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An acute bout of exercise can exacerbate pain, hindering participation in regular exercise and daily activities. The mechanisms underlying pain in response to acute exercise are poorly understood. We hypothesized that proton accumulation during muscle fatigue activates acid-sensing ion channel 3 (ASIC3) on muscle nociceptors to produce hyperalgesia. We investigated the role of ASIC3 using genetic and pharmacological approaches in a model of fatigue-enhanced hyperalgesia. This model uses two injections of pH 5.0 saline into muscle in combination with an electrically induced fatigue of the same muscle just prior to the second injection of acid to induce mechanical hyperalgesia. We show a significant decrease in muscle force and decrease in muscle pH after 6 min of electrical stimulation. Genetic deletion of ASIC3 using knockout mice and pharmacological blockade of ASIC3 with APETx2 in muscle prevents the fatigue-enhanced hyperalgesia. However, ASIC3 −/− mice and APETx2 have no effect on the fatigue response. Genetic deletion of ASIC3 in primary afferents innervating muscle using an HSV-1 expressing microRNA (miRNA) to ASIC3 surprisingly had no effect on the development of the hyperalgesia. Muscle fatigue increased the number of macrophages in muscle, and removal of macrophages from muscle with clodronate liposomes prevented the development of fatigue-enhanced hyperalgesia. Thus, these data suggest that fatigue reduces pH in muscle that subsequently activates ASIC3 on macrophages to enhance hyperalgesia to muscle insult.

Pain treatment is still ineffective in many conditions and remains one of the greatest challenges of modern medicine. Historically, due to the incredible variety of pharmacologically promising natural products (NPs) and the chemical complexity of their compounds, scientists have explored their use as a source of treatment for diseases or symptomatology. Fos protein and its precursor, the gene c-Fos, have been the subject of study in relation to the pathophysiology of pain as a possible tool to aid in its understanding. More recently, it has become a useful tool in the study of NPs with analgesic profile. Thus, this systematic review aimed to investigate the analgesic effect of NPs and derivatives through changes in Fos protein or c-Fos expression in nervous system central. The search terms “analgesics,” “Fos,” and “drug effects” were used in the databases PubMed, MEDLINE, Scopus, and Embase. Forty-six articles were identified. Twenty-five articles investigated Fos expression in the spinal cord, 1 in dorsal root ganglion, 11 in brain areas, and 9 investigated the association between the spinal cord and brain areas. Although Fos protein expression has been used as a tool in the studies of the mechanism of action of pain in relation to NPs with analgesic activity, the associations between brain areas and the spinal cord—and the possible pathways involved—have not yet been fully elucidated and deserve further study.

We evaluated if a nanostructured thermoreversible Pluronic F127-based hydrogel incorporated with Hyptis pectinata leaf essential oil (NE-EOH) produces a long-lasting anti-hyperalgesic effect on chronic muscle pain in an animal model. We induced chronic muscle pain by injecting the gastrocnemius with saline injections. Paw and muscle withdrawal thresholds and motor performance were evaluated after treatment and compared with morphine, diazepam, or vehicle. Naloxone and methysergide administration tested the involvement of opioid and serotonin receptors, respectively. Sites of action in the central nervous system for the NE-EOH were examined by measuring substance P (SP) levels in the spinal cord and Fos protein in the brainstem. NE-EOH increased paw and muscle withdrawal thresholds when compared with vehicle but had no effect on motor function. This analgesic effect was reversed by both naloxone and methysergide. NE-EOH decreased elevated substance P levels and reduced Fos-labeled neurons in the spinal cord and increased the number of Fos-labeled neurons in the periaqueductal gray (PAG), nucleus raphe magnus (NRM), and locus coeruleus (LC). NE-EOH was shown to produce a lasting anti-hyperalgesic effect. It uses opioid and serotonin receptors, activates brainstem inhibitory pathways, and reduces the release of excitatory neurotransmitters in the spinal cord and is a substance with potential to be used in the treatment of noninflammatory pain conditions.

Xylopia laevigata (Annonaceae) is a medicinal plant used in folk medicine to treat pain and inflammation. Thus, we investigated the possible antioxidant, antinociceptive, and anti-inflammatory effects of X. laevigata leaf essential oil (EOX) in animal models. Our EOX sample showed the presence of γ-muurolene (17.78%), δ-cadinene (12.23%), bicyclogermacrene (7.77%), and α-copaene (7.17%) as main compounds. EOX presented a strong antioxidant potential according to the DPPH, TBARS, and nitrite production tests. Additionally, pretreatment with EOX, in mice, also significantly produced ( P < 0.05 or P < 0.001 ) antinociceptive effect by reduction of nociceptive behavior (in formalin and writhing tests). The EOX showed c-Fos label in the olfactory bulb, piriform cortex, and periaqueductal gray. Acute administration of EOX exhibited a significant ( P < 0.01 or P < 0.001 ) anti-inflammatory profile in the carrageenan-induced peritonitis and by the carrageenan-induced hindpaw edema tests in mice. Our results provide evidence for the use of X. laevigata by traditional medicine practitioners in the management of pain and inflammatory disorders.

The search for more effective new drugs to treat Leishmaniasis is undoubtedly relevant. Our objective in this study was to investigate research publications addressing plants with anti-Leishmaniasis activity. An integrative review of the literature from 2000 to 2011 was carried out in the databases such as Latin-American and Caribbean Health Sciences (LILACS), Scientific Electronic Library Online (SciELO), and Medical Literature Analysis and Retrieval System Online (MEDLINE). In the initial search, 150 articles were found, with 25 based in LILACS, 68 in SciELO, and 46 in MEDLINE. From these data, after reading the abstracts that were available online, we excluded 12 from LILACS, 39 from SciELO, and 28 from MEDLINE for presenting article duplications. This left 61 articles to be read; however, only 18 of them answered the research questions and determined the final sample of this review. The results showed that research involving the search for new drugs against Leishmaniasis should be intensified, especially for the amastigote form, and studies with in vivo tests could become a great strategy for successfully finding new treatments for Leishmaniasis. It is believed that it is extremely important and urgent to conduct more trials in search of new effective drugs against Leishmaniasis that possess minimal adverse effects and that are easily accessible to the public.

O. basilicum leaves produce essential oils (LEO) rich in monoterpenes. The short half-life and water insolubility are limitations for LEO medical uses. β-Cyclodextrin (β-CD) has been employed to improve the pharmacological properties of LEO. We assessed the antihyperalgesic profile of LEO, isolated or complexed in β-CD (LEO/β-CD), on an animal model for fibromyalgia. Behavioral tests: mice were treated every day with either LEO/β-CD (25, 50 or 100 mg/kg, p.o.), LEO (25 mg/kg, p.o.), tramadol (TRM 4 mg/kg, i.p.) or vehicle (saline), and 60 min after treatment behavioral parameters were assessed. Therefore, mice were evaluated for mechanical hyperalgesia (von Frey), motor coordination (Rota-rod) and muscle strength (Grip Strength Metter) in a mice fibromyalgia model. After 27 days, we evaluated the central nervous system (CNS) pathways involved in the effect induced by experimental drugs through immunofluorescence protocol to Fos protein. The differential scanning analysis (DSC), thermogravimetry/derivate thermogravimetry (TG/DTG) and infrared absorption spectroscopy (FTIR) curves indicated that the products prepared were able to incorporate the LEO efficiently. Oral treatment with LEO or LEO-βCD, at all doses tested, produced a significant reduction of mechanical hyperalgesia and we were able to significantly increase Fos protein expression. Together, our results provide evidence that LEO, isolated or complexed with β-CD, produces analgesic effects on chronic non-inflammatory pain as fibromyalgia.

This study aimed to evaluate the orofacial antinociceptive effect of the Cymbopogon winterianus essential oil (LEO) complexed in β-cyclodextrin (LEO-CD) and to assess the possible involvement of the central nervous system (CNS). The LEO was extracted, chromatographed, and complexed in β-cyclodextrin. The complex was characterized by differential scanning calorimetry (DSC) and thermogravimetry derivative (TG/DTG). Male Swiss mice (2-3 months) were treated with LEO-CD (50–200 mg/kg, p.o.), vehicle (distilled water, p.o.), or standard drug (i.p.) and subjected to the orofacial nociception formalin-, capsaicin-, and glutamate-induced. After the formalin test, the animals were perfused and the brains subjected to immunofluorescence for Fos. The rota-rod test (7 rpm/min) was carried out. Geraniol (37.57%) was the main compound of LEO. DSC and TG/DTG proved the complexation. The orofacial nociceptive behavior was significantly (p<0.05) reduced. The number of Fos-positive cells was significantly changed in the dorsal raphe nucleus (p<0.01), locus coeruleus (p<0.001), trigeminal nucleus (p<0.05), and trigeminal thalamic tract (p<0.05). LEO-CD did not cause changes in motor coordination in the rota-rod test. Thus, our results suggested that LEO-CD has an orofacial antinociceptive profile, probably mediated by the activation of the CNS without changing the motor coordination.

This study aimed to evaluate the orofacial antinociceptive effect of the Cymbopogon winterianus essential oil (LEO) complexed in β-cyclodextrin (LEO-CD) and to assess the possible involvement of the central nervous system (CNS). The LEO was extracted, chromatographed, and complexed in β-cyclodextrin. The complex was characterized by differential scanning calorimetry (DSC) and thermogravimetry derivative (TG/DTG). Male Swiss mice (2-3 months) were treated with LEO-CD (50-200 mg/kg, p.o.), vehicle (distilled water, p.o.), or standard drug (i.p.) and subjected to the orofacial nociception formalin-, capsaicin-, and glutamate-induced. After the formalin test, the animals were perfused and the brains subjected to immunofluorescence for Fos. The rota-rod test (7 rpm/min) was carried out. Geraniol (37.57%) was the main compound of LEO. DSC and TG/DTG proved the complexation. The orofacial nociceptive behavior was significantly (p<0.05) reduced. The number of Fos-positive cells was significantly changed in the dorsal raphe nucleus (p<0.01), locus coeruleus (p<0.001), trigeminal nucleus (p<0.05), and trigeminal thalamic tract (p<0.05). LEO-CD did not cause changes in motor coordination in the rota-rod test. Thus, our results suggested that LEO-CD has an orofacial antinociceptive profile, probably mediated by the activation of the CNS without changing the motor coordination.

UNS $32760 super duplex stainless steel has excellent corrosion resistance and mechanical properties that are superior to those exhibited by austenitic and ferritic stainless steels, but which can still be improved by surface treatments. However, due attention should be paid to the corrosion resistance properties. Thus, the aim of this work is to investigate the effect of plasma nitriding and the duplex treatment on the corrosion resistance of UNS $32760 steel. A conventional plasma nitriding treatment lasting 4 and two duplex treatments were studied, which repeated the nitriding and then subjected to the deposition of titanium nitride films for 2 h and 4h using the cathode cage plasma deposition technique. The temperature used in all treatments was 723 k. The samples were evaluated by Optical Microscopy, Scanning Electron Microscopy (SEM), Energy Dispersive Spectroscopy (EDS) maps, X-ray Diffraction with routine application of Rietveld, Vickers Microhardness and Rockwell indentation adhesion test. The sample subjected only to nitriding treatment presented the highest surface hardness, 4.06 times higher than that presented by the base material. In the samples submitted to the duplex treatment the presence of stoichiometric titanium was observed on the nitride layer. The corrosion tests revealed on sample NC4 evidenced the positive effect of plasma nitriding on corrosion resistance.