Reduced nerve injury-induced neuropathic pain in kinin B1 receptor knock-out mice

Injury to peripheral nerves often results in a persistent neuropathic pain condition that is characterized by spontaneous pain, allodynia, and hyperalgesia. Nerve injury is accompanied by a local inflammatory reaction in which nerve-associated and immune cells release several pronociceptive mediators. Kinin B1 receptors are rarely expressed in nontraumatized tissues, but they can be expressed after tissue injury. Because B1 receptors mediate chronic inflammatory painful processes, we studied their participation in neuropathic pain using receptor gene-deleted mice. In the absence of neuropathy, we found no difference in the paw-withdrawal responses to thermal or mechanical stimulation between B1 receptor knock-out mice and 129/J wild-type mice. Partial ligation of the sciatic nerve in the wild-type mouse produced a profound and long-lasting decrease in thermal and mechanical thresholds in the paw ipsilateral to nerve lesion. Threshold changed neither in the sham-operated animals nor in the paw contralateral to lesion. Ablation of the gene for the B1 receptor resulted in a significant reduction in early stages of mechanical allodynia and thermal hyperalgesia. Furthermore, systemic treatment with the B1 selective receptor antagonist des-Arg9-[Leu8]-bradykinin reduced the established mechanical allodynia observed 7-28 d after nerve lesion in wild-type mice. Partial sciatic nerve ligation induced an upregulation in B1 receptor mRNA in ipsilateral paw, sciatic nerve, and spinal cord of wild-type mice. Together, kinin B1 receptor activation seems to be essential to neuropathic pain development, suggesting that an oral-selective B1 receptor antagonist might have therapeutic potential in the management of chronic pain

Evaluation of the antinociceptive and anti-inflammatory effects of the acetone extract from Anacardium occidentale L

The stem bark of Anacardium occidentale L. (Anacardiaceae), commonly called cashew, is used in Brazilian traditional medicine for the treatment of gastric and inflammatory disorders. The present study was carried out to investigate the in vivo anti-inflammatory activities of the acetone extract (AE) of the stem bark of A. occidentale. We evaluated the pharmacological activities of this plant material through the analgesic, antiedematogenic and chemotaxic inhibitory effects produced by the AE. The oral administration (p.o.) of mice with the AE (0.1, 0.3 and 1.0 g/kg) or positive control indomethacin (10 mg/kg) inhibited acetic acid-induced writhing by 18.9, 35.9, 62.9 and 68.9%, respectively (ID50% = 530 mg/kg). The highest dose of the AE was able to inhibit croton oil-induced ear edema formation by 56.8% (indomethacin at 10 mg/kg, p.o. - 57.6% inhibition). When submitted to the carrageenan-induced peritonitis test, the AE (0.1, 0.3 and 1.0 g/kg, p.o.) impaired leukocyte migration into the peritoneal cavity by 24.8, 40.5 and 49.6%, respectively. The positive control, dexamethasone (2 mg/kg, s.c.), inhibited leukocyte migration by 66.9%. These results indicate the presence of anti-inflammatory and antinociceptive principles in the acetone extract of Anacardium occidentale, and reinforce the plant's potential therapeutic use against pain and inflammatory diseases.As cascas do caule do Anacardium occidentale L. (Anacardiaceae), conhecido como cajueiro, são popularmente utilizadas no Brasil para o tratamento de doenças gástricas e inflamatórias. Este estudo teve como objetivo a avaliação farmacológica in vivo da atividade antiinflamatória do extrato acetônico (AE) obtido das cascas do A. occidentale, investigando os efeitos analgésico, antiedematogênico e inibitório sobre a quimiotaxia deste material botânico. A administração oral (p.o.) em camundongos com o AE (0,1; 0,3 e 1 g/kg) ou o controle positivo indometacina (10 mg/kg) inibiu as contorções abdominais induzidas pelo ácido acético em 18,9; 35,9; 62,9 e 68,9% respectivamente (ID50% = 530 mg/kg). Esta maior dose do AE também inibiu o edema de orelha produzido pelo óleo de cróton em 56,8% (indometacina, 10 mg/kg, p.o. - 57,6% de inibição). No teste da peritonite induzido pela carragenina, o AE (0,1; 0,3; e 1,0 mg/kg, p.o.) reduziu a migração de leucócitos para a cavidade peritoneal em 24,8; 40,5; e 49,6% respectivamente, enquanto que o controle positivo dexametasona (2 mg/kg, s.c.) inibiu a migração de leucócitos em 66,9%. Estes resultados indicam a presença de princípios ativos antiinflamatórios e antinociceptivos no extrato acetônico de Anacardium occidentale e reforçam o potencial terapêutico da planta em doenças que envolvem dor e inflamação

Study of the antinociceptive action of the ethanolic extract and the tripterpene 24-hydroxytormentic acid isolated from the stem bark of Ocotea suaveolens

We describe here the antinociceptive action of the crude extract (CE), the chemical isolation and characterisation and preliminary pharmacological analysis of 24-hydroxytormentic acid, isolated from the stem bark of Ocotea suaveolens (Lauraceae). The CE given by i.p. or p.o. routes, 30 min and 1 h prior, produced significant inhibition of abdominal constrictions caused by acetic acid and also inhibited both phases of formalin-induced licking in mice. The antinociception caused by the CE, given by i.p. and p.o. routes, lasted up to 4 and 2 h, respectively. When assessed in the hot-plate test, the CE was inactive. Its antinociceptive action was not associated with non- specific effects such as muscle relaxation or sedation. The antinociception of CE was not influenced by naloxone, L-arginine or DL-p-chlorophenylalanine methyl ester, when assessed against the formalin assay. The triterpene 24- hydroxytormentic acid, given i.p. 30 min before testing, produced significant, dose-related and equipotent antinociceptive action against both phases of formalin-induced licking in mice. These results demonstrate, for the first time, the occurrence of the triterpene 24-hydroxytormentic acid in the stern bark of Ocotea suaveolens, and show that the CE and 24- hydroxytormentic acid exhibit marked antinociception against the neurogenic and the inflammatory algesic responses induced by formalin in mice. The mechanism by which this compound and CE produces antinociception still remains unclear, but is unlikely to involve the activation of opioid, nitric oxide or serotonin systems or non-specific peripheral or central depressant actions

Reduced nerve injury-induced neuropathic pain in kinin B-1 receptor knock-out mice

Injury to peripheral nerves often results in a persistent neuropathic pain condition that is characterized by spontaneous pain, allodynia, and hyperalgesia. Nerve injury is accompanied by a local inflammatory reaction in which nerve-associated and immune cells release several pronociceptive mediators. Kinin B-1 receptors are rarely expressed in nontraumatized tissues, but they can be expressed after tissue injury. Because B-1 receptors mediate chronic inflammatory painful processes, we studied their participation in neuropathic pain using receptor gene-deleted mice. in the absence of neuropathy, we found no difference in the paw-withdrawal responses to thermal or mechanical stimulation between B-1 receptor knock-out mice and 129/J wild-type mice. Partial ligation of the sciatic nerve in the wild-type mouse produced a profound and long-lasting decrease in thermal and mechanical thresholds in the paw ipsilateral to nerve lesion. Threshold changed neither in the sham-operated animals nor in the paw contralateral to lesion. Ablation of the gene for the B-1 receptor resulted in a significant reduction in early stages of mechanical allodynia and thermal hyperalgesia. Furthermore, systemic treatment with the B-1 selective receptor antagonist des-Arg(9)-[Leu(8)]-bradykinin reduced the established mechanical allodynia observed 7-28d after nerve lesion in wild-type mice. Partial sciatic nerve ligation induced an upregulation in B-1 receptor mRNA in ipsilateral paw, sciatic nerve, and spinal cord of wild-type mice. Together, kinin B-1 receptor activation seems to be essential to neuropathic pain development, suggesting that an oral-selective B-1 receptor antagonist might have therapeutic potential in the management of chronic pain.Univ Fed Santa Catarina, Dept Pharmacol, Ctr Biol Sci, BR-88049900 Florianopolis, SC, BrazilEscola Paulista Med, Dept Biophys, BR-04023062 São Paulo, BrazilUniv Mogi Cruzes, BR-0878091 Mogi Das Cruzes, BrazilMax Delbruck Ctr Mol Med, D-13125 Berlin, GermanyEscola Paulista Med, Dept Biophys, BR-04023062 São Paulo, BrazilWeb of Scienc

Tinnitus: The sound of stress?

Background: Emotional stress is frequently associated with otologic symptoms as tinnitus and dizziness. Stress can contribute to the beginning or worsening of tinnitus. Objective: The objective of the study is to evaluate the presence of stress symptoms in patients with chronic, subjective tinnitus, and correlate its presence to annoyance associated with tinnitus. Methods: This is a cross-sectional study. One hundred and eighty patients with chronic, subjective tinnitus were included. Patients answered the Tinnitus Handicap Inventory (THI) to evaluate the impact of tinnitus in the quality of life and answered the Lipp's inventory symptoms of stress for adults (ISSL). The data obtained was organized using Excel® 2010, mean values, linear regression and p-value were calculated. Results: Of the 180 patients included in the study, 117 (65%) had stress symptoms, 52 of the 117 (44%) were in the resistance phase and 23 of the 117 (20%) in the exhaustion phase, the remaining was in the alert phase. There was a clear progressive increase in stress as THI raised, with more impact of tinnitus in quality of life. Conclusion: The presence of stress symptoms, measured by ISSL was observed in most of our patients with chronic subjective tinnitus, specially in the resistance and exhaustion phases and it is directly associated with tinnitus annoyance

The neurokinin-1 receptor is a target in pediatric rhabdoid tumors.

Rhabdoid tumors (RT) are among the most aggressive tumors in early childhood. Overall survival remains poor, and treatment only effectively occurs at the cost of high toxicity and late adverse effects. It has been reported that the neurokinin-1 receptor/substance P complex plays an important role in cancer and proved to be a promising target. However, its role in RT has not yet been described. This study aims to determine whether the neurokinin-1 receptor is expressed in RT and whether neurokinin-1 receptor (NK1R) antagonists can serve as a novel therapeutic approach in treating RTs. By in silico analysis using the cBio Cancer Genomics Portal we found that RTs highly express neurokinin-1 receptor. We confirmed these results by RT-PCR in both tumor cell lines and in human tissue samples of various affected organs. We demonstrated a growth inhibitory and apoptotic effect of aprepitant in viability assays and flow cytometry. Furthermore, this effect proved to remain when used in combination with the cytostatic cisplatin. Western blot analysis showed an upregulation of apoptotic signaling pathways in rhabdoid tumors when treated with aprepitant. Overall, our findings suggest that NK1R may be a promising target for the treatment of RT in combination with other anti-cancer therapies and can be targeted with the NK1R antagonist aprepitant