia.

The analgesic effects of the intrathecal coadministration of morphine with nimesulide, meloxicam and parecoxib, preferential cyclooxygenase-2 (COX-2) inhibitors, were studied in mice using a chemical model of visceral pain, the acetic acid writhing test. Isobolographic analysis was used to characterize the interactions between mixtures of morphine with each non-steroidal anti-inflammatory drug. Antinociception dose-response curves were analyzed to obtain the ED50's of each drug. A dose response curve for fixed ratio mixtures of morphine with COX-2 inhibitors was then performed and the observed ED50's were plotted on a two-dimensional isobologram. All the combinations tested showed synergistic interactions and the strength of the interaction was ranked as: morphine/parecoxib>morphine/meloxicam>morphine nimesulide. The results demonstrate that the intrathecal coadministration of COX-2 inhibitors significantly enhance morphine-induced antinociception and could result in an opioid sparing action which may be useful in the clinical treatment of severe pain. A sparing action means that less opioids have to be administered to obtain a given analgesic effect. Since intrathecal morphine is often used in clinical pain situations, the opioid sparing effect resulting from the synergy observed with the coadministration of COX-2 inhibitors may be clinically relevant. One of the most significant advantages should be the reduction of opioid toxicity which often acts as a major obstacle in pain treatment.

The present study was undertaken to characterize the interactions between nonsteroidal anti-inflammatory drugs and the alpha(2)-adrenoceptor agonist clonidine in an acute nociceptive test. The writhing test was selected as a model of acute visceral pain. Isobolograms were constructed to assess the interactions of clonidine and each nonsteroidal anti-inflammatory drugs, when coadministered intraperitoneally and intrathecally (i.t.). The simultaneous intraperitoneal administration of fixed ratios of ED(50) fractions of all nonsteroidal anti-inflammatory drugs (naproxen, piroxicam, paracetamol, dipyrone or metamizol and nimesulide) combined with clonidine resulted in synergistic interactions. The same combinations administered intrathecally were additive. The synergistic interactions between systemic nonsteroidal anti-inflammatory drugs and clonidine may involve supraspinal mechanisms.

The nonsteroidal anti-inflammatory drugs (NSAIDs) clonixin, diclofenac, piroxicam, ketoprofen, meloxicam, and paracetamol induced antinociception after intraperitoneal or intrathecal administration in mice submitted to an acute thermal algesiometric test without inflammation (tail-flick). Antinociception was evaluated by the increase in reaction time difference (Delta latency), between readings obtained before and after the administration of drugs. The antinociception induced by doses of NSAIDs producing between 20% and 30% of the maximum possible effect (MPE) 30 min after intraperitoneal and 15 min after intrathecal injections was compared with the antinociception obtained after pretreatment with 1 mg/kg atropine ip, 30 min before. Systemic atropine (1 mg/kg) significantly antagonized NSAID-induced antinociception in all cases, both after intraperitoneal and intrathecal administration. Cholinergic depletion by intracerebroventricular hemicholinium-3 (HC-3, 5 microg) 5 h before prevented the antinociceptive effect of all NSAIDs. These observations suggest that intrinsic muscarinic cholinergic facilitatory pathways represent an important modulating system in pain perception in this animal model of acute thermal pain. The results of the present work support the increasingly accepted notion that NSAIDs are effective analgesics even when inflammation is not present, acting by mechanisms that involve actions on spinal and supraspinal nociceptive transmission. It is suggested that, similar to morphine and clonidine, the active mechanism of NSAIDs may involve the release of acetylcholine (ACh) in the spinal cord.

The mechanism of action of tramadol includes the activation of opioid receptors, and the potential ability of the drug to induce tolerance and physical dependence has been evaluated in different animal species and humans. This work was designed to study the involvement of opioid receptors in the antinociceptive activity and the potential ability to develop tolerance, crosstolerance, and/or physical dependence of tramadol. The writhes induced by acetic acid administration was used as algesiometric test. After chronic administration of tramadol, tolerance was evaluated by measuring the antinociceptive activity, and physical dependence was measured by naloxone administration. Morphine was used as drug of comparison. The i.p. administration of tramadol produced a dose-dependent antinociception with an ED50 value of 7.82 +/- 1.16 mg/kg, which was unchanged after chronic administration of either tramadol (39.1 or 100 mg/kg) or morphine (1.05 or 100 mg/kg). By contrast, the ED50 for morphine (0.21 +/- 0.08 mg/kg) was significantly reduced only by chronic pretreatment with both doses of morphine (tolerance). Physical dependence was developed only in mice pretreated with morphine, as evidenced by the presence of jumps, wet-dog shakes, tachypnea, piloerection, seizures, diarrhea, and urination after the administration of naloxone (1 mg/kg). These findings suggest that the antinociceptive activity of tramadol in mice is due to activation of opioid and nonopioid mechanisms, and as opposed to morphine, is not likely to induce tolerance and physical dependence.

The endothelial layer was removed from the isolated mesenteric vascular bed of the rat by perfusion with hypotonic Tyrode solution for 12.5 min. This procedure damaged more than 95% of the endothelial cells. After endothelial removal, the response to norepinephrine was significantly enhanced, whereas the relaxation induced by acetylcholine (ACh) was completely abolished. The results of this work show that perfusion with hypotonic solutions provides a reliable method of endothelial removal in isolated perfused vascular beds, allowing the study of endothelial-dependent vascular responses.