Browsing by Author "Prieto, Juan"
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Item Adrenergic modulation of dexketoprofen antinociception in murine formalin orofacial pain(2021) Miranda, Hugo; Noriega, Viviana; Sierralta, Fernando; Prieto, JuanNon-steroidal anti-inflammatory drugs (NSAIDs) are widely used in pain whose mechanism of action is the inhibition of cyclooxygenase enzymes (COXs), however, there are evidence of other mechanisms of action, such as the inhibition of substance P, interaction with systems NO, monoaminergic and others. The objective of the present work was to study the participation of -1 (prazosin) and -2 (yohimbine) adrenoceptors antagonists in the antinociception of dexketoprofen, the S (+) enantiomer of ketoprofen. The antinociception evaluation was thru the mice orofacial formalin assay. Dexketoprofen (DEX) induced a dose-related antinociception 3.40 times more potent in phase I than in phase II. Prazosin i.p. decreased of the antinociception of DEX, 2.01 times in phase I and 4.02 times in phase II. Administered i.t. reduced the antinociception 5.30 times in phase I and 6.20 times in phase II. Yohimbine i.p. induced a reduction of the ED50 of 3.40 times in phase I and 4.50 times in phase II, after i.t. administration the reduction was 5.30 times in phase I and 6.20 times in phase II. The mechanism of antinociception induced by DEX is mediated by the activation of α-1 and α-2 adrenergic receptors at supraspinal and spinal levels.Item Antinociceptive synergism in preclinical studies: A review(2022) Miranda, Hugo; Noriega, Viviana; Sierralta, Fernando; Sotomayor, Ramón; Prieto, JuanIn the treatment of acute and chronic pain the most frequently used drugs are nonsteroidal anti-inflammatory drugs (NSAIDs), e.g., paracetamol; opioids, e.g., tramadol, and a group of drugs called coanalgesics or adjuvants (e.g., antidepressants, anticonvulsants). When the administration of an isolated drug produces a minimal analgesic effect, multimodal analgesia is usually used, which consists of the co-administration of two drugs, which can produce an increase in the sum of the effects of each component, generating a synergistic effect or supradditivity or superadditivity. Synergism has been the objective of pharmacology, due to its biomedical orientation, due to its outstanding effect in the therapeutics of pain and mainly cancer. Among the advantages of synergism is that (i) reduction of drug doses and increase in therapeutic effect, (ii) reduction of side effects of each component, (iii) possibility of an increase in the speed of appearance of the effect and prolongation of its action. The exact mechanism of the synergistic interaction has not been exhaustively described, there are only theories of events that can occur at the pharmacokinetic level, due to changes in the concentration of the agents in the site of action or at the pharmacodynamic level, due to changes in the mechanism of action of drugs. This work, was reviewed reports of the preclinical analgesic synergism of NSAIDs with opioids and the mechanisms of action involved in the therapy of these useful analgesic drugs, which may be relevant for pain relief.Item GABAergic Regulation of Astroglial Gliotransmission through Cx43 Hemichannels(2022) Jiménez, Ivanka; Reyes, Rachel; Lemunao, Yordan; Cárdenas, Kevin; Castro, Raimundo; Peña, Francisca; Lucero, Claudia; Prieto, Juan; Retamal, Mauricio; Orellana, Juan; Stehberg, JimmyGamma-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain. It is produced by interneurons and recycled by astrocytes. In neurons, GABA activates the influx of Cl- via the GABAA receptor or efflux or K+ via the GABAB receptor, inducing hyperpolarization and synaptic inhibition. In astrocytes, the activation of both GABAA and GABAB receptors induces an increase in intracellular Ca2+ and the release of glutamate and ATP. Connexin 43 (Cx43) hemichannels are among the main Ca2+-dependent cellular mechanisms for the astroglial release of glutamate and ATP. However, no study has evaluated the effect of GABA on astroglial Cx43 hemichannel activity and Cx43 hemichannel-mediated gliotransmission. Here we assessed the effects of GABA on Cx43 hemichannel activity in DI NCT1 rat astrocytes and hippocampal brain slices. We found that GABA induces a Ca2+-dependent increase in Cx43 hemichannel activity in astrocytes mediated by the GABAA receptor, as it was blunted by the GABAA receptor antagonist bicuculline but unaffected by GABAB receptor antagonist CGP55845. Moreover, GABA induced the Cx43 hemichannel-dependent release of glutamate and ATP, which was also prevented by bicuculline, but unaffected by CGP. Gliotransmission in response to GABA was also unaffected by pannexin 1 channel blockade. These results are discussed in terms of the possible role of astroglial Cx43 hemichannel-mediated glutamate and ATP release in regulating the excitatory/inhibitory balance in the brain and their possible contribution to psychiatric disorders.Item Hypertensive Nephropathy: Unveiling the Possible Involvement of Hemichannels and Pannexons(2022) Lucero, Claudia; Prieto, Juan; Marambio, Lucas; Balmazabal, Javiera; Alvear, Tanhia; Vega, Matías; Barra, Paola; Retamal, Mauricio; Orellana, Juan; Gómez, GonzaloHypertension is one of the most common risk factors for developing chronic cardiovascular diseases, including hypertensive nephropathy. Within the glomerulus, hypertension causes damage and activation of mesangial cells (MCs), eliciting the production of large amounts of vasoactive and proinflammatory agents. Accordingly, the activation of AT1 receptors by the vasoactive molecule angiotensin II (AngII) contributes to the pathogenesis of renal damage, which is mediated mostly by the dysfunction of intracellular Ca2+ ([Ca2+]i) signaling. Similarly, inflammation entails complex processes, where [Ca2+]i also play crucial roles. Deregulation of this second messenger increases cell damage and promotes fibrosis, reduces renal blood flow, and impairs the glomerular filtration barrier. In vertebrates, [Ca2+]i signaling depends, in part, on the activity of two families of large-pore channels: hemichannels and pannexons. Interestingly, the opening of these channels depends on [Ca2+]i signaling. In this review, we propose that the opening of channels formed by connexins and/or pannexins mediated by AngII induces the ATP release to the extracellular media, with the subsequent activation of purinergic receptors. This process could elicit Ca2+ overload and constitute a feed-forward mechanism, leading to kidney damage.Item Morphine at inflammatory experimental pain: A review(2022) Miranda, Hugo; Noriega, Viviana; Moreno, Francisca; Sierralta, Fernando; Sotomayor, Ramón; Prieto, JuanPain is a complex entity that can be described in several dimensions, such as, acute pain and chronic pain, characterized by its duration. After the tissue injury, the activation of the sensory nervous tissue occurs from where the different pro-inflammatory mediators are released with the consequent nociceptive transmission that characterizes the genesis of inflammatory pain. The main objective of this study was to review the role of the opioid system, using morphine and MOR opioid receptors as paradigm, in the antinociceptive modulation of inflammatory pain, by means of the formalin test as a model. Various pieces of evidence are compiled that establish the fundamental role of morphine in the inflammatory pain. Morphine has noticeable antinociceptive efficacy in to decrease the inflammatory pain. This review demonstrates the fundamental role that morphine plays in inflammatory pain states and that it could serve as the basis for a new pharmacotherapy of inflammatory pain.Item Nitric Oxide Mediated Dexketoprofen Antinociception(2020) Noriega, Viviana; Miranda, Hugo; Sierralta, Fernando; Sotomayor, Ramón; Prieto, Juan; Aguilera, VivianaNonsteroidal anti-inflammatory drugs (NSAIDs) are often used in the treatment of pain by their analgesic, anti-inflammatory and antipyretic properties. NSAIDs act via inhibition of cyclooxygenase enzymes, COX-1, COX-2 and COX-3. In this study, the antinociceptive activity of the dextrorotatory enantiomers of S (+) configuration of ketoprofen, denominate, dexketoprofen (DEX), was evaluated, before and after the pretreatment of mice with N( )-nitro-L-arginine methyl ester (L-NAME), in two models of pain. One model of tonic pain, the tail flick (TF) assay and in a second model of phasic pain, the acetic acid writhing test (WT). (DEX) administration produced a dose-dependent antinociceptive effect in both murine assays, but with different potency. The dose that produced 50 % of maximum possible effect (ED of antinociception of the WT was 3.87-fold more potent than TF. The pretreatment of mice with 1, 3 or 10 mg/kg, i.p of L-NAME produced a significant decrease of the antinociceptive effect of DEX, reflected with an important increase of ED in both assays. In conclusion, the results the application of DEX produced antinociception in the WT and TF models and in this effect the activation of NO pathway plays an important role.Item Nitridergic Modulation of COX-2 Efficacy(2022) Miranda, Hugo; Noriega, Viviana; Moreno, Francisca; Sierralta, Fernando; Sotomayor, Ramón; Prieto, JuanPain is a common unpleasant sensory and emotional experience, in which are frequently used in their treatment the nonsteroidal anti-inflammatory drugs (NSAIDs). A group of agents with antipyretic, analgesic, and anti-inflammatory properties due to the inhibition of cyclooxygenase enzymes (COXs). Among these drugs there are a group of selective inhibitors of COX-2 named coxib that include to parecoxib, celecoxib, rofecoxib and etoricoxib. Pharmacological information on the mechanism of action of coxibs is insufficient to determine the analgesic and anti-inflammatory efficacy of these agents. There are contradictory reports regarding the antinociceptive effects of the various coxibs at the preclinical level as well as the nitridergic modulation of such actions. The objective of the present study was to evaluate the antinociceptive efficacy of parecoxib, rofecoxib, celecoxib, and etoricoxib using the formalin hind paw assay in mice and the possible contribution of the nitridergic system in the efficacy of COX-2 agents. Antinociception was assessed in a murine formalin assay using dose-response curves to coxibs before and after i.p. administration of 5 mg/kg of L-NAME. Coxibs produced dose-dependent analgesia and anti-inflammation. L-NAME administration reduced the analgesic and anti-inflammatory effectiveness of parecoxib, rofecoxib, celecoxib, and etoricoxib. These findings suggest that the effect of these agents, in addition to COX-2 inhibition, would be mediated by other mechanisms, among which nitridergic modulation would be compromised.Item Noradrenergic modulation of Dex-ketoprofen analgesia in preclinical orofacial pain(2022) Miranda, Hugo; Noriega, Viviana; Moreno, Francisca; Sierralta, Fernando; Sotomayor, Ramón; Prieto, JuanDexketoprofen (DEX) is the dextrorotatory enantiomer of S (+) configuration with a high antinociceptive activity of ketoprofen. The aim of this study was to evaluate the pharmacological interaction of DEX with the noradrenergic antagonist's prazosin, yohimbine, propranolol and atenolol in the formalin orofacial pain in mice. Analgesia to nociceptive and inflammatory pain was evaluated by dose response curves to DEX before and after the i.p. administration of 1.0 mg/kg of prazosin, or yohimbine, or propranolol or atenolol. Results are presented as means ± SEM and differences were calculated by one-way ANOVA, followed by Tukey’s post-test. DEX produced a dose-related antinociceptive effect with varying potencies in both trial phases, with prazosin and yohimbine increasing the efficacy of DEX and propranolol and atenolol having no effect. These findings suggests that the increased efficacy of DEX cannot be explained by only inhibition of COXs, since it may be a consequence of multiple pharmacodynamic interactions induced by the activation of a-adrenoceptors in the opioidergic, cannabinoid, nitrergic or serotonergic mechanisms involved in pain. These results indicate that the combination of DEX with prazosin or yohimbine could be a new and effective alternative for the management of pain.Item Orthopedic surgery residents’ perception of online education in their programs during the COVID-19 pandemic: should it be maintained after the crisis?(2020) Figueroa, Francisco; Figueroa, David; Calvo-Mena, Rafael; Narvaez, Felipe; Medina, Natalia; Prieto, JuanBackground and purpose - During the COVID-19 pandemic, most of the teaching centers in Chile have shifted to online resources. We decided to do a survey on orthopedic residents regarding this type of education to assess for strengths and weaknesses of digital education in orthopedic programs.Methods - A survey was performed targeting 110 orthopedic residents belonging to different training programs around the country. 100 residents completed the survey.Results - 86% stated that their programs are using online education. When asked in detail, 86% had been involved in webinars, 28% had received online presentations, 12% had participated in online tests, and 7% had evaluated patients. Webinars were rated (1 = very unsatisfactory, 10 = very satisfactory) with a mean grade of 8.1 (1-10), online presentations 7.3 (1-10), online tests 3.8 (1-8), and online patient evaluations 2.9 (1-9). When asked if, after the end of the pandemic, they would continue using the online modalities, 82% would continue attending webinars, 72% would continue watching online presentations, 27% would continue performing online tests, and 33% of the residents would continue performing online evaluations of patients.Interpretation - Even though resident evaluation of online activities is positive, face-to-face theoretical activities are still valued as a necessary complement for orthopedic residency education.Item Receptors involved in dexketoprofen analgesia in murine visceral pain(2020) Noriega, Viviana; Sierralta, Fernando; Aranda, Nicolás; Sotomayor, Ramón; Prieto, Juan; Miranda, Hugo; Poblete, P.Various animal models, especially rodents, are used to study pain, due to the difficulty of studying it in humans. Many drugs that produce analgesia have been studied and there is evidence among which NSAIDs deserve to be highlighted. Dexketoprofen (DEX) provides a broad antinociceptive profile in different types of pain; therefore, this study was designed to evaluate the profile of antinociceptive potency in mice. Analgesic activity was evaluated using the acetic acid abdominal constriction test (writhing test), a chemical model of visceral pain. Dose-response curves for i.p. DEX administration (1, 3, 10, 30 and 100 mg/kg), using at least six mice in each of at least five doses, was obtained before and 30 min after pre-treatment with different pharmacological agents. Pretreatment of the mice with opioid receptor antagonists was not effective; however, the serotonin receptor antagonist and nitric oxide synthase inhibitor produce a significant increase in DEX-induced antinociception. The data from the present study shows that DEX produces antinociception in the chemical twisting test of mice, which is explained with difficulty by the simple inhibition of COX. This effect appears to be mediated by other mechanisms in which the contribution of the NO and 5-HT pathways has an important effect on DEX- induced antinociception.Publication SARS-CoV-2 spike protein S1 activates Cx43 hemichannels and disturbs intracellular Ca2+ dynamics(2023) Prieto, Juan; Lucero, Claudia; Rovegno, Maximiliano; Gómez, Gonzalo; Retamal, Mauricio A.; Orellana, JuanBackground: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the ongoing coronavirus disease 2019 (COVID-19). An aspect of high uncertainty is whether the SARS-CoV-2 per se or the systemic inflammation induced by viral infection directly affects cellular function and survival in different tissues. It has been postulated that tissue dysfunction and damage observed in COVID-19 patients may rely on the direct effects of SARS-CoV-2 viral proteins. Previous evidence indicates that the human immunodeficiency virus and its envelope protein gp120 increase the activity of connexin 43 (Cx43) hemichannels with negative repercussions for cellular function and survival. Here, we evaluated whether the spike protein S1 of SARS-CoV-2 could impact the activity of Cx43 hemichannels. Results: We found that spike S1 time and dose-dependently increased the activity of Cx43 hemichannels in HeLa-Cx43 cells, as measured by dye uptake experiments. These responses were potentiated when the angiotensin-converting enzyme 2 (ACE2) was expressed in HeLa-Cx43 cells. Patch clamp experiments revealed that spike S1 increased unitary current events with conductances compatible with Cx43 hemichannels. In addition, Cx43 hemichannel opening evoked by spike S1 triggered the release of ATP and increased the [Ca2+]i dynamics elicited by ATP. Conclusions: We hypothesize that Cx43 hemichannels could represent potential pharmacological targets for developing therapies to counteract SARS-CoV-2 infection and their long-term consequences.