Characterization and validation of a spontaneous acute and protracted oxycodone withdrawal model in male and female mice.

Opioid use disorder (OUD) is a serious health problem that may lead to physical dependence, in addition to affective disorders. Preclinical models are essential for studying the neurobiology of and developing pharmacotherapies to treat these problems. Historically, chronic morphine injections have most often been used to produce opioid-dependent animals, and withdrawal signs indicative of dependence were precipitated by administering an opioid antagonist. In the present studies, we have developed and validated a model of dependence on oxycodone (a widely prescribed opioid) during spontaneous withdrawal in male and female C57BL/6J mice. Dependence was induced by chronically administering oxycodone through osmotic minipumps at different doses for 7 days. Somatic withdrawal signs were measured after 3, 6, 24, and 48 h following minipump removal. Additionally, sensitivity to mechanical, thermal, and cold stimuli, along with anxiety-like behavior, were also measured. Our results indicated that spontaneous withdrawal following discontinuation of oxycodone produced an increase in total withdrawal signs after 60 and 120 mg/kg/day regimens of oxycodone administration. These signs were reversed by the administration of clinically approved medications for OUD. In general, both female and male mice showed similar profiles of somatic signs of spontaneous withdrawal. Spontaneous withdrawal also resulted in mechanical and cold hypersensitivity lasting for 24 and 14 days, respectively, and produced anxiety-like behaviors after 2 and 3 weeks following oxycodone removal. These results help validate a new model of oxycodone dependence, including the temporally distinct emergence of somatic, hyperalgesic, and anxiety-like behaviors, potentially useful for mechanistic and translational studies of opioid dependence.

Comparison of Pain-Like behaviors in two surgical incision animal models in C57BL/6J mice.

Background: Management of pain post-surgery is crucial for tissue healing in both veterinary and human medicine. Overuse of some analgesics such as opioids may lead to addictions and worsen pain syndromes (opioid-induced hyperalgesia), while underuse of it may affect the welfare of the patient. Therefore, the importance of using surgery models in laboratory animals is increasing, with the goal of improving our understanding of pain neurobiology and developing safer analgesics. Methods: We compared the widely used plantar incision model with the laparotomy surgery model and measured pain-related behaviors using both spontaneous and evoked responses in female and male C57BL/6J mice. Additionally, we assessed conditioned place preference (CPP) and sucrose preference tests to measure pain-induced motivation for the analgesic ketoprofen and anhedonia-like behavior. Results: Laparotomized mice showed increased abdominal sensitivity while paw-incised mice showed increased paw thermal and mechanical sensitivity up to seven days post-surgery. Laparotomy surgery reduced all spontaneous behaviors in our study however this effect dissipated by 24 h post-laparotomy. On the other hand, paw incision only reduced the percentage of cage hanging in a sex-dependent manner at 6 h post-incision. We also showed that both surgery models increased conditioned place preference for ketoprofen while preference for sucrose was only reduced at 24 h post-laparotomy. Laporatomy, but not paw incision, induced a decrease in body weight at 24 h post-surgery. Neither surgery model affected fluid intake. Conclusion: Our results indicate that post-surgery hypersensitivity and behavioral deficits may differ by the incision site. Furthermore, factors associated with the surgery including length of the incision, duration of the anesthesia, and the layers that received stitches may affect subsequent spontaneous behaviors. These findings may help to improve drug development or the choice of the effective analgesic, depending on the surgery type.

Sex-specific role for serotonin 5-HT2A receptor in modulation of opioid-induced antinociception and reward in mice.

Opioids are among the most effective analgesics and the mainstay of pain management. However, concerns about safety and abuse liability have challenged their widespread use by the medical community. Opioid-sparing therapies include drugs that in combination with opioids have the ability to enhance analgesia while decreasing opioid requirement as well as their side effects. Sex differences in antinociceptive responses to opioids have received increasing attention in recent years. However, the molecular mechanisms underlying sex differences related to opioid-sparing adjuncts remain largely unexplored. Using warm water tail-withdrawal as a mouse model of acute thermal nociception, our data suggest that adjunctive administration of the serotonin 5-HT2A receptor (5-HT2AR) antagonist volinanserin dose-dependently enhanced potency of the opioid analgesic oxycodone in male, but not female, mice. This antinociceptive-like response induced by oxycodone was also augmented in 5-HT2AR knockout (5-HT2AR-/-) male, but not female mice; an effect that was reversed by Cre-loxP-mediated selective expression of 5-HT2AR in dorsal root ganglion (DRG) neurons of 5-HT2AR-/- littermates. Pharmacological inhibition with volinanserin or genetic deletion in 5-HT2AR-/- animals potentiated the ability of oxycodone to reduce DRG excitability in male mice. Adjunctive volinanserin did not affect oxycodone-induced conditioned place preference (CPP), whereas it reduced oxycodone-induced locomotor sensitization in male and female mice. Together, these results suggest that adjunctive volinanserin augments opioid-induced antinociception, but not abuse-related behavior, through a sex-specific signaling crosstalk mechanism that requires 5-HT2AR expression in mouse DRG neurons. Ultimately, our results may pave the way for the clinical evaluation of volinanserin as a potential sex-specific opioid adjuvant.

Validation and characterization of oxycodone physical dependence in C57BL/6J mice.

Opioid use disorder is a growing concern in the United States. Mice were used to investigate the mechanisms involving opioid physical dependence and for evaluating medications for treating opioid use disorders. While there are many preclinical reports describing protocols for inducing physical dependence upon morphine, there are fewer preclinical reports describing more contemporary abused prescription opiates. The goal of this study was to characterize and validate a mouse model of oxycodone dependence. Male C57BL/6J mice were injected with saline or increasing doses of oxycodone (9-33 mg/kg) twice daily for 8 days. On the 9th day, mice were challenged with 1 mg/kg naloxone and observed for somatic signs. Mice were pretreated with oxycodone (17, 33, or 75 mg/kg) prior to withdrawal to determine if it could attenuate somatic withdrawal signs. Additional mouse groups were pretreated with 1 mg/kg clonidine. Lastly, we measured somatic signs for 6, 24, and 48 h post-withdrawal during spontaneous and precipitated withdrawal. Pretreating with oxycodone or clonidine dose-dependently prevented the emergence of withdrawal signs. Mice chronically treated with oxycodone exhibited more withdrawal signs than vehicle at 24 h after the final injection during spontaneous withdrawal. In contrast, mice that received repeated naloxone challenges showed peak withdrawal signs at 6 h, and withdrawal signs were significantly greater at all time points compared to vehicle. Reversal of withdrawal effects by positive controls, and establishing spontaneous and precipitated withdrawal paradigms, serve as validation of this model and provide a means to examine novel therapeutics to treat opioid withdrawal.

Targeting Peroxisome Proliferator-Activated Receptor-α (PPAR- α) to reduce paclitaxel-induced peripheral neuropathy.

BACKGROUND AND PURPOSE: Paclitaxel, a widely used anti-cancer drug, is frequently associated with prolonged and severe peripheral neuropathies (PIPN), associated with neuroinflammation. Currently, PIPN effective treatments are lacking. Peroxisome Proliferator-Activated Receptor-α (PPAR-⍺) can modulate inflammatory responses. Thus, the use of PPAR-⍺ agonists, such as fibrates (fenofibrate and choline-fenofibrate), currently used in dyslipidemia treatment, could represent an interesting therapeutic approach in PIPN. EXPERIMENTAL APPROACH: Our studies tested the efficacy of fenofibrate (150 mg/kg, daily, i.p.) and choline fenofibrate (60 mg/kg daily, p.o.) in reversing and preventing the development of PIPN (paclitaxel: 8 mg/kg, i.p., every other day for 4 days) in male and female C57BL/6J mice. Mechanical and cold hypersensitivity, conditioned place preference, sensory nerve action potential (SNAP), as well as the expression of PPAR-⍺, TNF-⍺, IL-1ß and IL-6 mRNA were evaluated. KEY RESULTS: While fenofibrate treatment partially reversed and prevented the development of mechanical hypersensitivity, this was completely reversed and prevented by choline-fenofibrate. Both fibrates were able to completely reverse and prevent cold hypersensitivity induced by paclitaxel. The reduction of SNAP amplitude induced by paclitaxel was also reversed by both fenofibrate and choline-fenofibrate. Our results indicate that suppression of paclitaxel-induced hypersensitivity by fibrates involves the regulation of PPAR-⍺ expression and decrease neuroinflammation in DRG. Finally, the co-treatment of Paclitaxel and fenofibric acid (fibrates active metabolite) was tested on different cancer cell lines, no decrease in the antitumoral effect of paclitaxel was observed. CONCLUSIONS AND IMPLICATIONS: Taken together, our results show for the first time the therapeutic potential (prevention and reversal) of fibrates in PIPN and opens to a potential pharmacological repurposing of these drugs.

Deficit in voluntary wheel running in chronic inflammatory and neuropathic pain models in mice: Impact of sex and genotype.

Patients with chronic pain report decreased general activity and emotional distress. Therefore, the development of various animal models that encompass different aspects of pain are crucial for the discovery of genetic differences and the assessment of novel analgesics to improve quality of life. C57BL/6J and DBA/2J mice received unilateral intraplantar injections of 100 % CFA, paclitaxel, or CCI surgery to compare their distance traveled in a voluntary wheel running assay, paw edema diameter, and mechanical sensitivity. Mechanical withdrawal thresholds were lower in both strains of mice that received CFA when compared to their vehicle. However, a decrease in distance traveled was observed in CFA-treated C57BL/6J but not DBA/2J mice. In a separate group, chemotherapy agent paclitaxel 8 mg/kg, i.p. was administered to both strains of mice to induce CIPN which was confirmed by lower mechanical thresholds in paclitaxel-treated mice compared to vehicle-treated mice. Only female C57BL/6J mice showed attenuation of distance traveled following treatment, whereas male C57BL/6J and DBA/2J mice did not. Lastly, C57BL/6J mice underwent chronic constriction injury (CCI) or sham surgery to observe the impact of another chronic neuropathic pain model in wheel running assay. CCI mice showed a gradual decrease in mechanical withdrawal threshold and a decrease in distance traveled compared to sham 5 days following the procedure. Comparing these chronic inflammatory and neuropathic pain models in different mouse strains may help us better understand genetic differences underlying pain perception and its impact on reflexive and nonreflexive outcome measures.

Pharmacological mechanisms of alcohol analgesic-like properties in mouse models of acute and chronic pain.

Alcohol use and chronic pain are highly comorbid. Acute alcohol use typically produces an analgesic effect. However, chronic use can worsen the progression of chronic pain. In rodent models, acute models of pain have primarily been used to investigate the relationship between alcohol and pain analgesia. Here, we use two models of chronic pain, chronic inflammatory and peripheral neuropathic pain, to investigate acute alcohol's antinociceptive and analgesic properties. We hypothesize that acute ethanol is acting through opioid receptors to create an analgesic-like effect in both reflexive and affective dimensions of pain. Using male and female C57BL/6J mice, oral ethanol administration (0-1.25 g/kg) showed a dose-dependent reversal of mechanical hypersensitivity in both Complete Freund's Adjuvant (CFA) and chronic constriction injury (CCI) models of chronic inflammatory and neuropathic pain. No sex differences were observed. Using the conditioned place preference (CPP) task to assess the subjective responses to ethanol's anti-nociceptive properties, CCI-injured animals showed a preference for the ethanol-paired side, suggesting a reduction in an aversive and pain-like state produced by nerve injury. These effects are likely mediated through the kappa and possibly the mu opioid systems, since ethanol-induced anti-nociception following CCI was fully reversed by pretreatment with the kappa selective antagonist, nor-BNI, or high doses of naltrexone. These data show that ethanol possesses analgesic-like properties in chronic inflammatory and neuropathic pain models in mice and provide new insight into ethanol as it relates to chronic pain.

The ß3 subunit of the nicotinic acetylcholine receptor is required for nicotine withdrawal-induced affective but not physical signs or nicotine reward in mice.

Nicotinic acetylcholine receptors (nAChRs) are the primary target for nicotine, the addictive component in tobacco products. These pentameric receptors are made up of various subunits which contribute to the diverse functions of nAChR subtypes. The ß3 subunit of the nAChR has been understudied in nicotine dependence, even though it is expressed in brain regions important for drug reward. Therefore, we assessed nicotine dependence behaviors in ß3 wildtype (WT) and knockout (KO) male and female mice. We evaluated nicotine reward in the conditioned place preference (CPP) test and then measured nicotine withdrawal signs after chronic exposure to the drug. For the withdrawal studies, mice were continuously infused with 24 mg/kg/day of nicotine using surgically implanted osmotic mini-pumps for 14 days. Mini-pumps were removed at day 15, and withdrawal signs (somatic signs, hyperalgesia, anhedonia-like measure using the sucrose preference test and anxiety-like behaviors using the light dark boxes) were collected at 24 h intervals for three days following spontaneous withdrawal of nicotine. Nicotine-induced CPP did not differ between ß3 KO and WT mice. ß3 KO mice displayed similar somatic symptoms and hyperalgesia compared to WT mice but showed significant absence in affective (anhedonia and anxiety-like behaviors) withdrawal signs in nicotine-dependent mice. These observations suggest that the ß3 nicotinic subunits do not seem to influence nicotine reward but plays an important role in affective nicotine withdrawal signs. Given the health burden of tobacco use disorder and the modest effect of smoking cessation aids, it is important to understand underlying factor contributing to nicotine dependence. The results of this study will further our knowledge of the role of the ß3 nAChR subunit in nicotine reward and withdrawal behaviors in hopes of finding new molecular targets for smoking cessation aids.

Razonamiento clínico inductivo o deductivo: una propuesta cualitativa en kinesiología / nductive or deductive clinical reasoning: a proposal qualitative in kinesiology

Introducción: a través del proceso de razonamiento clínico, los profesionales de la salud evalúan críticamente sus intervenciones, siendo esta habilidad necesaria para reconocer qué factores son relevantes para el usuario, a fin de realizar juicios clínicos apropiados que contribuyan a la condición de salud óptima del paciente. La literatura indica que el proceso en un estudiante puede no ser lineal, siendo necesario retroceder y buscar nuevas soluciones y patrones para determinar una elección terapéutica. Objetivo: describir el proceso de razonamiento clínico realizado en estudiantes de ciclo intermedio de Kinesiología en la Universidad de Concepción. Método: investigación cualitativa y descriptiva. 7 estudiantes de tercer y cuarto año de la Universidad de Concepción participaron en la recolección de datos, siguiendo un proceso de consentimiento informado. Se aplicó un cuestionario sociodemográfico y se analizaron los problemas kinesiológicos de un caso clínico mediante asociación libre. Los registros se obtuvieron con una grabadora y luego se realizó un análisis de contenido utilizando CAQDAS Atlas-ti 7.5.2. Resultados: a partir de la lectura de los documentos grabados, surgieron 335 unidades asociadas al razonamiento clínico de los estudiantes de Kinesiología. Estas unidades se agruparon en 58 códigos y estos a su vez, en 2 categorías: razonamiento deductivo y razonamiento inductivo. Discusión: el análisis del proceso es esencial para identificar qué estrategias buscan los estudiantes para resolver en un caso clínico, qué diferencias y particularidades existen entre los estudiantes, y qué metodologías de enseñanza son las más adecuadas para guiar apropiadamente las decisiones terapéuticas que enfrentarán los profesionales de la salud en forma diaria.(AU)

Introduction: Through the clinical reasoning process, health professionals critically evaluate their interventions, being these skills required to recognize which factors are relevant to the user, in order to make appropriate clinical judgments that contribute to the optimal health condition of the user. The literature shows that the student´s process may not be linear, needing to go back and look for new solutions and patterns to determine a therapeutic choice. Objective: Describe the process of clinical reasoning carried out in Physiotherapy students who study in the intermediate cycle at the University of Concepción. Method: Qualitative and descriptive research. 7 students from third and fourth year at the Universidad de Concepción started the sample collection, following an informed consent process. A socio-demographic questionnaire was applied, and kinesthetic problems of a clinical case were analyzed by free association. Records were obtained with a tape recorder and then a content analysis was performed using CAQDAS Atlas-ti 7.5.2. Results: From the listening of the recorded documents, 335 units emerged associated with the clinical reasoning of the Physiotherapy students. These units were grouped into 58 codes and these in turn, in 2 categories: deductive reasoning and inductive reasoning. Discussion: Analysis of the process is essential to identify which strategies students seek to resolve a case, what differences and particularities exist among students, and which teaching strategies are best suited to adequately guide the therapeutic decisions they will face as health professionals on a daily basis.(AU)

Efectos médicos del consumo de bebidas energéticas: revisión de la literatura / Medical and dental effects of energy drinks consumption: literature review

El consumo de bebidas energéticas ha mostrado alzas exponenciales en los últimos años a nivel mundial, tanto en adultos, jóvenes, e incluso niños. Dentro de sus componentes es posible encontrar: cafeína, guaraná, taurina, ging-seng, L-carnitina, creatina o glucoronolactona, ácido cítrico y ácido fosfórico, entre otros. Un consumo responsable y ocasional no debería presentar mayores problemas, pero esto no ocurre. Los efectos médicos provocados por su consumo indiscriminado son: cefaleas, palpitaciones, insomnio, sudoración, dolor abdominal, vómitos, náuseas, reflujo gastroesofágico, parestesias faciales, meteorismo, tremor, diarrea e incluso adicción, entre otros. Mientras que a nivel odontológico, específicamente sobre el esmalte dental, el efecto más severo y de mayor impacto es la erosión y en menor medida la tinción dental, temática que aún no ha sido investigada a cabalidad, también se ha descrito el desarrollo de hipersensibilidad. Una oportuna prevención y diagnóstico, son fundamentales para minimizar los daños provocados por el prolongado consumo de éstos productos. También se hace indispensable evitar una posible tendencia o "moda" asociada a la mezcla de bebidas energéticas y bebidas alcohólicas e incluso con fármacos, de la cual no se conocen en profundidad los posibles riesgos que podrían llegar a ocasionar. El alto consumo de bebidas energéticas mantenido en el tiempo se asocia con efectos negativos a nivel médico y odontológico. Se hace necesario seguir investigando para prevenir, tratar y rehabilitar las consecuencias que produce el consumo de estos productos

The energy drinks have undergone exponential hikes over the last years worldwide, in adults, youth, and even children. Among its components can be found: caffeine, guarana, taurine, ging-Seng, L-carnitine, creatinine or glucuronolactone, citric acid and phosphoric acid, among others. A responsible and occasional consumption should not pose major problems, but this is not the case. The medical effects are usually caused by their abuse, like: headaches, palpitations, insomnia, sweating, abdominal pain, vomiting, nausea, gastroesophageal reflux, facial numbness, bloating, tremor, diarrhea and even addiction, among others. While in the dental level, specifically on the dental enamel, the most severe impact is the erosion and the lesser impact is tooth staining, which has not yet been fully investi-gated, also have been described the development of hypersensitivity. A timely prevention and diagnosis are essential to minimize the damage caused by prolonged use of these products. It is essential to avoid a possible trend or "fad" associated with mixing energy drinks and alcohol and even drugs, of which they are not fully known the possible risks that could potentially cause. Due to its exponential growth it is essential to have an updated knowledge about the consumption of these beverages. The high consump-tion of energy drinks maintained over time is associated with negative effects at the medical and dental level. Further research is necessary to prevent, treat and rehabilitate the consequences produced by the consumption of these products

Factores asociados al fracaso académico en estudiantes universitarios de Barranquilla (Colombia) / Factors associated with academic failure in university students of Barranquilla (Colombia)

El fracaso académico es un problema que afrontan los estudiantes que presentan un rendimiento académico deficiente, lo cual los lleva en poco tiempo a desertar o son expulsados del sistema educativo. Se considera que es un problema multicausal, pero para afrontarlo es necesario indagar desde los mismos estudiantes qué es lo que más los puede estar afectando. Para indagar sobre los factores asociados a este problema se llevó a cabo un estudio descriptivo con estudiantes de psicología en una universidad privada de Barranquilla (Colombia). Se entrevistó a 38 estudiantes que asistían a un programa exclusivo para aquellos con muy bajo rendimiento académico y que estaban en riesgo de salir del programa o habían sido remitidos por los profesores. Los resultados indican que los estudiantes no recibieron una orientación vocacional adecuada antes de ingresar a los estudios superiores que les permitiera analizar sus capacidades y habilidades con respecto a una carrera profesional. Además manifiestan limitaciones en sus competencias de concentración y atención, en la distribución del tiempo, en la deficiente utilización de técnicas de estudio, y en la poca asistencia a clases por la baja motivación en las actividades académicas. La relación con su familia la consideraron satisfactoria. Se observa que las acciones para reducir el fracaso deben ser emprendidas antes del ingreso a la universidad, con estrategias de estudio y afrontamiento que les brinden a los jóvenes las mejores opciones entre sus intereses y capacidades con las oportunidades que les ofrece la sociedad en la cual vivirán.

Academic failure is a problem faced by students with deficient academic performance. This eventually leads them to drop out or to be expelled of the academic system. This is considered a multi-causal problem, but in order to face it, it is necessary to find out among the affected students, what is the main reason for this. In order to search for the associated factors, a descriptive study was developed with Psychology students in a private university of Barranquilla. 38 students assisting to a special program for low performance students at risk of being expelled of their programs were interviewed, as well as some others who had been submitted by their teachers. Results indicate that these students had not received professional orientation before starting their undergraduate studies, which would have allowed them to analyze their capabilities and abilities with respect to a professional career. They also report some limitations in their concentration and attention abilities, in time distribution, deficient use of study techniques, low class assistance due to lack of motivation in academic activities. They rated as satisfactory their family relations. It was observed that the actions to be taken to reduce failure must be developed before registering at the university. They should include study and management strategies that would offer students better opportunities to develop their interests and abilities in the options offered by the society in which they will live.