Experimental model of periodontitis and rheumatoid arthritis potentiates the deleterious effects on functional capacity, leukocyte migration, synovial and periodontal tissues in Wistar rats.

OBJECTIVE: This study aimed to evaluate whether ligature-induced periodontitis and rheumatoid arthritis (RA) potentiate the deleterious effects on functional capacity, periodontal and synovial tissues, leukocyte migration, and interleukin 17 (IL-17) levels, and to investigate the repercussions of single Freund's Complete Adjuvant (FCA) injection associated with periodontitis. MATERIALS AND METHODS: Fifty-one male Wistar rats were randomised into six groups: control (CG, n = 8), RA (RAG, n = 9), periodontitis (PG, n = 9), periodontitis and RA (PRAG, n = 9), periodontitis and intradermal injection (PIDG, n = 9), and periodontitis and intra-articular injection (PIAG, n = 7). The animals underwent ligature placement and one or two injections with FCA to induce RA. Motor disability, nociceptive threshold, joint edema, and muscle strength were assessed, and the animals were euthanized on day 30. Synovial fluid, hemimandibles, and knee joints were collected. RESULTS: PRAG showed no reduction of edema or improvement of muscle strength, whereas it showed most significant changes in leukocyte migration, morphological analyses of the synovial membrane (SM), and radiographic and histometric analyses of the jaw. The PIAG showed some alterations, though not permanent. CONCLUSION: Ligature-induced periodontitis and RA induced by two FCA injections accentuated the deleterious effects on functional capacity, leukocyte migration, synovial and periodontal tissues.

Physical Exercise and Low-Level Laser Therapy Systemic Effects on the Ankle Joint in an Experimental Rheumatoid Arthritis Model.

OBJECTIVE: The purpose of this study was to analyze the systemic effects of stair climbing exercise, low-level laser therapy (LLLT), and the association of both treatments on pelvic member functionality and ankle joint histomorphometric aspects of Wistar rats submitted to experimental rheumatoid arthritis (RA) protocol. METHODS: Male Wistar rats were randomly distributed into the following 8 groups: control; control LLLT; control exercise; control LLLT and exercise; arthritis group; arthritis LLLT; arthritis exercise; and arthritis LLLT and exercise, with n = 8 for functional and n = 5 for histomorphometrical tests. The experimental RA was induced by complete Freund adjuvant injection in the knee joint cavity. Functionality was evaluated by proprioception and motor function using Sciatic Functional Index and maximum angle reached at an inclined plane. Histomorphometrical aspects were evaluated in the ankle joint after histological routine. RESULTS: The arthritis LLLT and exercise group had positive effects in Sciatic Functional Index (F [3.96] = 11.3, P < .001) and in inclined plane (F [3.4] = 36.1, P < .001). The arthritis exercise group presented a greater number of chondrocytes in the tibia (Wald [1; 6605.6] = 25.2, P < .001) and talus (Wald [1; 15958.6] = 19.8, P = .006) in relation to the other groups. The arthritis group morphology showed significant degenerative lesions as subintima with angiogenesis, inflammatory cells, flocculated articular cartilage, chondrocytes disorganization and pannus. Even with the higher chondrocytes number, the arthritis exercise group had morphological characteristics more similar to the control group. CONCLUSION: Low-level laser therapy and exercise restored functionality, and exercise restored morphological aspects of tissues in experimentally induced RA in rats.

Development and in vivo evaluation of lipid-based nanocarriers containing Jatropha isabellei dry extract from the dichloromethane fraction intended for oral treatment of arthritic diseases

In this study, a dichloromethane fraction dry extract from the underground parts of Jatropha isabellei (DFJi) was used to prepare lipid nanocarriers (LNCJi) aimed at providing the oral delivery of terpenic compounds in the treatment of arthritis. The lipid nanocarriers were prepared by the spontaneous emulsification method. The lipid nanocarriers displayed sizes ranging from 180 to 200 nm and zeta potential values of around -18 mV. A high value of entrapment efficiency (> 90%) was obtained for jatrophone, which was used as the chemical marker of DFJi. LNCJi stored at 4°C were demonstrated to be stable through measurements of transmitted light after analytical centrifugation of the samples. In vitro drug release studies conducted in biorelevant dissolution media demonstrated that jatrophone release was faster from LNCJi than from free DFJi. When tested in an acute arthritis model, the LNCJi exhibited antinociceptive properties after oral administration of a 50 mg/kg dose, unlike the free DFJi, although no reduction in articular diameter was observed. These results suggest that an increase in the oral absorption of DFJi constituents may have occurred through the carrying of this fraction in LNCJi, thus improving the antinociceptive activity of this compound

Intra-articular injection of 2-pyridylethylamine produces spinal NPY-mediated antinociception in the formalin-induced rat knee-joint pain model.

Low doses of histamine or H1R agonist 2-pyridylethylamine (2-PEA) into the knee-joint were found to decrease formalin-induced articular nociception in rats. In this study, we evaluated the participation of spinal NPY in the antinociceptive effect produced by 2-PEA. Injection of formalin (1.5%) into one of the knee-joints causes the limping of the respective limb due to nociception, which was registered each 5 min over 60 min. Neuropeptide Y1 receptor (Y1R) content in the spinal cord was evaluated by western-blotting. Intrathecal (i.t.) injection of Y1R agonist Leu31, Pro34-NPY (0.7-7 µmol) decreased nociception, while injection of the antagonist BIBO 3304 (4 µmol), increased nociception. Antinociception produced by 2-PEA was reversed by a sub-effective i.t. dose of the Y1R antagonist. Similarly, this antinociceptive effect was prevented by i.t. pretreatment with the neurotoxin NPY-saporin (750 ng), which also reduced immunoblotting for Y1R in spinal cord homogenates. These data support the idea that antinociception induced by H1R agonists in the knee-joint of rats may be mediated by the spinal release of NPY, and this peptide seems to be acting via Y1R.

Intrathecally injected tramadol reduces articular incapacitation and edema in a rat model of lipopolysaccharide (LPS)-induced reactive arthritis.

AIMS: Intrathecal injection of morphine presents analgesic and antiedematogenic effects in rats. However, it is unknown whether tramadol, which possess a mixed mechanism of action, can also produce analgesic and antiedematogenic effects similarly. MAIN METHODS: Male Wistar rats received carrageenan and LPS in the right knee joint. Tramadol (10 µg) was injected intrathecally 20 min before articular LPS injection. Incapacitation and articular edema were measured 5 h after LPS stimulation. Synovial fluid was collected for leukocyte counting and western blot analysis. Whole joint and lumbar spinal cord were also collected for histology and immunohistochemistry, respectively. Intrathecal pretreatments groups were with the NKCC1 blocker bumetanide, TRPV1 agonist resiniferatoxin, µ-opioid receptor antagonist CTOP and serotonergic neurotoxin 5,7-DHT, all previously to tramadol. KEY FINDINGS: Tramadol treatment caused the reduction of incapacitation and edema. It also reduced c-Fos protein expression in the spinal cord dorsal horn and slightly reduced TNF-α levels in synovial fluid, but neither reduced cell migration nor tissue damage. Bumetanide and resiniferatoxin prevented the analgesic and antiedematogenic effects of tramadol. CTOP prevented the analgesic and the antiedematogenic effects, but 5,7-DHT prevented only tramadol-induced analgesia. SIGNIFICANCE: Spinal NKCC1 cotransporter and peptidergic peripheral afferents seem to be important for the analgesic and antiedematogenic effects of tramadol, as well as µ-opioid receptor. However, the monoamine uptake inhibition effect of tramadol seems to be important only to the analgesic effect.

Efeito de ondas curtas por método indutivo na lombalgia crônica inespecífica em indivíduos sedentários / Effect of inductive shortwave on chronic non-specific low back pain in sedentary individuals

OBJETIVOS: Avaliar a eficácia do tratamento com ondas curtas por método indutivo em indivíduos sedentários com lombalgia crônica inespecífica. MÉTODOS: Um ensaio clínico quase-experimental e cruzado foi realizado com indivíduos lombálgicos e sedentários. A amostra foi recrutada entre acadêmicos da Universidade Estadual do Oeste do Paraná (Unioeste) na faixa etária entre 18 e 25 anos, que apresentavam dor lombar de origem postural não traumática há mais de três meses, eram sedentários, e aceitaram participar da pesquisa. O protocolo de intervenção consistiu na aplicação de ondas curtas por método indutivo por 15 minutos, uma vez ao dia, três vezes por semana, com intervalo de um dia entre cada aplicação. Na semana seguinte os voluntários recebiam tratamento placebo também por três vezes na semana, com tempo semelhante àquele realizado na semana tratamento, porém o equipamento era apenas ligado, sem emissão do campo eletromagnético. O protocolo foi aplicado por duas semanas. As variáveis analisadas foram o grau de incapacidade funcional, avaliado pelo Índice de Incapacidade de Oswestry (ODI) e pelo Questionário de Incapacidade de Roland-Morris (QIRM), no início do experimento e ao final de cada semana; e a dor, avaliada pela Escala Visual Analógica (EVA), antes e após cada sessão. Os dados foram apresentados em média e desvio-padrão ou mediana e quartis e o nível de significância aceito foi de 5%. RESULTADOS: Vinte voluntários participaram do estudo. Para a ODI houve redução dos valores de incapacidade ao longo da semana de tratamento, com retorno aos valores iniciais na semana placebo; já para o QIRM não houve diferenças entre o tratamento e o placebo. Pela EVA, houve redução na intensidade da dor ao longo dos três dias de terapia, fato que ocorreu apenas no segundo dia do placebo. CONCLUSÕES: O tratamento com ondas curtas na modalidade indutiva foi eficaz na diminuição da dor em pacientes sedentários com lombalgia crônica, contribuindo para melhora da capacidade funcional.

AIMS: To evaluate the efficacy of inductive shortwave treatment in sedentary individuals with non-specific chronic low back pain. METHODS: A quasi-experimental and cross-over trial was performed with sedentary individuals with chronic back pain. The sample was recruited among students from the State University of Western Paraná (Unioeste), aged between 18 and 25 years old, who had low back pain of non-traumatic postural origin for more than three months, were sedentary, and accepted to participate in the study. The intervention protocol consisted in the application of short waves by inductive method for 15 minutes, once a day, three times a week, with interval of one day between each application. In the following week, volunteers also received placebo treatment three times a week, with time similar to that performed in the treatment week, but the equipment was only switched on, without emission of the electromagnetic field. The protocol was applied for two weeks. The variables analyzed were the degree of functional disability, assessed by the Oswestry Disability Index (ODI) and the Roland-Morris Disability Questionnaire (QIRM), at the beginning of the experiment and at the end of each week; and pain, assessed by the Visual Analogue Scale (VAS), before and after each session. Data were presented as mean and standard deviation or median and quartiles, and the accepted level of significance was 5%. RESULTS: Twenty volunteers participated in the study. For ODI, there was a reduction in the disability values throughout the treatment week, with a return to previous values in the placebo week; there were no differences between treatment and placebo for the MIRR. By VAS, there was a reduction in pain intensity over the three days of therapy, which occurred only on the second day of the placebo. CONCLUSIONS: Treatment with short waves in the inductive modality was effective in reducing pain in sedentary patients with chronic low back pain, contributing to improve functional capacity

Antinociceptive and anti-inflammatory activities of the Jatropha isabellei dichloromethane fraction and isolation and quantitative determination of jatrophone by UFLC-DAD.

CONTEXT: Jatropha isabellei Müll. Arg. (Euphorbiaceae) has been used in the traditional medicine to treat arthritis. OBJECTIVE: To evaluate the anti-inflammatory and antinociceptive activities of the dichloromethane fraction (DFJi) from underground parts of J. isabellei, and to develop an analytical method to quantify the diterpene jatrophone. MATERIALS AND METHODS: Anti-inflammatory and antinociceptive activities of the DFji were determined by an acute arthritis model through assessment of the paw elevation time (PET) and articular diameter (AD) of Wistar rats treated orally (50, 100 or 200 mg/kg in a single-dose), and intravenously (0.1, 1, 10, 25 or 50 mg/kg in a bolus administration). The isolation of jatrophone from the DFji was carried out and confirmed by spectroscopic techniques. A UFLC-DAD method was developed and validated. RESULTS: When orally administered, the highest dose (200 mg/kg) of DFJi was able to significantly reduce the PET to 24.8 ± 1.4 s (p < 0.01), when compared with the control group (33.7 ± 1.8 s). The administration of the intravenous dose of 10 mg/kg reduced the PET to 14.8 ± 0.3 s (p < 0.001). The oral and intravenous administration of the DFJi at dose of 200 and 10 mg/kg significantly prevented the formation of edema, reducing the AD in 25.3% and 32.5% (p < 0.01), respectively. The UFLC-DAD method allowed the quantification of jatrophone, which was found to be around 90 µg/mg of fraction. DISCUSSION AND CONCLUSION: The DFJi displayed antinociceptive and antiedematogenic activities, representing a promising plant product for the arthritis treatment.

Histaminergic Pharmacology Modulates the Analgesic and Antiedematogenic Effects of Spinally Injected Morphine.

BACKGROUND: Histamine receptors are known to participate in spinal cord nociceptive transmission, and previous studies have suggested that histaminergic receptors are involved in the analgesic effects of morphine. Herein, we investigated the effect of intrathecal injection of histaminergic agonists and antagonists in a model of acute articular inflammation and their interaction with morphine. METHODS: After carrageenan injection in the right knee joint, articular incapacitation was measured hourly, for up to 6 hours, by the paw elevation time during 1-minute periods of stimulated walking. Inflammatory edema was also assessed hourly by determining an increase in articular diameter. Spinal treatments were administered 20 minutes before knee-joint carrageenan injection and were compared with the saline-treated control group. RESULTS: Intrathecally injected histamine increased incapacitation and articular edema, whereas the H1R antagonist, cetirizine, decreased both parameters. The H3R agonist, immepip, decreased both incapacitation and edema, but the H3R antagonist, thioperamide, increased both incapacitation and edema. Morphine inhibited both incapacitation and edema. Furthermore, combining a subeffective dose of morphine with cetirizine or immepip potentiated the analgesic and antiedematogenic effect. CONCLUSIONS: Histamine seems to act at the spinal level via H1 and H3 receptors to modulate acute arthritis in rats. An H1R antagonist and H3R agonist were found to potentiate the analgesic and antiedematogenic effects of morphine, suggesting that histaminergic and opioid spinal systems may be explored for means of improving analgesia, as well as peripheral anti-inflammatory effects.

Histamine produces opposing effects to serotonin in the knee joint of rats.

UNLABELLED: Formalin injected in the knee joint of rats produces concentration-dependent nociception, edema, and plasma leakage (PL). Herein, we investigated the effect of histamine H1 receptor (H1R) antagonists in this model. Articular nociception was inferred from the paw elevation time (PET; seconds) during 1-minute periods of stimulated walking, determined every 5 minutes, throughout a 60-minute experimental session. Edema was evaluated by the increase in articular diameter (AD; mm), and PL was measured by the amount of Evans blue dye in the synovial fluid (PL; µg/mL). Loratadine and cetirizine, given systemically, both increased the PET. None of the treatments changed the AD and PL. Loratadine given locally with formalin increased the PET but was without effect when given in the contralateral knee. Systemic loratadine was also without effect when formalin was coinjected with sodium cromoglycate. Histamine and the selective H1R agonist 2-pyridylethylamine decreased the PET and potentiated morphine spinal analgesia, but did not affect the AD and PL. Cetirizine prevented the antinociceptive effect of the H1R agonist. The N-methyl-D-aspartate/histamine-site agonist tele-methylhistamine coinjected with formalin only increased PET. Serotonin alone had no effect on the PET and increased the AD, and the highest dose increased the PL. When coinjected with formalin, serotonin only caused hypernociception, and the highest dose also increased AD. NAN 190, cyproheptadine, and ondansetron (respectively, 5-HT1, 5-HT2, and 5-HT3 receptor antagonists) decreased the PET without changing the AD or PL. Collectively, these results suggest that in rats, the H1R plays an antinociceptive role within the knee joint, while serotonin receptors play a pronociceptive role. PERSPECTIVE: The present study revealed an antinociceptive mechanism that has previously not been detected by traditional nociceptive tests. Our observations may help to improve the development of new pharmacological strategies for the treatment of clinically relevant pains that generally originate in deep structures.