The role of adenosine A1 receptor in the peripheral tramadol's effect in the temporomandibular joint of rats.

Peripheral tramadol's delivery in the temporomandibular joint (TMJ) leads to significant analgesic outcomes and inflammatory process's resolvent actions. Mechanistically, these properties are apart from the opioid system. Nevertheless, the molecular mechanisms behind these effects are still unclear. Therefore, the present study investigated the hypothesis that adenosine A1 receptors are involved in the tramadol-induced analgesic and anti-inflammatory effects in the TMJ. Animals were pretreated with an intra-TMJ injection of DPCPX (antagonist of A1 receptor) or tramadol and subsequent nociceptive challenge with an intra-TMJ injection of 1.5% formalin. For over 45 min, the nociceptive behavior was quantitated, and by the end of this assessment, the animals were euthanized, and the periarticular tissue was collected. Lastly, an in vitro assay of BMDM (Bone Marrow-Derived Macrophages) was performed to investigate tramadol activity in macrophages. The intra-TMJ injection of tramadol ameliorates formalin-induced hypernociception along with inhibiting leukocyte migration. The tramadol's peripheral anti-inflammatory effect was mediated by the adenosine A1 receptor and was associated with increased protein expression of α2a-adrenoceptor in the periarticular tissues (p < 0.05: ANOVA, Tukey's test). Also, tramadol inhibits formalin-induced leukocyte migration and protein expression of P2X7 receptors in the periarticular tissue (p < 0.05); however, DPCPX did not alter this effect (p > 0.05). Moreover, DPCPX significantly reduced the protein expression of the M2 macrophage marker, MRC1. In BMDM, tramadol significantly reduces inflammatory cytokines release, and DPCPX abrogated this effect (p < 0.05). We identify tramadol's peripheral effect is mediated by adenosine A1 receptor, possibly expressed in macrophages in the TMJ tissue. We also determined an important discovery related to the activation of A1R/α2a receptors in the tramadol action.

Effectiveness of Pilates and circuit-based exercise in reducing arthralgia in women during hormone therapy for breast cancer: a randomized, controlled trial.

OBJECTIVE: To investigate the effect of Pilates compared with circuit-based exercise in reducing arthralgia in women during hormone therapy for breast cancer. DESIGN: Single-blind randomized controlled trial, parallel. SETTING: University hospital of Brasilia and Brazilian Association for Assistance to People with Cancer. PARTICIPANTS: Sixty women with arthralgia were recruited. Eligibility criteria included women complaining of arthralgia during hormone therapy for breast cancer. The exclusion criteria were women with active cancer, lymphedema, limitations to physical exercise, or limitation to answer some questionnaires. MAIN OUTCOME MEASURES: Primary: Pain. Secondary: Function, flexibility, and sleep quality. Outcomes were assessed at baseline and the end of the intervention (8 weeks) by the same blinded evaluator. INTERVENTION: Sixty participants were randomly assigned 20 to each of the three groups: Pilates, circuit-based exercise, and control groups. Exercise was performed twice per week for 75 min, over a period of 8 weeks. Participants in the control group were instructed to continue their usual activities. The Kolmogorov-Smirnov test was used to verify the normality of the outcomes. Intergroup differences were calculated using Kruskal-Wallis test with post hoc Mann Whitney U testing and the parametric data between the three groups with ANOVA of repeated measures with Bonferroni post hoc. RESULTS: The Pilates group demonstrated a significant difference in pain reduction compared to the circuit group (mean difference: -1.95 points, p = 0.020). CONCLUSION: Pilates was more effective than circuit-based exercise in reducing arthralgia in women during hormone therapy for breast cancer. TRIAL REGISTRATION: http://www.ensaiosclinicos.gov.br/rg/RBR-3wsdhs/ Registered on Octob 16th 2017.

Poloxamer micellar system for intra-articular injection of 15-deoxy-Δ12,14-prostaglandin J2 with improved bioavailability and anti-inflammatory properties in the temporomandibular joint of rats.

Painful conditions of the temporomandibular joint (TMJ) are challenging to manage and most attempts often result in unsatisfactory outcomes. In such context, nanocarrier systems, such as polymeric micelles, have been showing encouraging results in solving therapeutic limitations. Poloxamers are widely used, especially PL 407, because of their high biocompatibility and approval by the Food and Drug Administration (FDA) for clinical use. 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) has shown important antinociceptive and anti-inflammatory activity. The present study evaluated the efficacy and viability of the micellar system of PL-15dPGJ2 in a formalin-induced acute pain model in the temporomandibular joint of rats. The PL-15dPGJ2 was prepared and characterized. The animals were pretreated with an intra-articular injection of PL-15dPGJ2 followed by the formalin challenge. The nociceptive response was evaluated at different time-periods and the periarticular tissue and articular wash were collected for analysis. We found that intra-articular injection of PL-15d-PGJ2 produced pain relief at lower concentrations and in a sustained manner compared with free 15d-PGJ2. Moreover, a strong anti-inflammatory effect was observed with decreased levels of key pro-inflammatory cytokines and modulation of the leukocyte migration process. Our findings suggest that 15d-PGJ2 combined with a poloxamer micellar system provided clinical relevance in terms of bioavailability, long-lasting effect, and safe dosage. The formulation investigated herein is a promising micellar carrier system for managing pain conditions of the TMJ.

Hesperidin methyl chalcone interacts with NFκB Ser276 and inhibits zymosan-induced joint pain and inflammation, and RAW 264.7 macrophage activation.

Arthritis can be defined as a painful musculoskeletal disorder that affects the joints. Hesperidin methyl chalcone (HMC) is a flavonoid with analgesic, anti-inflammatory, and antioxidant effects. However, its effects on a specific cell type and in the zymosan-induced inflammation are unknown. We aimed at evaluating the effects of HMC in a zymosan-induced arthritis model. A dose-response curve of HMC (10, 30, or 100 mg/kg) was performed to determine the most effective analgesic dose after intra-articular zymosan stimuli. Knee joint oedema was determined using a calliper. Leukocyte recruitment was performed by cell counting on knee joint wash as well as histopathological analysis. Oxidative stress was measured by colorimetric assays (GSH, FRAP, ABTS and NBT) and RT-qPCR (gp91phox and HO-1 mRNA expression) performed. In vitro, oxidative stress was assessed by DCFDA assay using RAW 264.7 macrophages. Cytokine production was evaluated in vivo and in vitro by ELISA. In vitro NF-κB activation was analysed by immunofluorescence. We observed HMC reduced mechanical hypersensitivity and knee joint oedema, leukocyte recruitment, and pro-inflammatory cytokine levels. We also observed a reduction in zymosan-induced oxidative stress as per increase in total antioxidant capacity and reduction in gp91phox and increase in HO-1 mRNA expression. Accordingly, total ROS production and macrophage NFκB activation were diminished. HMC interaction with NFκB p65 at Ser276 was revealed using molecular docking analysis. Thus, data presented in this work suggest the usefulness of HMC as an analgesic and anti-inflammatory in a zymosan-induced arthritis model, possibly by targeting NFκB activation in macrophages.

Evaluation of monosodium iodoacetate dosage to induce knee osteoarthritis: Relation with oxidative stress and pain.

AIM: To determine the dose of monosodium iodoacetate (MIA) required to induce oxidative stress, as well as pain and edema; to confirm the induction of knee osteoarthritis (OA) symptoms in rats by the presence of reactive oxygen species (ROS) and reduction of antioxidant agents; and to verify the presence of histopathological injury in these affected joints. METHOD: Biological markers of oxidative stress, pain, knee edema, and cartilage degeneration provided by different doses of MIA (0.5; 1.0 or 1.5 mg) in rat knee joints were analyzed. The animal evaluations were conducted during 15 days for mechanical and cold hypersensitivity, spontaneous pain and edema. After that, blood serum, intra-articular lavage and structures of knee, spinal cord and brainstem were collected for biochemical analysis; moreover, the knees were removed for histological evaluation. RESULTS: This study demonstrates that the highest dose of MIA (1.5 mg) increased the oxidative stress markers and reduced the antioxidant reactions, both in the focus of the lesion and in distant sites. MIA also induced the inflammatory process, characterized by pain, edema, increase in neutrophil count and articular damage. CONCLUSION: This model provides a basis for the exploration of underlying mechanisms in OA and the identification of mechanisms that may guide therapy and the discovery of OA signals and symptoms.

A randomised trial of electro-acupuncture for arthralgia related to aromatase inhibitor use.

BACKGROUND: Arthralgia is a common and debilitating side-effect experienced by breast cancer patients receiving aromatase inhibitors (AIs) and often results in premature drug discontinuation. METHODS: We conducted a randomised controlled trial of electro-acupuncture (EA) as compared to waitlist control (WLC) and sham acupuncture (SA) in postmenopausal women with breast cancer who self-reported arthralgia attributable to AIs. Acupuncturists performed 10 EA/SA treatments over 8 weeks using a manualised protocol with 2 Hz electro-stimulation delivered by a TENS unit. Acupuncturists administered SA using Streitberger (non-penetrating) needles at non-traditional acupuncture points without electro-stimulation. The primary end-point was pain severity by Brief Pain Inventory (BPI) between EA and WLC at Week 8; durability of response at Week 12 and comparison of EA to SA were secondary aims. FINDINGS: Of the 67 randomly assigned patients, mean reduction in pain severity was greater in the EA group than in the WLC group at Week 8 (-2.2 versus -0.2, p=0.0004) and at Week 12 (-2.4 versus -0.2, p<0.0001). Pain-related interference measured by BPI also improved in the EA group compared to the WLC group at both Week 8 (-2.0 versus 0.2, p=0.0006) and Week 12 (-2.1 versus -0.1, p=0.0034). SA produced a magnitude of change in pain severity and pain-related interference at Week 8 (-2.3, -1.5 respectively) and Week 12 (-1.7, -1.3 respectively) similar to that of EA. Participants in both EA and SA groups reported few minor adverse events. INTERPRETATIONS: Compared to usual care, EA produced clinically important and durable improvement in arthralgia related to AIs in breast cancer patients, and SA had a similar effect. Both EA and SA were safe.

Glucocorticoids as a novel approach to the treatment of disabling side effects of sodium stibogluconate.

WHAT IS KNOWN AND OBJECTIVE: Intravenous sodium stibogluconate (SbV) is the mainstay of treatment for mucocutaneous leishmaniasis. Incidence of this disease is increasing in the UK, partly because of returning military personnel. SbV has a side effect profile that requires treatment interruption in up to 28% of patients. Side effects can be unpleasant and - in the case of QTc prolongation - dangerous. CASE SUMMARY: A volunteer medical worker returning from Guatemala was diagnosed with mucocutaneous leishmaniasis. Because of previous renal problems, NSAIDs were contraindicated. Severe side effects of myalgia and arthralgia would have necessitated a treatment interruption, but a trial of prednisolone gave excellent symptomatic relief. The patient's QTc, amylase and C-reactive protein also fell following initiation of steroid treatment. The SbV treatment course was completed successfully. WHAT IS NEW AND CONCLUSION: This is the first reported case of the dangerous and disabling side effects of SbV being treated very effectively with glucocorticoids. Of note is the normalization of the apparently sodium stibogluconate-induced prolongation of the QTc interval. Further investigation into this potential beneficial effect is warranted.

Disabling acne fulminans.

Acne fulminans is a rare manifestation that may occur during the evolution of acne vulgaris primarily in male adolescents. Use of isotretinoin, testosterone, and exacerbated immune responses in the body are related triggers. Signs, symptoms and laboratory findings such as fever, hepatomegaly, polyarthralgia, leukocytosis, plaquetose, increased inflammatory markers and transaminases, are characteristic. A bone scan can detect osteolytic lesions in multiple skeletal sites. The treatment is performed with prednisolone, isotretinoin and antibiotics if secondary infection is present. This case describes a male patient with a diagnosis of grade III acne, who developed acne fulminans and bilateral sacroiliitis with inability to ambulate, after initiation of therapy with isotretinoin.

Acne fulminans incapacitante / Disabling Acne Fulminans

Acne fulminans é uma manifestação rara, que pode ocorrer durante a evolução da acne vulgar, principalmente, em adolescentes masculinos. Uso de isotretinoína, testosterona, e reações imunológicas exacerbadas no organismo são desencadeantes relacionados. Sinais, sintomas e alterações laboratoriais como: febre, hepatomegalia, poliartralgia, leucocitose, plaquetose, aumento de provas inflamatórias e transaminases, são característicos. A cintilografia óssea pode detectar lesões líticas em vários sítios do esqueleto. O tratamento é realizado com prednisolona, isotretinoína e antibióticos se infecções secundárias. Este caso relata um paciente masculino com diagnóstico de acne grau III, que desenvolveu acne fulminans e sacroileíte bilateral, com incapacidade de deambulação após início de terapia com isotretinoína.

Acne fulminans is a rare manifestation that may occur during the evolution of acne vulgaris primarily in male adolescents. Use of isotretinoin, testosterone, and exacerbated immune responses in the body are related triggers. Signs, symptoms and laboratory findings such as fever, hepatomegaly, polyarthralgia, leukocytosis, plaquetose, increased inflammatory markers and transaminases, are characteristic. A bone scan can detect osteolytic lesions in multiple skeletal sites. The treatment is performed with prednisolone, isotretinoin and antibiotics if secondary infection is present. This case describes a male patient with a diagnosis of grade III acne, who developed acne fulminans and bilateral sacroiliitis with inability to ambulate, after initiation of therapy with isotretinoin.

Putative antinociceptive action of nitric oxide in the caudal part of the spinal trigeminal nucleus during chronic carrageenan-induced arthritis in the rat temporomandibular joint.

In order to investigate a putative role for nitric oxide (NO) in the central nociceptive processing following carrageenan-induced arthritis in the rat temporomandibular joint (TMJ), we analyzed the immunoreactivity, gene expression and activity of nitric oxide synthases (NOS) in the caudal part of the spinal trigeminal nucleus (Sp5C) during the acute (24 h), chronic (15 days) and chronic-active (14 days-24 h) arthritis. In addition, evaluation of head-withdrawal threshold was carried out in all phases of arthritis under chronic inhibition of nNOS with the selective inhibitor 7-nitroindazole (7-NI). Neurons with nNOS-like immunoreactivity (nNOS-LI) were concentrated mainly in the lamina II of the Sp5C, showing no significant statistical difference during arthritis. Only a discrete percentage of nNOS-LI neurons expressed Fos immunoreactivity. The mRNA expression for both nNOS and endothelial nitric oxide synthases (eNOS) presented no noticeable differences among the groups. No expression of inducible nitric oxide synthase (iNOS) was detected in the Sp5C by either immunohistochemistry or reverse-transcription polymerase chain reaction (RT-PCR). Ca(2+)-dependent NOS activity in the ipsilateral Sp5C was significantly higher (108.3+/-49.2%; P<0.01) in animals during the chronic arthritis. Interestingly, this increased activity was completely abolished 24 h later, in the chronic-active arthritis. Finally, head-withdrawal threshold decreased significantly in the chronic arthritis in animals under 7-NI chronic inhibition. In conclusion, nNOS immunoreactivity and mRNA expression are stable in the Sp5C during TMJ arthritis evolution, but its activity significantly increases in the chronic-phases supporting an antinociceptive role of the nNOS as evidenced by pain threshold experiment.

Sleep pattern in an experimental model of osteoarthritis.

Osteoarthritis (OA) is a major healthcare burden of increasing prevalence. It has been demonstrated that the relationship between pain and sleep produces changes in sleep patterns and pain perception. However, electrophysiological studies in animal models of pain are limited. The current study examined the effect of chronic articular pain on sleep patterns in an experimental model of OA. Rats were implanted with electrodes for electrocorticography and electromyography. OA was induced in these rats by the intra-articular administration of monosodium iodoacetate into the left knee joint. Sleep recordings were monitored during light and dark periods lasting 12h each and were evaluated at baseline as well as on days 1, 10, 15, 20 and 28 after iodoacetate injection or assignment to sham or control groups. The pain threshold was also assessed by hot plate testing in other groups of rats at the same time points. The results demonstrated that OA significantly reduced the thermal pain threshold from day 10 until the end of experiment. OA rats exhibited reduced sleep efficiency, slow-wave sleep, paradoxical sleep and an increased number of microarousals during the light periods compared with the baseline as well as control and sham groups. These changes in sleep pattern occurred mostly between days 10 and 28. In the dark period, sleep disturbances were also characterized by decreased sleep efficiency, slow-wave sleep, and paradoxical sleep, although sleep was only initially fragmented. Thus, pain associated with the rat OA model causes alterations in sleep architecture by disrupting the sleep pattern.

Changes in synaptic effectiveness of myelinated joint afferents during capsaicin-induced inflammation of the footpad in the anesthetized cat.

The present series of experiments was designed to examine, in the anesthetized cat, the extent to which the synaptic efficacy of knee joint afferents is modified during the state of central sensitization produced by the injection of capsaicin into the hindlimb plantar cushion. We found that the intradermic injection of capsaicin increased the N2 and N3 components of the focal potentials produced by stimulation of intermediate and high threshold myelinated fibers in the posterior articular nerve (PAN), respectively. This facilitation lasted several hours, had about the same time course as the paw inflammation and was more evident for the N2 and N3 potentials recorded within the intermediate zone in the L6 than in the L7 spinal segments. The capsaicin-induced facilitation of the N2 focal potentials, which are assumed to be generated by activation of fibers signaling joint position, suggests that nociception may affect the processing of proprioceptive and somato-sensory information and, probably also, movement. In addition, the increased effectiveness of these afferents could activate, besides neurons in the intermediate region, neurons located in the more superficial layers of the dorsal horn. As a consequence, normal joint movements could produce pain representing a secondary hyperalgesia. The capsaicin-induced increased efficacy of the PAN afferents producing the N3 focal potentials, together with the reduced post-activation depression that follows high frequency autogenetic stimulation of these afferents, could further contribute to the pain sensation from non-inflamed joints during skin inflammation in humans. The persistence, after capsaicin, of the inhibitory effects produced by stimulation of cutaneous nerves innervating non-inflamed skin regions may account for the reported reduction of the articular pain sensations produced by trans-cutaneous stimulation.

A novel method for subarachnoid drug delivery in the medullary region of rats.

This study describes a novel method for direct subarachnoid drug delivery to the medullary dorsal horn region of rats, without introducing a catheter. The reliability of the method was demonstrated by a pharmacological validation; that is, morphine administration to the medullary region blocked the nociceptive response to formalin injected in the temporomandibular joint (TMJ) region, an effect that was prevented by co-administration of naloxone. The method proposed offers many advantages over the existing methods for medullary drug delivery with catheter implantation. It is easy to be employed, it does not induce any sign of motor impairment, and it does not require the neck surgery performed to implant a catheter in the medullary dorsal horn region. Therefore, it is a useful method for subarachnoid drug delivery in behavioral trigeminal pain studies, particularly when nociceptive behavioral measures that require normal neck muscle activity to occur, such as head withdraw or head flinch, are evaluated.

[Occupational exposure and health effects of metallic mercury among dentists and dental assistants: a preliminary study. Valencia, Venezuela; 1998]. / Exposición ocupacional y efectos a la salud del mercurio metálico entre odontólogos y asistentes dentales: un estudio preliminar. Valencia, Venezuela; 1998.

The aim of this investigation was to establish mercury (Hg) health effects on dentists and dental assistants, its relationship with exposure conditions and the potential renal damage Hg-related. The total population was 66 people, with a sample of 37 (56%), 22 dentists (59.5%, 19 male, 3 female) and 15 dental assistants (40.5%, all female). This was accomplished by an interview, Hg in urine (Hg-U) and N-acetyl-B-D-glucosaminidase activity in urine (NAG-U). Average values of Hg-U for dentists were 22.4 +/- 6.4 micrograms/g creatinine and 22.2 +/- 6.1 micrograms/g creatinine for dental assistants NAG-U average values were 2.9 +/- 3 U/L and 5.2 +/- 8.1 U/L respectively. There were no statistically significant differences between these averages (p > 0.05). There was no correlation between the quantity of amalgam prepared and working hours with Hg-U and NAG-U. Most frequent symptoms referred by dentists were: irritability (54.5%), cephalalgia (45.4%), arthralgias (40.9%), and the ones more referred by assistants were arthralgias (53.3%), irritability (46.7%) and cephalalgia (46.7%). It was not found a significative risk of having them among these groups. There is a need for further investigations including environmental monitoring of Hg, clinical evaluation and neurobehavioural tests to detect early effects. It is important to enforce personal safety measures to control the exposure.

Exposicion ocupacional y efectos a la salud del mercurio metalico entre odontologos y asistentes dentales: un estudio preliminar: Valencia, Venezuela; 1998 / Occupational exposure and health effects of metallic mercury among dentists and dental assistants: a preliminary study, Valencia, Venezuela; 1998

Esta investigación pretendió establecer los efectos del Hg sobre la salud de odontólogos y asistentes dentales, su relación con condiciones de exposición, y el posible daño renal debido al Hg. La población fue de 66 personas, la muestra, 37 (56 por ciento), 22 odontólogos (59,5 por ciento, 19 hombres, 3 mujeres) y 15 asistentes dentales mujeres (40,5 por ciento). Se realizaron: encuesta opcional, Hg en orina (Hg-O) y actividad de N-Acetil-beta-D-glucosaminidasa en orina (BAG-O), como biomarcador precoz de daño renal. Los valores de HgO para los odontólogos fueron 22.4 más o menos 6,4 micra g/g creatinina, para los asistentes, 22,2 más o menos 6,1 mu g/g creatinina (p>0.05), y los de BAG-O, de 2,9 más o menos 3 U/L y de 5,2 más o menos 8,1 U/L, respectivamente, no existiento diferencias estadísticamente significativas (p0,05). No se detectó correlación entre el námero de amalgamas preparadas y de horas trabajadas con Hg-O y NAG-O. Los síntomas más frecuentes referidos por los odontólogos fueron irritabilidad, 54,5 por ciento, cefalea, 45,4 por ciento y artralgias, 40,9 por ciento. Por los asistentes, artralgia, 53,5 por ciento, irritabilidad, 46,7 por ciento, y cefalea, 46,7 por ciento, no existiendo riesgo significativo de sufrirlo para ningún grupo. Se requieren nuevas investigaciones que incluyan monitoreo ambiental del Hg, evaluación médica y pruebas neuroconductuales para detectar efectos precoces, asá como la aplicación de medidas de control en pro de la salud del personal.

[Occupational exposure to lead in production units in Maracaibo, Venezuela]. / Exposición ocupacional a plomo en unidades productivas en Maracaibo, Venezuela.

A medical occupational study was performed in 40 workers belonging to productive units in telecommunication works, 22 to car radiator mechanics and 11 to battery repairs. A practical medical and occupational study was applied to the group and also were determined their blood lead and air lead exposure levels. Seventy-three individuals, without risk of laboral exposure to lead, without familiar, pathological and occupational antecedents, and healthy at the time of the test, to whom the blood lead levels were determined served as control group. The mean values of plumbemia in exposure workers to inorganic lead exceed the level threshold of the COVENIN 2277-85 norm (30 micrograms/dl) (Telecommunication work, 40.10 micrograms/dl, radiators mechanics, 37.40 micrograms/dl and battery repairs, 45.77 micrograms/dl), values that were significantly higher (p < 0.0001) compared with the ones obtained in the non-exposed population. The factors that can influence the variability of the results were analyzed and it was established a correlation between the plumbemia of the radiator mechanics and battery repairmen and the length of occupational period and air lead levels (p < 0.0001). The inherent factors to the climatic, occupational and personal conditions of technicians in telecommunications, are presented as elements able to explain the lack of correlation between blood lead levels and length of occupational period and air lead. The clinical findings in exposed workers were unspecific. The workers do not practice or follow the basic sanitary regulations, personal protection and industrial security. This work will contribute to establish a basic description, to further and more complex observational prospective studies in order to determine the occurrence of alterations that are derived from occupational lead exposure.