Concomitant use of pre-emptive analgesia with local and general anesthesia in rat uterine pain surgical model.

Preemptive analgesia is used for postoperative pain management, providing pain relief with few adverse effects. In this study, the effect of a preemptive regime on rat behavior and c-fos expression in the spinal cord of the uterine surgical pain model was evaluated. It was a lab-based experimental study in which 60 female Sprague-Dawley rats; eight to 10 weeks old, weighing 150-300 gm were used. The rats were divided into two main groups: (i) superficial pain group (SG) (with skin incision only), (ii) deep pain group (with skin and uterine incisions). Each group was further divided into three subgroups based on the type of preemptive analgesia administered i.e., "tramadol, buprenorphine, and saline subgroups." Pain behavior was evaluated using the "Rat Grimace Scale" (RGS) at 2, 4, 6, 9 and 24 h post-surgery. Additionally, c-fos immunohistochemistry was performed on sections from spinal dorsal horn (T12-L2), and its expression was evaluated using optical density and mean cell count 2 hours postoperatively. Significant reduction in the RGS was noted in both the superficial and deep pain groups within the tramadol and buprenorphine subgroups when compared to the saline subgroup (p ≤ .05). There was a significant decrease in c-fos expression both in terms of number of c-fos positive cells and the optical density across the superficial laminae and lamina X of the spinal dorsal horn in both SD and DG (p ≤ .05). In contrast, the saline group exhibited c-fos expression primarily in laminae I-II and III-IV for both superficial and deep pain groups and lamina X in the deep pain group only (p ≤ .05). Hence, a preemptive regimen results in significant suppression of both superficial and deep components of pain transmission. These findings provide compelling evidence of the analgesic efficacy of preemptive treatment in alleviating pain response associated with uterine surgery.

A novel tramadol-polycaprolactone implant could palliate heroin conditioned place preference and withdrawal in rats: behavioral and neurochemical study.

Drug dependence is a chronic brain disease characterized by craving and recurrent episodes of relapse. Tramadol HCl is a promising agent for withdrawal symptoms management, considering its relatively low abuse potential and safety. Oral administration, however, is not preferred in abstinence maintenance programs. Introducing an implantable, long-lasting formula is suggested to help outpatient abstinence programs achieve higher rates of treatment continuation. Tramadol implants (T350 and T650) were prepared on polycaprolactone polymer ribbons by the wet method. Male Wistar rats were adapted to heroin-conditioned place preference (CPP) at escalating doses (3-30 mg/kg, intraperitoneally, for 14 days). Implants were surgically implanted in the back skin of rats. After 14 days, the CPP score was recorded. Naloxone (1 mg/kg, intraperitoneally) was used to induce withdrawal on day 15, and symptoms were scored. Elevated plus maze and open field tests were performed for anxiety-related symptoms. Striata were analyzed for neurochemical changes reflected in dopamine, 3,4-dihydroxyphenyl acetic acid, gamma-aminobutyric acid, and serotonin levels. Brain oxidative changes including glutathione and lipid peroxides were assessed. The tramadol implants (T350 and T650) reduced heroin CPP and limited naloxone-induced withdrawal symptoms. The striata showed increased levels of 3,4-dihydroxyphenyl acetic acid, and serotonin and decreased levels of gamma-aminobutyric acid and dopamine after heroin withdrawal induction, which were reversed after implanting T350 and T650. Implants restore the brain oxidative state. Nonsignificant low naloxone-induced withdrawal score after the implant was used in naive subjects indicating low abuse potential of the implants. The presented tramadol implants were effective at diminishing heroin CPP and withdrawal in rats, suggesting further investigations for application in the management of opioid withdrawal.

Combined antiallodynic effects of Neurotropin®-tramadol and Neurotropin®-mirogabalin in rats with L5-spinal nerve ligation.

We aimed to examine the efficacy of combination therapies of Neurotropin® with tramadol and Neurotropin with mirogabalin for neuropathic pain management. A neuropathic pain model (L5 spinal nerve ligation model: L5-SNL) using male Wistar rats was generated through tight ligation of the left fifth lumbar nerve using silk sutures. Mechanical allodynia was assessed using the 50% paw withdrawal threshold. The combined antiallodynic effects were evaluated using isobolographic analyses. Small intestinal transit was evaluated using the charcoal meal test, and motor coordination using the rota-rod test. Neurotropin (50-200 NU/kg, p.o.), tramadol (7.5-60 mg/kg, p.o.), and mirogabalin (3-30 mg/kg, p.o.) showed a dose-dependent antiallodynic effect in L5-SNL rats. The combined antiallodynic effects of Neurotropin and tramadol were additive or synergistic, whereas those of Neurotropin and mirogabalin were additive. Neurotropin (100-400 NU/kg, p.o.) did not affect the small intestinal transit, whereas tramadol (30-100 mg/kg, p.o.) significantly inhibited it. Neurotropin (100-400 NU/kg, p.o.) did not affect the walking time, whereas mirogabalin (10-100 mg/kg, p.o.) significantly decreased it. Neurotropin dose-dependently ameliorated mechanical allodynia in rats, and combination therapy with Neurotropin-tramadol or Neurotropin-mirogabalin may alleviate neuropathic pain without aggravating the adverse effects of tramadol and mirogabalin.

Bioenergetics disruption, oxidative stress, and inflammation as underlying mechanisms of tramadol-induced nephrotoxicity.

Tramadol (TR), a commonly prescribed pain reliever for moderate to severe pain, has been associated with kidney damage. This study investigates TR-induced nephrotoxicity mechanisms, focusing on its effects on renal proximal tubular cells (PTCs). The study findings demonstrate that TR disrupts PTC bioenergetic processes, leading to oxidative stress and inflammation. Significant toxicity to PTCs was observed with estimated effective concentration 50 values of 9.8 and 11.5 µM based on 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays, respectively. TR also interferes with the function of PTC transporters, including organic cation uptake transporter 1, organic cation transporter 2, P-glycoprotein, and multidrug resistance protein 2. Furthermore, bioenergetics assays showed that TR reduced the activities of mitochondrial complexes I and III, adenosine triphosphate production, mitochondrial membrane potential, and oxygen consumption rate while increasing lactate release. TR also increased the production of reactive oxygen species, lipid peroxidation thiobarbituric acid reactive substances end products, and the expression of the NRf2 gene while decreasing reduced glutathione (GSH-R) stores and catalase and superoxide dismutase antioxidant activities. Additionally, TR increased the production of inflammatory cytokines (TNF-α and IL-6) and their coding genes expression. Interestingly, the study found that antioxidants like GSH-R, inhibitors of IL-6 and TNF-α, and mitochondrial activating Co-Q10 could protect cells against TR-induced cytotoxicity. The study suggests that TR causes nephrotoxicity by disrupting bioenergetic processes, causing oxidative stress and inflammation, but antioxidants and agents targeting mitochondria may have protective and curative potential.

Intradermal Sterile Water Injection: Safe and Effective Alternative for Relief of Acute Renal Colic in the Emergency Department.

BACKGROUND: The optimal pain relief method for acute renal colic in the emergency department remains controversial. OBJECTIVE: We compared the safety and efficacy of intradermal sterile water injection (ISWI) to treatment with intramuscular (IM) diclofenac, intravenous (IV) opioids, and IV paracetamol in patients with acute renal colic. METHODS: This randomized, single-blind study included 320 patients with renal colic to one of four treatment groups. The first group received ISWI at four different points around the most painful flank area. Patients in the DI, PARA, and TRAM groups received 75 mg IM diclofenac, 1 g IV paracetamol, and 100 mg IV tramadol, respectively. Pain intensity was measured using a visual analog scale (VAS) before treatment and 15, 30, and 60 min after treatment. RESULTS: VAS scores 15 and 30 min after treatment were significantly lower in group ISWI than in groups DI, PARA, and TRAM. However, there were no significant differences in the decrease in the pain score at baseline and at 60 min after treatment. In addition, fewer patients required rescue analgesia in group ISWI than in group TRAM. However, no significant differences were observed between group ISWI and group DI or PARA in terms of the need for rescue analgesia. Finally, there were significantly fewer adverse events in group ISWI than in groups DI and TRAM. CONCLUSIONS: ISWI had similar efficacy, faster pain relief, and lower need for rescue analgesia compared with diclofenac, paracetamol, and tramadol for the management of acute renal colic. In addition, ISWI was well-tolerated and had no adverse effects.

Analgesic and Psychotropic Effects of a New Bradykinin Antagonist.

A bradykinin B1 receptors antagonist PAV-0056, an 1,4-benzodiazepin-2-one derivative, intragastrically administrated to mice at doses of 0.1 and 1 mg/kg causes analgesia in the "formalin test" not inferior to that of diclofenac sodium (10 mg/kg) and tramadol (20 mg/kg). PAV-0056 at doses of 0.1 and 10 mg/kg has no anxiolytic and central muscle relaxant effects in mice and does not damage the gastric mucosa in rats. Based on the results of the conditioned place preference test, PAV-0056 also does not induce addiction in mice.

Neuro-protective effect of pre-treatment with Sorghum bicolor and vitamin C on tramadol induced brain oxidative stress and anxiety-like behaviour in male albino rats.

The study focused on the neuroprotective role of Sorghum bicolor and vitamin C in the amelioration of oxidative stress and anxiety-like behavoiur induced by tramadol in male albino rats. The study design involved 7 groups and a control group with 5 male albino rats in each group. Tramadol (40 mg/kg) treatment was administered for 21 days. Tramadol 40mg/kg was administered in all groups. Pretreatment with varying doses of Sorghum bicolor and Vitamin C was done in three of the groups. Behavioral assessment of anxiety and locomotors actions of the groups were compared using Elevated Plus Maze (EPM) and Open Field Test (OFT). In conclusion, Sorghum bicolor and Vitamin C tramadol ameliorated oxidative stress and anxiety-like behaviour induced by tramadol. Pretreatment with Sorghum bicolor or vitamin C (100mg) can also reduced anxiogenic responses in male albino rats that are induced by chronic tramadol use.

Effect of Intraligamentary Tramadol Hydrochloride on Anesthetic Success During Endodontic Management of Mandibular Molars: A Randomized Clinical Controlled Trial.

OBJECTIVE: Tramadol hydrochloride has shown local anesthetic properties similar to lidocaine, apart from a central analgesic effect. The present study evaluated the effect of the administration of tramadol alone or in addition to 2% lidocaine, as supplementary intraligamentary injections. METHODS: One hundred and five patients, with a failed primary inferior alveolar nerve block (IANB), were randomly allocated to one of the three supplementary intraligamentary groups: 2% lidocaine with 1: 80,000 epinephrine; tramadol hydrochloride (50 mg/mL); and 2% lidocaine with 1: 80,000 epinephrine plus tramadol hydrochloride. Patients received 1.2 mL doses (0.6 mL of each root). Patients reporting pain ≤54 on Heft Parker visual analogue scale (Heft-Parker VAS), were categorized as successful anesthesia. A finger pulse oximeter was used to measure the heart rates. The anesthetic success rates, gender, and type of tooth were compared using the Pearson chi-square test. The heart rates and age were statistically evaluated using the one-way analysis of variance test. The level of significance was set at 0.05 (p=0.05). RESULTS: The initial IANB was successful in 31% of cases. There were significant differences in the anesthetic success rates of different supplementary intraligamentary injections (χ2= 33.6, p<0.001, df=2). The 2% lidocaine-plus-tramadol resulted in significantly higher success rates than the two groups. There were no significant changes in the baseline heart rates of all groups (p>0.05). CONCLUSION: The addition of tramadol to 2% lidocaine with 1: 80,000 epinephrine, given as supplementary intraligamentary injection, can help in achieving successful anesthesia during the endodontic management of mandibular molars with irreversible pulpitis resistant to IANB injections.

Crizotinib inhibits the metabolism of tramadol by non-competitive suppressing the activities of CYP2D1 and CYP3A2.

Objectives: To investigate the interaction between tramadol and representative tyrosine kinase inhibitors, and to study the inhibition mode of drug-interaction. Methods: Liver microsomal catalyzing assay was developed. Sprague-Dawley rats were administrated tramadol with or without selected tyrosine kinase inhibitors. Samples were prepared and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used for analysis. Besides, liver, kidney, and small intestine were collected and morphology was examined by hematoxyline-eosin (H&E) staining. Meanwhile, liver microsomes were prepared and carbon monoxide differential ultraviolet radiation (UV) spectrophotometric quantification was performed. Results: Among the screened inhibitors, crizotinib takes the highest potency in suppressing the metabolism of tramadol in rat/human liver microsome, following non-competitive inhibitory mechanism. In vivo, when crizotinib was co-administered, the AUC value of tramadol increased compared with the control group. Besides, no obvious pathological changes were observed, including cell morphology, size, arrangement, nuclear morphology with the levels of alanine transaminase (ALT) and aspartate transaminase (AST) increased after multiple administration of crizotinib. Meanwhile, the activities of CYP2D1 and CYP3A2 as well as the total cytochrome P450 abundance were found to be decreased in rat liver of combinational group. Conclusions: Crizotinib can inhibit the metabolism of tramadol. Therefore, this recipe should be vigilant to prevent adverse reactions.

Evaluation of histological and ultrastructural changes provoked by prenatal tramadol on postnatal cortical cerebellar neuronal development in rats: possible implication of Ki67, GFAP and MicroRNA-7/P53 signalling trajectories.

Tramadol is a novel centrally acting analgesic. Despite, its implementation during pregnancy may impair neuronal survival and synaptic development in neonatal cerebella. The current investigation assessed the histological and ultrastructural alterations in postnatal cortical cerebellar neuronal development induced by prenatal tramadol. 30 offsprings were divided to control group I: fifteen pups born to mothers given saline from D10 till D21 of gestation. Tramadol-treated group II: fifteen pups born to mothers received tramadol HCL (50 mg/kg/day) from D10 till D21 of gestation. Pups were categorized into three subgroups (a, b, and c) and offered for sacrifice on the seventh, fourteenth and twenty-first post-natal days. Light microscopic examination revealed the overcrowding and signs of red degeneration affecting purkinje cell layer. Neurodegenerative signs of both purkinje and granule cell neurons were also confirmed by TEM in form of chromatin condensation, dilated Golgi channels, disrupted endoplasmic reticulum, marked infolding of the nuclear envelope and decrease in granule cell precursors. In addition, the astrocytic processes and terminal nerve axons appeared with different degrees of demyelination and decreased number of oligodendrocytes and degenerated mitochondria. Furthermore, group II exhibited an increase in P53 immune expression. The area percentage of apoptotic cells detected by TUNEL assay was significantly increased. Besides to the significant decrease of Ki67 immunoreactivity in the stem neuronal cell progenitors. Quantitative PCR results showed a significant decline in micro RNA7 gene expression in tramadol treated groups resulting in affection of multiple target genes in P53 signaling pathways, improper cortical size and defect in neuronal development.

Comparison of Preoperative Analgesics on the Efficacy of Inferior Alveolar Nerve Block with Patients Having Symptomatic Irreversible Pulpitis: A Double-Blinded, Randomized Controlled Trial.

OBJECTIVE: The objective of this study was to evaluate the effectiveness of preoperative analgesics on inferior alveolar nerve blocks (IANB) during root canal treatment in patients with symptomatic irreversible pulpitis of the mandibular molars. METHODS: This study was a randomized, double-blinded, superiority trial with a parallel study design. A total of 120 subjects with symptomatic irreversible pulpitis were randomly assigned to one of four groups: group A (con- trol, Vitamin E, Evion 400 mg), group B (Diclofenac sodium, Voltral SR100 100 mg), group C (Piroxicam, Feldene 20 mg), and group D (Tramadol, Tramal 50 mg). The patients recorded preoperative pain levels, and after admin- istration of local anaesthesia intraoperative pain levels using the Heft-Parker visual analogue scale before and after the oral administration of the analgesics. Statistical analysis was performed using the Kruskal-Wallis test. RESULTS: All the analgesic groups showed a significant effect on the efficacy of the inferior alveolar nerve block in contrast to the control group (p<0.05). However, no significant difference was found between the drug groups on the effectiveness of the inferior alveolar nerve block (p>0.05). No side effects were reported in the present study. CONCLUSION: Preoperative analgesics significantly increase the effectiveness of inferior alveolar nerve block in patients with symptomatic irreversible pulpitis. Therefore, preoperative analgesics should be considered to increase the effectiveness of inferior alveolar nerve block in patients with symptomatic irreversible pulpitis on the mandibular molars. (EEJ-2023-02-033).

Opioids in the immune system: from experimental studies to clinical practice

SUMMARY INTRODUCTION: Opioids interact with both innate and adaptive immune systems and have direct effects on opioid receptors located on immune cells. Research on this topic has provided evidence of the opioid influence on the immune response associated with surgical stress. The immunological effects of opioids are currently being investigated, particularly whether they influence the outcome of surgery or the underlying disease regarding important aspects like infection or cancer progression. This review addresses background research related to the influence of the opioid receptor on the immune system, the immunosuppressive effect associated with major opioids during the perioperative period, and their clinical relevance. The objective of the study was to review the effects of opioids on the immune system. Methods: A search strategy was conducted in PubMed, Embase, and the Cochrane databases using the terms "immunosuppression," "immune system," "surgical procedures," "analgesics," "opioids" and "perioperative care." Results: The immunosuppressive effect of opioids was identified over 30 years ago. They include signaling and acting directly through immune cells, including B and T lymphocytes, NK cells, monocytes, and macrophages, as well as activating the downstream pathways of the hypothalamic-pituitary-adrenal (HPA) axis leading to the production of immunosuppressive glucocorticoids in the peripheral and sympathetic nervous system.

RESUMO INTRODUÇÃO: Os opioides interagem com ambos os sistemas imunes, inato e adaptativo, através de efeitos diretos sobre os receptores dos opioides localizados nas células imunes. As pesquisas neste assunto têm fornecido evidência da influência dos opioides sobre a resposta imune associada ao estresse cirúrgico. Os efeitos imunológicos dos opioides estão sendo pesquisados na atualidade, principalmente se eles determinam o resultado da cirurgia ou doença consequente devido a fatos importantes como infecção ou progressão do câncer. Essa revisão tem como alvo ver antecedentes em pesquisa relativa à influência dos receptores dos opioides no sistema imunológico, o efeito imunossupressor associado com opioides maiores durante o período peri-operatório e sua importância clínica. O objectivo da pesquisa foi revisar os efeitos dos opioides no sistema imunológico. MÉTODOS: Uma estrategia de procura foi dirigida na mídia PubMed, e no cadastro de Embase e The Cochrane, usando os termos "imunosuppressão", "sistema imunológico", "procedimentos cirúrgicos", "analgésicos", "opioides" e "cuidado peri-operatório". RESULTADOS: O efeito imunosuppressor dos opioides foi identificado há mais de 30 anos. Os efeitos imunosupressores incluem sinalização e ação diretamente através das células imunes, mesmo com os linfócitos B e T, células NK, monócitos e macrófagos, também como ativando as vias de corrente do eixo hipotálamo- hipófise- adrenal (HPA) levando à produção de glucocorticoides imunossupresores no sistema nervoso periférico e simpático.

Analgesic effects of Marasmius androsaceus mycelia ethanol extract and possible mechanisms in mice

Marasmius androsaceus is a medicinal fungus mainly used to treat various forms of pain in China. This study investigated the analgesic effects of an ethanol extract of M. androsaceus (MAE) and its potential molecular mechanisms. Oral administration of MAE (50, 200, and 1000 mg/kg) had significant analgesic effects in an acid-induced writhing test, a formalin test, and a hot-plate test, with effectiveness similar to tramadol (the positive control drug). The autonomic activity test showed that MAE had no harmful effects on the central nervous system in mice. MAE resulted in significantly enhanced levels of noradrenalin and 5-hydroxytryptamine in serum but suppressed both of these neurotransmitters in the hypothalamus after 30 s of hot-plate stimulation. Co-administration with nimodipine (10 mg/kg; a Ca2+ channel blocker) strongly enhanced the analgesic effect in the hot-plate test compared to MAE alone. Moreover, MAE down-regulated the expression of calmodulin-dependent protein kinase II (CaMKII) in the hypothalamus after a 30-s thermal stimulus. These results suggested that the analgesic ability of MAE is related to the regulation of metabolism by monoamine neurotransmitters and Ca2+/CaMKII-mediated signaling, which can potentially aid the development of peripheral neuropathic pain treatments obtained from M. androsaceus.

Influence of tramadol on functional recovery of acute spinal cord injury in rats

Abstract Purpose: To evaluate the influence tramadol on functional recovery of acute spinal cord injury in rats. Methods: Ten rats were divided into two groups (n = 5). All animals were submitted by a laminectomy and spinal cord injury at eighth thoracic vertebra. In control group, the rats didn't receive any analgesic. In tramadol group, the rats received tramadol 4mg/Kg at 12/12h until 5 days by subcutaneous. Animals were following by fourteen days. Was evaluated the Basso, Beattie, Bresnahan scale (locomotor evaluation) and Rat Grimace Scale (pain evaluation) at four periods. Results: There no difference between the groups in locomotor evaluation in all periods evaluated (p>0.05) and in both groups there was a partial recover of function. The tramadol group show a lower pain levels at the first, third and seventh postoperatively days when comparing to the control group. Conclusion: The tramadol as an analgesic agent don't influence on functional recovery of acute spinal cord injury in rats

Influence of remote ischemic conditioning and tramadol hydrochloride on oxidative stress in kidney ischemia/reperfusion injury in rats

Abstract Purpose: To evaluate the effects of tramadol hydrochloride associated to remote ischemic perconditioning on oxidative stress. Methods: Twenty five male rats (Wistar) underwent right nephrectomy and were distributed into five groups: Sham group (S); Ischemia/Reperfusion group (I/R) with 30 minutes of renal ischemia; Remote ischemic perconditioning group (Per) with three cycles of 10 minutes of I/R performed during kidney ischemia; Tramadol group (T) treated with tramadol hydrochloride (40mg/kg); remote ischemic perconditioning + Tramadol group (Per+T) with both treatments. Oxidative stress was assessed after 24 hours of reperfusion. Results: Statistical differences were observed in MDA levels between I/R group with all groups (p<0.01), in addition there was difference between Tramadol with Sham, Per and Per+T groups (p<0.05), both in plasma and renal tissue. Conclusion: Remote ischemic perconditioning was more effective reducing renal ischemia-reperfusion injury than administration of tramadol or association of both treatments.

Analgesia en primigesta en trabajo de parto con Clorhidrato de Tramadol IM, desde 1 de septiembre de 2013 a 28 de febrero de 2014. Hospital Boliviano Holandés (H.M.B.H.) / Analgesia in primigravida in labor with tramadol hydrochloride IM, from September 1, 2013 to February 28, 2014. Hospital Bolivian Dutch (H.M.B.H.)

Introducción: el trabajo de parto es generalmente un acontecimiento doloroso, 75% de las primigestas en trabajo de parto pueden llegar a presentar dolor intenso asociado con aumento de la presión arterial, el consumo de oxígeno y producen la liberación de catecolaminas que pueden afectar el flujo sanguíneo uterino y comprometer al feto...

Introduction: the labor is usually a painful event; 75% of first time pregnant women in labor could contain intense pain associated with increased blood pressure, oxygen consumption and produce catecholamine release that may affect the flow Uterine blood and engage the fetus...

Local analgesic effect of tramadol is not mediated by opioid receptors in early postoperative pain in rats / O efeito analgésico de tramadol não é mediado por receptores opioides na dor de ratos no pós-operatório imediato / El efecto analgésico del tramadol no está mediado por receptores opiáceos en el dolor en ratones en el postoperatorio inmediato

BACKGROUND AND OBJECTIVES: Tramadol is known as a central acting analgesic drug, used for the treatment of moderate to severe pain. Local analgesic effect has been demonstrated, in part due to local anesthetic-like effect, but other mechanisms remain unclear. The role of peripheral opioid receptors in the local analgesic effect is not known. In this study, we examined role of peripheral opioid receptors in the local analgesic effect of tramadol in the plantar incision model. METHODS: Young male Wistar rats were divided into seven groups: control, intraplantar tramadol, intravenous tramadol, intravenous naloxone-intraplantar tramadol, intraplantar naloxone-intraplantar tramadol, intravenous naloxone-intravenous tramadol, and intravenous naloxone. After receiving the assigned drugs (tramadol 5 mg, naloxone 200 µg or 0.9% NaCl), rats were submitted to plantar incision, and withdrawal thresholds after mechanical stimuli with von Frey filaments were assessed at baseline, 10, 15, 30, 45 and 60 min after incision. RESULTS: Plantar incision led to marked mechanical hyperalgesia during the whole period of observation in the control group, no mechanical hyperalgesia were observed in intraplantar tramadol group, intraplantar naloxone-intraplantar tramadol group and intravenous naloxone-intraplantar tramadol. In the intravenous tramadol group a late increase in withdrawal thresholds (after 45 min) was observed, the intravenous naloxone-intravenous tramadol group and intravenous naloxone remained hyperalgesic during the whole period. CONCLUSIONS: Tramadol presented an early local analgesic effect decreasing mechanical hyperalgesia induced by plantar incision. This analgesic effect was not mediated by peripheral opioid receptors. .

JUSTIFICATIVA E OBJETIVOS: Tramadol é conhecido como um fármaco analgésico de ação central, usado para o tratamento de dor moderada a grave. O efeito analgésico local foi demonstrado, em parte devido ao efeito semelhante ao anestésico local, mas outros mecanismos permanecem obscuros. O papel dos receptores opioides periféricos no efeito analgésico local não é conhecido. Neste estudo, examinamos o papel dos receptores opioides periféricos no efeito analgésico local de tramadol em modelo de incisão plantar. MÉTODOS: Ratos Wistar, jovens e machos, foram divididos em sete grupos: controle, tramadol intraplantar, tramadol intravenoso, tramadol intraplantar-naloxona intravenosa, tramadol intraplantar-naloxona intraplantar, tramadol intravenoso-naloxona intravenosa e naloxona intravenosa. Após receber os medicamentos designados (5 mg de tramadol, 200 mg de naloxona ou NaCl a 0,9%, os ratos foram submetidos à incisão plantar e os limiares de retirada após estímulos mecânicos com filamentos de von Frey foram avaliados no início do estudo e nos minutos 10, 15, 30, 45 e 60 após a incisão. RESULTADOS: A incisão plantar levou à hiperalgesia mecânica acentuada durante todo o período de observação no grupo controle; hiperalgesia mecânica não foi observada nos grupos tramadol intraplantar, tramadol intraplantar-naloxona intraplantar e tramadol intraplantar-naloxona intravenosa. No grupo tramadol intravenoso, um aumento tardio do limiar de retirada (após 45 minutos) foi observado. Os grupos tramadol intravenoso-naloxona intravenosa e naloxona intravenosa permaneceram hiperalgésicos durante todo o período. CONCLUSÕES: Tramadol apresentou efeito analgésico local inicial e diminuiu a hiperalgesia mecânica induzida pela incisão plantar. Esse efeito analgésico não foi mediado por receptores opioides periféricos. .

JUSTIFICACIÓN Y OBJETIVOS: Al tramadol se le conoce como un medicamento analgésico de acción central usado para el tratamiento del dolor moderado a intenso. El efecto analgésico local quedó demostrado, en parte, a causa del efecto similar al del anestésico local, pero otros mecanismos permanecen sin clarificar. El rol de los receptores opiáceos periféricos en el efecto analgésico local no se conoce. En este estudio, examinamos el papel de los receptores opiáceos periféricos en el efecto analgésico local del tramadol en un modelo de incisión plantar. MÉTODOS: Ratones Wistar, jóvenes y machos, fueron divididos en 7 grupos: control, tramadol intraplantar, tramadol intravenoso, tramadol intraplantar-naloxona intravenosa, tramadol intraplantar-naloxona intraplantar, tramadol intravenoso-naloxona intravenosa, y naloxona intravenosa. Después de recibir los medicamentos designados (5 mg de tramadol, 200 µg de naloxona o NaCl al 0,9%), los ratones fueron sometidos a la incisión plantar, y los umbrales de retirada de la pata posteriores a los estímulos mecánicos con filamentos de von Frey fueron evaluados al inicio del estudio y en los minutos 10, 15, 30, 45 y 60 después de la incisión. RESULTADOS: La incisión plantar conllevó hiperalgesia mecánica acentuada durante todo el período de observación en el grupo control; la hiperalgesia mecánica no fue observada en los grupos tramadol intraplantar, tramadol intraplantar-naloxona intraplantar, y tramadol intraplantar-naloxona intravenosa. En el grupo tramadol intravenoso, fue observado un aumento tardío del umbral de retirada (después de 45 min); los grupos tramadol intravenoso-naloxona intravenosa y naloxona intravenosa permanecieron hiperalgésicos durante todo el período. CONCLUSIONES: El tramadol presentó un efecto analgésico local inicial, disminuyendo la hiperalgesia mecánica inducida por la incisión plantar. Ese efecto analgésico no fue mediado por receptores opiáceos periféricos. .

Tramadol Alleviates Myocardial Injury Induced by Acute Hindlimb Ischemia Reperfusion in Rats / Tramadol Atenua Lesões Miocárdicas Induzidas pela Reperfusão Pós- Isquêmica Aguda de Membros Posteriores em Ratos

AbstractBackground:Organ injury occurs not only during periods of ischemia but also during reperfusion. It is known that ischemia reperfusion (IR) causes both remote organ and local injuries.Objective:This study evaluated the effects of tramadol on the heart as a remote organ after acute hindlimb IR.Methods:Thirty healthy mature male Wistar rats were allocated randomly into three groups: Group I (sham), Group II (IR), and Group III (IR + tramadol). Ischemia was induced in anesthetized rats by left femoral artery clamping for 3 h, followed by 3 h of reperfusion. Tramadol (20 mg/kg, intravenous) was administered immediately prior to reperfusion. At the end of the reperfusion, animals were euthanized, and hearts were harvested for histological and biochemical examination.Results:The levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were higher in Groups I and III than those in Group II (p < 0.05). In comparison with other groups, tissue malondialdehyde (MDA) levels in Group II were significantly increased (p < 0.05), and this increase was prevented by tramadol. Histopathological changes, including microscopic bleeding, edema, neutrophil infiltration, and necrosis, were scored. The total injuryscore in Group III was significantly decreased (p < 0.05) compared with Group II.Conclusion:From the histological and biochemical perspectives, treatment with tramadol alleviated the myocardial injuries induced by skeletal muscle IR in this experimental model.

ResumoFundamento:Lesões a órgãos ocorrem não apenas durante períodos de isquemia, mas paradoxalmente, também durante a reperfusão. Sabe-se que a reperfusão pós-isquêmica (RPI) causa lesões tanto remotas quanto locais no órgão afetado.Objetivo:Este estudo avaliou os efeitos do tramadol no coração como órgão remoto, após RPI aguda dos membros posteriores.Métodos:Trinta ratos Wistar, machos, adultos e saudáveis, foram distribuídos aleatoriamente em três grupos: Grupo I (controle), Grupo II (RPI) e Grupo III (RPI + tramadol). Isquemia foi induzida em ratos anestesiados através do pinçamento da artéria femoral esquerda por 3 horas, seguidas de 3 horas de reperfusão. Tramadol foi administrado (20 mg/kg, IV) imediatamente antes da reperfusão. Ao final da reperfusão, os animais foram sacrificados e seus corações coletados para exames histológicos e bioquímicos.Resultados:Os níveis de superóxido-dismutase (SOD), catalase (CAT) e glutationa-peroxidase (GPx) foram maiores nos grupos I e III que no grupo II (p < 0.05). Em comparação aos outros grupos, os níveis tissulares de malondialdeído (MDA) estavam significativamente mais elevados no grupo II (p < 0.05), o que foi evitado pelo uso de tramadol. Foram pontuadas as alterações histopatológicas, incluindo micro-hemorragia, edema, infiltração por neutrófilos e necrose. A pontuação total das lesões do grupo III foi significativamente menor (p < 0.05) em comparação ao grupo II.Conclusão:Do ponto de vista histológico e bioquímico, o tratamento com tramadol diminuiu as lesões miocárdicas induzidas pela RPI da musculatura esquelética neste modelo experimental.

Effects of opioids on local anesthesia in the rat: a codeine and tramadol study

Opioids are central analgesics that act on the CNS (central nervous system) and PNS (peripheral nervous system). We investigated the effects of codeine (COD) and tramadol (TRAM) on local anesthesia of the sciatic nerve. Eighty Wistar male rats received the following SC injections in the popliteal fossa: local anesthetic with epinephrine (LA); local anesthetic without vasoconstrictor (LA WV); COD; TRAM; LA + COD; LA + TRAM; COD 20 minutes prior to LA (COD 20' + LA) or TRAM 20 minutes prior to LA (TRAM 20' + LA). As a nociceptive function, the blockade was considered the absence of a paw withdraw reflex. As a motor function, it was the absence of claudication. As a proprioceptive function, it was the absence of hopping and tactile responses. All data were compared using repeated-measures analysis of variance (ANOVA). Opioids showed a significant increase in the level of anesthesia, and the blockade duration of LA + COD was greater than that of the remaining groups (p < 0.05). The associated use of opioids improved anesthesia efficacy. This could lead to a new perspective in controlling dental pain.