RESUMO
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.
Assuntos
Modelos Animais de Doenças , Dor Pós-Operatória , Proteínas Proto-Oncogênicas c-fos , Ratos Sprague-Dawley , Útero , Animais , Feminino , Proteínas Proto-Oncogênicas c-fos/metabolismo , Dor Pós-Operatória/tratamento farmacológico , Útero/cirurgia , Útero/efeitos dos fármacos , Anestesia Geral/métodos , Analgesia/métodos , Tramadol/farmacologia , Tramadol/uso terapêutico , Medição da Dor , Ratos , Anestesia Local/métodos , Comportamento Animal/efeitos dos fármacos , Buprenorfina/farmacologia , Buprenorfina/uso terapêuticoRESUMO
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 (1â 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.
Assuntos
Heroína , Naloxona , Poliésteres , Ratos Wistar , Síndrome de Abstinência a Substâncias , Tramadol , Animais , Tramadol/farmacologia , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Masculino , Heroína/farmacologia , Heroína/administração & dosagem , Ratos , Poliésteres/farmacologia , Naloxona/farmacologia , Implantes de Medicamento , Dependência de Heroína/tratamento farmacológico , Relação Dose-Resposta a Droga , Analgésicos Opioides/farmacologia , Analgésicos Opioides/administração & dosagem , Antagonistas de Entorpecentes/farmacologiaRESUMO
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.
Assuntos
Modelos Animais de Doenças , Hiperalgesia , Neuralgia , Ratos Wistar , Nervos Espinhais , Tramadol , Animais , Tramadol/administração & dosagem , Tramadol/farmacologia , Masculino , Neuralgia/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Nervos Espinhais/efeitos dos fármacos , Ligadura/efeitos adversos , Quimioterapia Combinada , Relação Dose-Resposta a Droga , Ratos , Trânsito Gastrointestinal/efeitos dos fármacos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Compostos Bicíclicos com Pontes , PolissacarídeosRESUMO
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.
Assuntos
Metabolismo Energético , Inflamação , Estresse Oxidativo , Tramadol , Estresse Oxidativo/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Tramadol/efeitos adversos , Tramadol/farmacologia , Metabolismo Energético/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/patologia , Humanos , Linhagem Celular , Animais , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacologiaRESUMO
Tramadol, an analgesic classified as an "atypical opioid", exhibits both opioid and non-opioid mechanisms of action. This study aimed to explore these mechanisms, specifically the opioid-, cannabinoid-, nitric oxide-, and potassium channel-based mechanisms, which contribute to the peripheral antinociception effect of tramadol, in an experimental rat model. The nociceptive threshold was determined using paw pressure withdrawal. To examine the mechanisms of action, several substances were administered intraplantarly: naloxone, a non-selective opioid antagonist (50 µg/paw); AM251 (80 µg/paw) and AM630 (100 µg/paw) as the selective antagonists for types 1 and 2 cannabinoid receptors, respectively; nitric oxide synthase inhibitors L-NOArg, L-NIO, L-NPA, and L-NIL (24 µg/paw); and the enzyme inhibitors of guanylatocyclase and phosphodiesterase of cGMP, ODQ, and zaprinast. Additionally, potassium channel blockers glibenclamide, tetraethylammonium, dequalinium, and paxillin were used. The results showed that opioid and cannabinoid receptor antagonists did not reverse tramadol's effects. L-NOarg, L-NIO, and L-NPA partially reversed antinociception, while ODQ completely reversed, and zaprinast enhanced tramadol's antinociception effect. Notably, glibenclamide blocked tramadol's antinociception in a dose-dependent manner. These findings suggest that tramadol's peripheral antinociception effect is likely mediated by the nitrergic pathway and sensitive ATP potassium channels, rather than the opioid and cannabinoid pathways.
Assuntos
Canabinoides , Tramadol , Ratos , Animais , Analgésicos Opioides/farmacologia , Tramadol/farmacologia , Tramadol/uso terapêutico , Óxido Nítrico/metabolismo , Ratos Wistar , Canais de Potássio/metabolismo , Hiperalgesia/metabolismo , Nitroarginina , Receptores de Canabinoides/metabolismo , Glibureto , Analgésicos/farmacologia , Analgésicos/uso terapêutico , GMP Cíclico/metabolismo , Canabinoides/efeitos adversosRESUMO
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.
Assuntos
Cólica , Cólica Renal , Tramadol , Humanos , Acetaminofen/farmacologia , Acetaminofen/uso terapêutico , Cólica Renal/tratamento farmacológico , Diclofenaco/farmacologia , Diclofenaco/uso terapêutico , Tramadol/farmacologia , Tramadol/uso terapêutico , Método Simples-Cego , Dor , Serviço Hospitalar de Emergência , Água , Método Duplo-CegoRESUMO
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.
Assuntos
Analgésicos , Animais , Camundongos , Ratos , Masculino , Analgésicos/farmacologia , Diclofenaco/farmacologia , Tramadol/farmacologia , Psicotrópicos/farmacologia , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Ansiolíticos/farmacologia , Antagonistas de Receptor B1 da Bradicinina/farmacologia , Ratos Wistar , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodosRESUMO
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.
Assuntos
Ansiedade , Ácido Ascórbico , Comportamento Animal , Estresse Oxidativo , Sorghum , Tramadol , Animais , Tramadol/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Masculino , Ácido Ascórbico/farmacologia , Ansiedade/prevenção & controle , Ansiedade/induzido quimicamente , Ansiedade/tratamento farmacológico , Ratos , Comportamento Animal/efeitos dos fármacos , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Ratos Wistar , Analgésicos Opioides/farmacologia , Ansiolíticos/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacosRESUMO
INTRODUCTION: Differences in pain thresholds may have implications in pain management, as they may account in part for the variability in analgesic requirements between individuals. We planned to investigate the influence of endogenous sex hormones on the analgesic modulation of tramadol in lean and high-fat diet-induced obese Wistar rats. METHODS: The whole study was carried out on 48 adult Wistar rats (24 male: 12 obese and 12 lean and 24 female: 12 obese and 12 lean). Each male and female rat group was further subdivided into two groups (n = 6/group) and treated with normal saline/tramadol for 5 days. On the fifth day, 15 min after tramadol/normal saline treatment, animals were tested for pain perception toward noxious stimuli. Later, endogenous 17 beta-estradiol and free testosterone levels in serum were estimated through ELISA methods. RESULTS: The present study revealed that female rats experienced more pain sensitivity to noxious stimuli compared to male rats. High-fat diet-induced obese rats experienced more pain sensations to noxious stimuli than lean rats. Obese male rats were found to have significantly low free testosterone and high 17 beta-estradiol levels compared to lean male rats. An increase in serum 17 beta-estradiol level led to increased pain sensation to noxious stimuli. While an increase in free testosterone level resulted in the lowering of pain sensation to noxious stimuli. CONCLUSION: The analgesic effect of tramadol was more pronounced in male rats compared to female rats. The analgesic effect of tramadol was more marked in lean rats compared to obese rats. Additional research to elucidate obesity-induced endocrine changes and the mechanisms driving sex hormones in pain perception is needed to foster future interventions to reduce disparities in pain.
Assuntos
Tramadol , Ratos , Masculino , Feminino , Animais , Tramadol/farmacologia , Tramadol/uso terapêutico , Ratos Wistar , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Dieta Hiperlipídica/efeitos adversos , Solução Salina/uso terapêutico , Dor/tratamento farmacológico , Dor/etiologia , Analgésicos/uso terapêutico , Hormônios Esteroides Gonadais , Estradiol/farmacologia , Testosterona , Obesidade/tratamento farmacológicoRESUMO
The role of the lateral habenula (LHb) as a hub for receiving and relaying signals from the limbic system to serotonergic, dopaminergic, and norepinephrinergic regions in the brainstem makes this area a critical region in the control of reward and addiction. Behavioral evidence reveals the vital role of the LHb in negative symptoms during withdrawal. In this investigation, we study the role of the LHb N-Methyl D-Aspartate receptor (NMDAR) in the modulation of tramadol reward. Male adult Wistar rats were used in this study. The effect of intra-LHb micro-injection of NMDAR agonist (NMDA, 0.1, 0.5, 2â µg/rat) and antagonist (D-AP5, 0.1, 0.5, 1â µg/rat) was evaluated in conditioned place preference (CPP) paradigm. The obtained results showed that intra-LHb administration of NMDA induced place aversion dose-dependently, while blockade of NMDAR in the LHb using D-AP5 micro-injection led to an increased preference score in the CPP task. Co-administration of NMDA (0.5â µg/rat) with tramadol (4â mg/kg) reduced preference score, while co-administration of D-AP5 (0.5â µg/rat) with a non-effective dose of tramadol (1â mg/kg) potentiate the rewarding effect of tramadol. LHb receives inputs from the limbic system and projects to the monoaminergic nuclei in the brainstem. It has been declared that NMDAR is expressed in LHb, and as obtained data revealed, these receptors could modulate the rewarding effect of tramadol. Therefore, NMDA receptors in the LHb might be a new target for modulating tramadol abuse.
Assuntos
Habenula , Tramadol , Ratos , Masculino , Animais , Receptores de N-Metil-D-Aspartato , Tramadol/farmacologia , Ratos Wistar , N-Metilaspartato/farmacologia , Habenula/metabolismoRESUMO
AIMS: Opioids are associated with increased risk of sudden cardiac death. This may be due to their effects on the cardiac sodium channel (Nav1.5) current. In the present study, we aim to establish whether tramadol, fentanyl, or codeine affects Nav1.5 current. METHODS AND RESULTS: Using whole-cell patch-clamp methodology, we studied the effects of tramadol, fentanyl, and codeine on currents of human Nav1.5 channels stably expressed in HEK293 cells and on action potential (AP) properties of freshly isolated rabbit ventricular cardiomyocytes. In fully available Nav1.5 channels (holding potential -120â mV), tramadol exhibited inhibitory effects on Nav1.5 current in a concentration-dependent manner with an IC50 of 378.5 ± 33.2â µm. In addition, tramadol caused a hyperpolarizing shift of voltage-gated (in)activation and a delay in recovery from inactivation. These blocking effects occurred at lower concentrations in partially inactivated Nav1.5 channels: during partial fast inactivation (close-to-physiological holding potential -90â mV), IC50 of Nav1.5 block was 4.5 ± 1.1â µm, while it was 16 ± 4.8â µm during partial slow inactivation. The tramadol-induced changes on Nav1.5 properties were reflected by a reduction in AP upstroke velocity in a frequency-dependent manner. Fentanyl and codeine had no effect on Nav1.5 current, even when tested at lethal concentrations. CONCLUSION: Tramadol reduces Nav1.5 currents, in particular, at close-to-physiological membrane potentials. Fentanyl and codeine have no effects on Nav1.5 current.
Assuntos
Analgésicos Opioides , Tramadol , Animais , Humanos , Coelhos , Analgésicos Opioides/farmacologia , Tramadol/farmacologia , Células HEK293 , Bloqueadores dos Canais de Sódio/farmacologia , Fentanila/farmacologia , Miócitos Cardíacos , CodeínaRESUMO
BACKGROUND: Tramadol is one of the most commonly abused substances in the Middle East. Furthermore, smoking is extremely common among the population. METHODS: An experimental study was performed on Sprague-Dawley rats to explore the effects of both nicotine and tramadol on the liver and testes. The tramadol was administered at 10 and 20 mg/kg, respectively, while the nicotine was administered at 125 mg/kg. Histological examination and androgen receptor ELISA assay showed mild effects on the liver and proofed safety on the testis. Western blot analysis of BIP (immunoglobulin heavy-chain binding protein) and CHOP (CCAAT-enhancer-binding protein homologous protein) revealed that fewer problems were induced by adding nicotine to tramadol. Autophagy marker LCIII and apoptosis marker caspase-8 showed similar effects to CHOP and BIP on liver samples. The real-time PCR of BIP expression showed similar but not identical results. CONCLUSIONS: The results showed mild endoplasmic reticulum stress, autophagy, and apoptosis in the liver samples. Histological examination revealed stable spermatogenesis with average androgen receptor blood levels in the different groups.
Assuntos
Testículo , Tramadol , Ratos , Masculino , Animais , Nicotina/farmacologia , Tramadol/metabolismo , Tramadol/farmacologia , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Ratos Sprague-Dawley , Fígado/metabolismo , Apoptose , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo EndoplasmáticoRESUMO
BACKGROUND: Tramadol (TRA) is an analgesic prescribed for treating mild to moderate pains, the abuse of which has increased in recent years. Chronic tramadol consumption produces neurotoxicity, although the mechanisms are unclear. The present study investigated the involvement of apoptosis and autophagy signaling pathways and the mitochondrial system in TRA-induced neurotoxicity. MATERIALS AND METHODS: Sixty adult male Wistar rats were divided into five groups that received standard saline or TRA in doses of 25, 50, 75, 100, or 150 mg/kg intraperitoneally for 21 days. On the 22nd day, the Open Field Test (OFT) was conducted. Jun N-Terminal Kinase (JNK), B-cell lymphoma-2 (Bcl-2), Beclin1, and Bcl-2-like protein 4 (Bax) proteins and tumor necrosis factor α (TNF-α) and interleukin 1ß (IL-1ß) were measured in rat hippocampal tissue. RESULTS: TRA at doses 75, 100, and 150 mg/kg caused locomotor dysfunction in rats and increased total and phosphorylated forms of JNK and Beclin-1, Bax, and Caspase-3. TRA at the three higher doses also increased the phosphorylated (inactive) form of Bcl-2 level while decreasing the unphosphorylated (active) form of Bcl-2. Similarly, the protein levels of TNF-α and IL-1ß were increased dose-dependently. The mitochondrial respiratory chain enzymes were reduced at the three higher doses of TRA. CONCLUSION: TRA activated apoptosis and autophagy via modulation of TNF-α or IL-1ß/JNK/Bcl-2/Beclin1 and Bcl-2/Bax signaling pathways and dysfunction of mitochondrial respiratory chain enzymes.
Assuntos
Tramadol , Ratos , Masculino , Animais , Ratos Wistar , Tramadol/farmacologia , Tramadol/metabolismo , Proteína Beclina-1/genética , Proteína Beclina-1/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismo , Apoptose , Autofagia , Hipocampo/metabolismoRESUMO
BACKGROUND: The choroid plexus (CP) is the principal source of cerebrospinal fluid (CSF). It can produce and release a wide range of materials, including growth and neurotrophic factors which have a crucial role in the maintenance and proper functioning of the brain. Tramadol is a synthetic analog of codeine, mainly prescribed to alleviate mild to moderate pains. Nevertheless, it causes several side effects, such as emotional instability and anxiety. METHODS: In this study, we focused on alterations in the expression of inflammatory and apoptotic genes in the CP under chronic tramadol exposure. Herein, rats were treated daily with tramadol at 50 mg/kg doses for three weeks. CSF samples were collected, with superoxide dismutase (SOD) and glutathione (GSH) measured in the CSF. RESULTS: We found that tramadol reduced the SOD and GSH levels in the CSF. Furthermore, the stereological analysis revealed a significant increase in the CP volume, epithelial cells, and capillary number upon tramadol administration. Tramadol elevated the number of blob mitochondria in CP. Also, we observed the upregulation of inflammatory and apoptosis genes following tramadol administration in the CP. CONCLUSIONS: Our findings indicate that tramadol induces neurotoxicity in the CP via apoptosis, inflammation, and oxidative stress.
Assuntos
Tramadol , Ratos , Animais , Tramadol/farmacologia , Plexo Corióideo/metabolismo , Estresse Oxidativo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Glutationa/metabolismo , Apoptose , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND: Paracetamol, codeine, and tramadol are commonly used to manage mild pain, and their availability without prescription or medical consultation raises concerns about potential opioid addiction. OBJECTIVE: This study aims to explore the perceptions and experiences of Twitter users concerning these drugs. METHODS: We analyzed the tweets in English or Spanish mentioning paracetamol, tramadol, or codeine posted between January 2019 and December 2020. Out of 152,056 tweets collected, 49,462 were excluded. The content was categorized using a codebook, distinguishing user types (patients, health care professionals, and institutions), and classifying medical content based on efficacy and adverse effects. Scientific accuracy and nonmedical content themes (commercial, economic, solidarity, and trivialization) were also assessed. A total of 1000 tweets for each drug were manually classified to train, test, and validate machine learning classifiers. RESULTS: Of classifiable tweets, 42,840 mentioned paracetamol and 42,131 mentioned weak opioids (tramadol or codeine). Patients accounted for 73.10% (60,771/83,129) of the tweets, while health care professionals and institutions received the highest like-tweet and tweet-retweet ratios. Medical content distribution significantly differed for each drug (P<.001). Nonmedical content dominated opioid tweets (23,871/32,307, 73.9%), while paracetamol tweets had a higher prevalence of medical content (33,943/50,822, 66.8%). Among medical content tweets, 80.8% (41,080/50,822) mentioned drug efficacy, with only 6.9% (3501/50,822) describing good or sufficient efficacy. Nonmedical content distribution also varied significantly among the different drugs (P<.001). CONCLUSIONS: Patients seeking relief from pain are highly interested in the effectiveness of drugs rather than potential side effects. Alarming trends include a significant number of tweets trivializing drug use and recreational purposes, along with a lack of awareness regarding side effects. Monitoring conversations related to analgesics on social media is essential due to common illegal web-based sales and purchases without prescriptions.
Assuntos
Mídias Sociais , Tramadol , Humanos , Acetaminofen/efeitos adversos , Acetaminofen/farmacologia , Codeína/efeitos adversos , Codeína/farmacologia , Aprendizado de Máquina , Dor , Tramadol/efeitos adversos , Tramadol/farmacologiaRESUMO
Pulsed radiofrequency (PRF) therapy is one of the most common treatment options for neuropathic pain, albeit the underlying mechanism has not been hitherto elucidated. In this study, we investigated the efficacy and mechanism of PRF therapy on resiniferatoxin (RTX)-induced mechanical allodynia, which has been used as a model of postherpetic neuralgia (PHN). Adult male rats were intraperitoneally injected with a vehicle or RTX. Furthermore, PRF current was applied on a unilateral sciatic nerve in all RTX-treated rats. On both ipsilateral and contralateral sides, the paw mechanical withdrawal thresholds were examined and L4-6 dorsal root ganglia (DRG) were harvested. In the DRG of rats with RTX-induced mechanical allodynia, NaV1.7, a voltage-gated Na+ channel, was upregulated following the enhancement of extracellular signal-regulated kinase phosphorylation. Early PRF therapy, which was applied 1 week after RTX exposure, suppressed this NaV1.7 upregulation and showed an anti-allodynic effect; however, late PRF therapy, which was applied after 5 weeks of RTX exposure, failed to inhibit allodynia. Interestingly, late PRF therapy became effective after daily tramadol administration for 7 days, starting from 2 weeks after RTX exposure. Both early PRF therapy and late PRF therapy combined with early tramadol treatment suppressed NaV1.7 upregulation in the DRG of rats with RTX-induced mechanical allodynia. Therefore, NaV1.7 upregulation in DRG is related to the development of RTX-induced neuropathic pain; moreover, PRF therapy may be effective in the clinical management of patients with PHN via NaV1.7 upregulation inhibition.
Assuntos
MAP Quinases Reguladas por Sinal Extracelular , Canal de Sódio Disparado por Voltagem NAV1.7 , Neuralgia Pós-Herpética , Neuralgia , Terapia por Radiofrequência , Tramadol , Animais , Diterpenos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Gânglios Espinais , Humanos , Hiperalgesia/terapia , Masculino , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Neuralgia/induzido quimicamente , Neuralgia/terapia , Neurônios , Fosforilação , Ratos , Ratos Sprague-Dawley , Canais de Sódio , Tramadol/farmacologia , Regulação para CimaRESUMO
Tramadol is widely used to control pain in various diseases, but the relevant mechanisms are less known despite the severe risks of abuse. The medial prefrontal cortex (mPFC) is one of the critical centers of the reward system. Studies have shown that orexins and endocannabinoids are likely to play an important role in addiction. In this study, the effect of orexin receptor-2 (OX2R) and endocannabinoid receptor-1 (CB1R) blockade on the neuronal activity of mPFC was investigated in response to tramadol in male rats. Tramadol was injected intraperitoneally, and its effects on the firing of mPFC pyramidal neurons were investigated using in vivo extracellular single-unit recording. Tramadol affected the pyramidal neuronal activity of the mPFC. AM251 (18 nmol/4 µl), as a selective CB1R antagonist, and TCS-OX2-29 (50 nmol/4 µl), as a selective OX2R antagonist, individually or simultaneously were microinjected into the lateral ventricle of the brain (intracerebroventricular, ICV). The results showed that the ratio of neurons with the excitatory/inhibitory or no responses was significantly changed by tramadol (p < .05). These changes were prevented by blockade of CB1Rs alone or blockade of OX2Rs and CB1Rs simultaneously (p < .05). However, blockade of these receptors in the vehicle group had no significant effect on neuronal activity. The findings of this study indicate the potential role of orexin and endocannabinoid systems in mediating the effects of tramadol in mPFC and the possible interaction between the two systems via OX2 and CB1 receptors. However, further studies are needed to identify these effects by examining intracellular signaling.
Assuntos
Antagonistas dos Receptores de Orexina , Tramadol , Animais , Antagonistas de Receptores de Canabinoides/farmacologia , Endocanabinoides , Masculino , Neurônios , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Receptor CB1 de Canabinoide , Receptores de Canabinoides , Tramadol/farmacologiaRESUMO
AIMS: We investigated the changes in bladder and urethral function after cerebral infarction (CI) and the influence of tramadol on these functions. METHODS: Twenty-eight female Sprague Dawley rats were divided into normal and CI groups. In the awake condition, metabolic cage study and blood pressure were evaluated. Under urethane anesthesia, the intravenous effect of tramadol (0.01-1 mg/kg), which has both µ-opioid receptor stimulation and inhibition of norepinephrine and serotonin reuptake, on continuous cystometry, and simultaneous measurements of bladder and urethral perfusion pressure (UPP) were recorded. Infarcted lesions were examined by staining with triphenyltetrazolium chloride, a marker of mitochondrial enzyme activity. RESULTS: CI rats showed impaired sympathetic activity with Horner's syndrome and lower blood pressure. In metabolic cage study, urinary frequency during the dark phase was increased in CI rats. On bladder activity, in CI rats, the baseline pressure threshold for inducing bladder contractions was significantly lower (p < 0.01), and the intercontraction interval was prolonged after tramadol administration. On urethral activity, the baseline UPP was significantly lower in CI rats than in normal rats and it did not change after tramadol administration. Residual urine rate was significantly increased in normal rats, but not in CI rats. CI rats showed brain infarction including the cortex and hypothalamus, which is a center of the autonomic nervous system. CONCLUSIONS: CI-induced ischemic brain damage results in impairment of both bladder and urethral functions, in addition to decreased sympathetic activity. Bladder overactivity after CI can be improved by tramadol; however, urethral activity cannot be improved by it.
Assuntos
Tramadol , Bexiga Urinária , Ratos , Feminino , Animais , Tramadol/farmacologia , Ratos Sprague-Dawley , Uretra , Infarto CerebralRESUMO
AIM: The current study aimed to evaluate the antinociceptive effect of lidocaine, tramadol, and their combination for lumbosacral epidural analgesia in rabbits undergoing knee surgery. MATERIALS AND METHODS: This study was performed on 24 male New Zealand white rabbits weighing 2.8 to 3.0 kg and was allocated into three groups. All groups were anaesthetized by intramuscular (IM) injection of 35 mg/kg ketamine and 5 mg/kg xylazine, 0.1 mg/kg butorphanol. Rabbits in Group A received epidural analgesia of 4 mg/kg lidocaine 2%; Group B rabbits received epidural analgesia of 4 mg/kg tramadol 5%, and Group C rabbits received epidural analgesia of a combination of 4 mg/kg lidocaine and 4 mg/kg tramadol. Prior to and during surgery, the following parameters were recorded in a regular pre-set time interval: onset time of analgesia (OT), duration of flaccid paralysis (DFP), duration of analgesia (DA), onset and duration of sensory blockade, onset and duration of motor blockade, heart rate (HR), respiratory rate (RR), and rectal temperature (RT). RESULTS: The mean OT demonstrated a significant decrease (P < 0.05) in Group C (46.5 ± 1.4 sec) compared to Group A and B (61.0 ± 2.4 and 54.5 ± 3.5 sec), respectively. DFP was significantly lower (P < 0.05) in Group C (35.5 ± 2.9 min) than in Group A and B (17.6 ± 1.4 and 21.8 ± 3.6), respectively. DA showed a significant increase (P < 0.05) in group C (45.8 ± 3.3 min) compared to groups A and B, respectively (23.3 ± 1.1 and 31.5 ± 2.3). Heart rate, RR, and RT significantly decreased in Group C compared to the other groups. CONCLUSION: According to the current study findings, lumbosacral epidural administration of lidocaine combined with tramadol could be a better choice for potentiating the analgesia than administration of either drug separately and may be safely used in rabbits undergoing knee surgery.
Assuntos
Analgesia Epidural , Tramadol , Animais , Masculino , Coelhos , Analgesia Epidural/veterinária , Analgésicos , Lidocaína/farmacologia , Lidocaína/uso terapêutico , Dor/veterinária , Tramadol/farmacologia , Tramadol/uso terapêuticoRESUMO
This network meta-analysis aimed to assess the efficacy and safety of "on-demand" and "daily" use of paroxetine for patients with premature ejaculation (PE). We searched PubMed, Embase and Cochrane Library from inception to October 2021 to collect randomized controlled trials, and 24 articles including 2, 308 patients were finally involved. The results indicated that paroxetine (daily or on-demand) was superior to placebo at increasing intravaginal ejaculatory latency time (IELT), and 20 mg paroxetine daily was significantly better than fluoxetine and tramadol in improving IELT. Besides, 20 mg paroxetine on-demand was less effective than 20 mg paroxetine on-demand plus phosphodiesterase-5 inhibitors (PDEI5) and tramadol monotherapy in increasing IELT. Tramadol monotherapy was more effective than paroxetine monotherapy in improving sexual satisfaction score. Although patients treated with paroxetine had more coitus/week than patients treated with placebo, it was less than patients treated with PDEI5. These findings were robust to sensitivity analyses. The common adverse events related with paroxetine were fatigue, yawning and abnormal sleep (10.96%), gastrointestinal upset (10.80%). The "on-demand" and "daily" use of paroxetine can significantly improve the clinical symptoms of patients with PE and were well tolerated. Combination therapy and tramadol monotherapy can also be used as alternative treatments.