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.
Many plants produce (−)‐linalool, a plant‐derived monoterpene alcohol, including members of the Lamiaceae (mints) and Lauraceae family (laurels, cinnamon, rosewood). The anti‐inflammatory and ...analgesic effects of (−)‐linalool have been widely suggested for various studies. Poor chemical stability and short half‐life restrain the clinical applications of some essential oil and monoterpenes, including (−)‐linalool. However, β‐cyclodextrin (β‐CD) has been used to increase solubility and stability of lipophilic compounds and also to improve the pharmacological effects. In this study, the antinociceptive effect of (−)‐linalool and (−)‐linalool/β‐CD was examined using the acetic acid writhing reflex, formalin and hotplate tests in rodents. (−)‐Linalool and (−)‐linalool/β‐CD demonstrated strong antinociceptive activity in all the chemical‐ and heat‐induced mice models (p < 0.01 or p < 0.001). These findings imply the involvement of both peripheral and central antinociceptive mechanisms. In peritonitis induced by carrageenan, isolated monoterpene or β‐CD complex also reduced total leucocyte migration and TNF‐α levels in peritoneal fluid. The inclusion complexes, (−)‐linalool/β‐CD, revealed that the antinociceptive effect was significantly (p < 0.01) improved when compared with (−)‐linalool alone. Such results were unlikely to be provoked by any motor abnormality. Together, our results suggest that β‐CD might represent an important tool for improvement of analgesic and anti‐inflammatory profiles of (−)‐linalool and other water‐insoluble compounds, such as lipophilic monoterpenes or essential oils.
The treatment of orofacial pain remains a major challenge for modern medicine. Thus, we prepared and physicochemically characterized a new β‐cyclodextrin complex containing Lippia grata leaf ...essential oil (β‐CD/EO) to investigate their possible antinociceptive activity in animal models of orofacial pain. The results of Differential scanning calorimeter (DSC) and Thermogravimetry/derivative thermogravimetry (TG/DTG) showed that the products prepared by Slurry complexation (SC) method were able to incorporate greater amounts of EO. In the X‐ray diffractogram, it was shown that complex between EO and β‐CD was formed. Male Swiss mice were pre‐treated with β‐CD/EO (6, 12 or 24 mg/kg, per os, gavage, p.o.), morphine (5 mg/kg, i.p.) or vehicle (distilled water, p.o.) 1 hr before treatment with formalin (20 μL, 2%), capsaicin (20 μL, 2.5 μg) or glutamate (40 μL, 25 μM) into the right upper lip. Our results demonstrated that p.o. treatment with β‐CD/EO was significantly (p < 0.05 or p < 0.001) capable of reducing the nociceptive face‐rubbing behaviour in both phases of the formalin test. β‐CD/EO‐treated mice were also significantly (p < 0.05 or p < 0.001) protected against nociception induced by capsaicin and glutamate. For the action in the central nervous system (CNS), ninety minutes after the treatment, the mice were perfused, the brains collected, crioprotected, cut in a criostate and submitted to an immunofluorescence protocol for Fos protein. The immunofluorescence protocol demonstrated that the β‐CD/EO significantly activated (p < 0.05; p < 0.01 or p < 0.001) the motor cortex, the Locus ceruleus, the nucleus raphe magnus and the periaqueductal gray of the CNS. These effects apparently did not alter, in tested doses, the motor coordination of mice in the rota‐rod test. Our results proposed that β‐CD/EO might present an important draft of drug to the study of new compounds for the treatment of orofacial pain.
Context: Pain corresponds to the most frequent reason for visits to physicians, and its control by conventional drugs is accompanied by several side effects, making treatment difficult. For this ...reason, new chemical entities derived from natural products still hold great promise for the future of drug discovery to pain treatment.
Objective: The objective of this study was to evaluate the antinociceptive and anti-inflammatory profiles of p-cymene (PC), a monocyclic monoterpene, and its possible mechanisms of action.
Materials and methods: Mice treated acutely with PC (25, 50, or 100 mg/kg, i.p.) were screened for carrageenan-induced hyperalgesia and the inflammatory components of its cascade (30-180 min), carrageenan-induced pleurisy (4 h), and tail-flick test (1-8 h). Also, we observed the PC effect on the generation of nitric oxide by macrophages and the activation of neurons in the periaqueductal gray (PAG) by immunofluorescence.
Results: PC reduced (p < 0.001) the hyperalgesia induced by carrageenan, TNF-α, dopamine, and PGE
2
. PC decrease total leukocyte migration (100 mg/kg: p < 0.01), neutrophils (50 and 100 mg/kg: p < 0.05 and 0.001), and TNF-α (25, 50, and 100 mg/kg: p < 0.01, 0.05, and 0.001, respectively), besides reducing NO production (p < 0.05) in vitro. PC produced antinociceptive effect in tail-flick test (p < 0.05), which was antagonized by naloxone, naltrindole, nor-BNI, and CTOP, and increased (p < 0.001) the number of c-Fos-immunoreactive neurons in PAG.
Discussion and conclusion: These results provide information about the anti-hyperalgesic and anti-inflammatory properties of PC suggesting a possible involvement of the opioid system and modulating some pro-inflammatory cytokines.
The Portulaca oleracea L. (Portulacaceae) is a cosmopolitan species with a wide range of biological activities, including antioxidant and neuroprotective actions. We investigated the effects of P. ...oleracea extracts in a 6-hydroxydopamine rat model of Parkinson's disease, a debilitating disorder without effective treatments. Chemical profiles of aqueous and ethanolic extracts of whole plant were analyzed by thin layer chromatography and the antioxidant activity was assessed by 2,2-diphenyl-1-picrilhidrazila method. Male Wistar rats received intrastriatal 6-hydroxydopamine and were treated with vehicle or extracts (oral, 200 and 400 mg/kg) daily for two weeks. The behavioral open field test was conducted at days 1 and 15. Immunohistochemical analysis was performed 4 weeks after surgery to quantify tyrosine-hydroxylase cell counts in the substantia nigra pars compacta. Extracts presented antioxidant activity in concentrations above 300 µg/kg. The chromatographic analysis revealed the presence of Levodopa, alkaloids, flavonoids, saponins, tannins, terpenoids and polysaccharides. Both extracts improved motor recovery 15 days after lesion and protected from tyrosine-hydroxylase cell loss after 4 weeks, but these effects were more evident for the aqueous extract. Because the dopamine precursor is present, in addition to antioxidant compounds and neuroprotective effects, P. oleracea can be considered as potential strategy for treating Parkinson's disease.
Hecogenin is a steroidal sapogenin largely drawn from the plants of the genus Agave, commonly known as 'sisal', and is one of the important precursors used by the pharmaceutical industry for the ...synthesis of steroid hormones. Hecogenin acetate (HA) is a steroidal sapogenin-acetylated that produces antinociceptive activity. Thus, we evaluate the antihyperalgesic profile of HA in mice in inflammatory models, as well as its possible involvement with c-fos expression on spinal cord area and cytokines to produces analgesic profile. Acute pretreatment with HA (5, 10, or 20 mg/kg; i.p.) inhibited the development of mechanical hyperalgesia induced by carrageenan, TNF-α, dopamine and PGE2. Additionally, the immunofluorescence data demonstrated that acute pretreatment with HA, at all doses tested, significantly inhibited Fos-like expression in the spinal cord dorsal horn normally observed after carrageenan-inflammation. Moreover, HA did not affect the motor performance of the mice as tested in the Rota rod test. This antinociceptive profile seems to be related, at least in part, to a reduction of pro-inflammatory cytokines, as IL-1β. The present results suggest that HA attenuates mechanical hyperalgesia by blocking the neural transmission of pain at the spinal cord levels and by cytokines-inhibitory mechanisms.
The present study evaluated the carvacrol (CARV) effect on hyperalgesia and nociception induced by sarcoma 180 (S180) in mice.
Carvacrol treatment (12.5–50mg/kgs.c.) once daily for 15days was started ...24h after injection of the sarcoma cells in the hind paw (s.c.). Mice were evaluated for mechanical sensitivity (von Frey), spontaneous and palpation-induced nociception, limb use and tumor growth on alternate days. CARV effects on the central nervous system were evaluated through immunofluorescence for Fos protein. Molecular docking studies also were performed to evaluate intermolecular interactions of the carvacrol and muscimol, as ligands of interleukin-10 and GABAA receptors.
CARV was able to significantly reduce mechanical hyperalgesia and spontaneous and palpation-induced nociception, improve use paw, decrease the number of positively marked neurons in lumbar spinal cord and activate periaqueductal gray, nucleus raphe magnus and locus coeruleus. CARV also caused significant decreased tumor growth. Docking studies showed favorable interaction overlay of the CARV with IL-10 and GABAA.
Together, these results demonstrated that CARV may be an interesting option for the development of new analgesic drugs for the management of cancer pain.
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Citronellol (CT) is a monoterpenoid alcohol present in the essential oil of many medicinal plants, such as Cymbopogon citratus. We evaluated the antinociceptive effects of CT on orofacial nociception ...in mice and investigated the central pathway involved in the effect. Male Swiss mice were pretreated with CT (25, 50 and 100 mg/kg, i.p.), morphine (5 mg/kg, i.p.) or vehicle (saline + tween 80 0.2%). Thirty minutes after the treatment, we injected formalin (20 μl, 2%), capsaicin (20 μl, 2.5 μg) or glutamate (40 μl, 25 μM) into the right limb. For the action in the CNS, ninety minutes after the treatment, the animals were perfused, the brains collected, crioprotected, cut in a criostate and submitted in an immunofluorescence protocol for Fos protein. CT produced significant (p < 0.01) antinociceptive effect, in all doses, in the formalin, capsaicin and glutamate tests. The immunofluorescence showed that the CT activated significantly (p < 0.05) the olfactory bulb, the piriform cortex, the retrosplenial cortex and the periaqueductal grey of the CNS. Together, our results provide first‐time evidence that this monoterpene attenuates orofacial pain at least, in part, through an activation of CNS areas, mainly retrosplenial cortex and periaqueductal grey.
Snakebites are a public health problem, especially in tropical countries. However, treatment with antivenom has limited effectiveness against venoms’ local effects. Here, we investigated the ability ...of Abarema cochliacarpos hydroethanolic extract (EAc) to protect mice against injection of Bothrops leucurus venom. Swiss mice received perimuscular venom injection and were subsequently treated orally with EAc in different doses. Treatment with EAc 100, 200, and 400 mg/kg reduced the edema induced by B. leucurus in 1%, 13%, and 39%, respectively. Although lower doses showed no antihypernociceptive effect in the Von Frey test, the higher dose significantly reduced hyperalgesia induced by the venom. Antimyotoxic activity of EAc was also observed by microscopy assessment, with treated muscles presenting preserved structures, decreased edema, and inflammatory infiltrate as compared to untreated ones. Finally, on the rotarod test, the treated mice showed better motor function, once muscle fibers were preserved and there were less edema and pain. Treated mice could stand four times more time on the rotating rod than untreated ones. Our results have shown that EAc presented relevant activities against injection of B. leucurus venom in mice, suggesting that it can be considered as an adjuvant in the treatment of envenomation.
•We tested the anti-hyperalgesic and anti-edematogenic effects of citronellol (CT).•CT is able to reduce the mechanical hyperalgesia and paw edema.•CT reduced the Fos activation on spinal cord lamina ...I.•We are suggesting the possible involvement of descending pain-inhibitory mechanisms in the analgesic effect of CT.
We evaluated the anti-hyperalgesic effect of citronellol (CT) and investigated the spinal cord lamina I involvement in this effect. Male mice were pre-treated with CT (25, 50 and 100mg/kg, i.p.), indomethacin (10mg/kg, i.p.), dipyrone (60mg/kg, i.p.) or vehicle (saline+Tween 80 0.2%). Thirty minutes after the treatment, 20μL of carrageenan (CG; 300μg/paw), PGE2 (100ng/paw), dopamine (DA; 30μg/paw) or TNF-α (100pg/paw) were injected into the hind paw subplantar region and the mechanical threshold was evaluated with an electronic anesthesiometer. The CT effect on edema formation was evaluated after the right paw subplantar injection of CG (40μL; 1%) through the plethysmometer apparatus. To evaluate the CT action on the spinal cord, the animals were treated with CT (100mg/kg; i.p.) or vehicle (Saline+Tween 80 0.2%; i.p.) and, after 30min, 20μL of CG (300μg/paw; i.pl.) was injected. Ninety minutes after the treatment, the animals were perfused, the lumbar spinal cord collected, crioprotected, cut and submitted in an immunofluorescence protocol for Fos protein. CT administration produced a significantly reduction (p<0.05) in the mechanical hyperalgesia induced by CG, TNF-α, PGE2 and DA when compared with control group. The treatment with CT also significantly (p<0.05) decreased the paw edema. The immunofluorescence showed that the CT decrease significantly (p<0.05) the spinal cord lamina I activation. Thus, our results provide that CT attenuates the hyperalgesia, at least in part, through the spinal cord lamina I inhibition.
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