Involvement of nuclear factor κB and descending pain pathways in the anti-hyperalgesic effect of ß-citronellol, a food ingredient, complexed in ß-cyclodextrin in a model of complex regional pain syndrome - Type 1.

Complex regional pain syndrome type 1 (CRPS-1) is a painful syndrome without effective treatment. In order to explore possible new treatments, we used an animal model of CRPS-1 to examine the effects of ß-Citronellol (ßCT), a monoterpene found in a variety of plants that has been shown to have analgesic effects. We aimed to assess its effects alone, and complexed with ß-cyclodextrin (ßCD), which has been previously used to enhance the effects of a number of medicines. The ßCT-ßCD was characterized physiochemically using high performance liquid chromatography (HPLC) and differential scanning calorimetry (DSC) and shown to have 80% efficiency. In the animal model, Swiss mice were treated with ßCT, ßCT-ßCD, vehicle, pregabalin or sham and evaluated for hyperalgesia and motor coordination. Inflammatory mediators were measured by Western blot or ELISA and the descending pain pathway by immunofluorescence. ßCT was shown to have an anti-hyperalgesic effect (without affecting motor coordination) that reduced inflammatory mediators and activated the descending pain pathway, and these effects were increased with complexation in ßCD. Our results showed ßCT-ßCD to be a promising treatment for CRPS-1.

p-Cymene attenuates cancer pain via inhibitory pathways and modulation of calcium currents.

BACKGROUND: Oncological pain is one of the most prevalent and difficult-to-treat symptoms in patients with cancer. p-Cymene (PC) is a monoterpene found in more than 100 different plant species, endowed with various pharmacological properties-particularly antinociceptive. HYPOTHESIS/PURPOSE: PC has antinociceptive effect in a model of oncologic pain due to the activation of the descending inhibitory pathway of pain. STUDY DESIGN: A pre-clinical, longitudinal, blind and randomized study. METHODS: Male Swiss mice were induced with S180 cells in the right hind paw, then treated daily with PC (12.5, 25 and 50 mg/kg, s.c.) and screened for mechanical hyperalgesia, spontaneous nociception, nociception induced by non-noxious palpation, tumor growth, changes in the neuromuscular function and existence of bone degradation in the tumor area. The effect of PC on Ca2+ currents (electrophysiological records), histological and neurochemical changes (immunofluorescence for Fos) were also evaluated. RESULTS: PC reduced (p < 0.05) the mechanical hyperalgesia, the spontaneous (p < 0.001) and non-noxious palpation (p < 0.001) nociceptions, not changing the tumor development, neuromuscular function or histopathological aspects of the paw affected. PC reduced Fos expression in the spinal cord (p < 0.001) and increased this expression in the PAG (p < 0.05) and in the NRM (p < 0.01). PC decreased the density of calcium channel currents (p < 0.05). CONCLUSION: These results suggest the antinociceptive effect of PC on oncologic pain, probably acting in both ascending and descending pain pathways, and modulating the calcium channel currents in order to exert its effects.

Molecular mechanism underlying orofacial antinociceptive activity of Vanillosmopsis arborea Baker (Asteraceae) essential oil complexed with ß-cyclodextrin.

BACKGROUND: Vanillosmopsis arborea Baker has recognized economic value owing to the high content of (-)-α-bisabolol (BISA) in the essential oil of its stem (EOVA). The antinociceptive effect of EVOA has already been demonstrated, and ß-cyclodextrin (ßCD) is known to improve the analgesic effect of various substances. PURPOSE: Thus, we aimed to evaluate the orofacial antinociceptive effect of a complex containing EOVA-ßCD in rodents. METHODS: EOVA was obtained by simple hydrodistillation, and the essential oil was complexed with ßCD. The animals (n = 6/group) were treated orally with EOVA-ßCD (10 or 50 mg/kg), or vehicle (control), and subjected to cutaneous orofacial nociception (formalin, capsaicin, acidic saline or glutamate), corneal (hypertonic saline) or temporomandibular (formalin) tests. The expression of FOS protein was analyzed in the spinal cord. Molecular docking was performed using the 5-HT3 and M2 receptors and BISA. RESULTS: The oral administration of EOVA-ßCD reduced nociceptive behaviour. Moreover, EOVA-ßCD decreased FOS expression. The molecular docking study indicates that BISA interacts with 5-HT3 and M2 receptors, indicating the potential mechanism of action of the tested compound. CONCLUSIONS: Our results indicate that EOVA-ßCD possesses orofacial antinociceptive effect, indicating that this complex can be used in analgesic drug development.

Evidence for the involvement of TNF-α, IL-1ß and IL-10 in the antinociceptive and anti-inflammatory effects of indole-3-guanylhydrazone hydrochloride, an aromatic aminoguanidine, in rodents.

BACKGROUND: Indole-3-guanylhydrazone hydrochloride (LQM01) is a new derivative of aminoguanidine hydrochloride, an aromatic aminoguanidine. METHODS: Mice were treated with LQM01 (5, 10, 25 or 50 mg/kg, i.p.), vehicle (0.9% saline i.p.) or a standard drug. The mice were subjected to carrageenan-induced pleurisy, abdominal writhing induced by acetic acid, the formalin test and the hot-plate test. The model of non-inflammatory chronic muscle pain induced by saline acid was also used. Mice from the chronic protocol were assessed for withdrawal threshold, muscle strength and motor coordination. LQM01 or vehicle treated mice were evaluated for Fos protein. RESULTS: LQM01 inhibits TNF-α and IL-1ß production, as well as leukocyte recruitment during inflammation process. The level of IL-10 in LQM01-treated mice increased in pleural fluid. In addition, LQM01 decreased the nociceptive behavior in the acetic acid induced writhing test, the formalin test (both phases) and increased latency time on the hot-plate. LQM01 treatment also decreased mechanical hyperalgesia in mice with chronic muscle pain, with no changes in muscle strength and motor coordination. LQM01 reduced the number of Fos positive cells in the superficial dorsal horn. This compound exhibited antioxidant properties in in vitro assays. CONCLUSIONS: LQM01 has an outstanding anti-inflammatory and analgesic profile, probably mediated through a reduction in proinflammatory cytokines release, increase in IL-10 production and reduction in neuron activity in the dorsal horn of the spinal cord in mice. GENERAL SIGNIFICANCE: Beneficial effects of LQM01 suggest that it has some important clinical features and can play a role in the management of 'dysfunctional pain' and inflammatory diseases.

Fos Protein as a Marker of Neuronal Activity: a Useful Tool in the Study of the Mechanism of Action of Natural Products with Analgesic Activity.

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.

Nanoemulsion Thermoreversible Pluronic F127-Based Hydrogel Containing Hyptis pectinata (Lamiaceae) Leaf Essential Oil Produced a Lasting Anti-hyperalgesic Effect in Chronic Noninflammatory Widespread Pain in Mice.

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. Graphical Abstract.

Anti-hyperalgesic effect of Lippia grata leaf essential oil complexed with ß-cyclodextrin in a chronic musculoskeletal pain animal model: Complemented with a molecular docking and antioxidant screening.

BACKGROUND: Due to its unclear pathophysiology, the pharmacological treatment of fibromyalgia is a challenge for researchers. Studies using medicinal plants, such as those from the genus Lippia, complexed with cyclodextrins (CDs) have shown innovative results. OBJECTIVE: The present research intended to evaluate the effect of an inclusion complex containing ß-cyclodextrin (ßCD) inclusion complex with Lippia grata (LG) essential oil in a chronic musculoskeletal pain model, its central activity and its possible interaction with neurotransmitters involved in pain. METHODS: After acid saline-induced chronic muscle pain, male mice were evaluated for primary and secondary hyperalgesia and muscle strength. Moreover, an antagonist assay was performed to assess the possible involvement of the opioidergic, serotonergic and noradrenergic pathways. In addition, Fos protein in the spinal cord was assessed, and a docking study and antioxidant assays were performed. RESULTS: The treatment with LG-ßCD, especially in the dose of 24mg/kg, was able to significantly decrease (p<0.05) the paw withdrawal and muscle threshold. Furthermore, LG-ßCD was shown to affect the opioidergic and serotonergic pathways. There were no significant changes in muscle strength. Fos protein immunofluorescence showed a significant decrease in expression in the dorsal horn of the spinal cord. The main compounds of LG showed through the docking study interaction energies with the alpha-adrenergic and µOpioid receptors. In all antioxidant assays, LG exhibited stronger antioxidant activities than LG-ßCD. CONCLUSION: This study suggested that LG-ßCD could be considered as a valuable source for designing new drugs in the treatment of chronic pain, especially musculoskeletal pain.

Cyclodextrins as Complexation Agents to Improve the Anti-inflammatory Drugs Profile: a Systematic Review and Meta-Analysis.

BACKGROUND: Anti-inflammatory drugs can be ineffective in treating some inflammatory conditions. Improved drug delivery systems like cyclodextrins (CDs) could enhance their efficacy and safety. OBJECTIVE: We conducted a systematic review to evaluate the anti-inflammatory activity of compounds complexed in CDs, analyzing whether these complexes improved their pharmacological action. METHODS: The search terms 'Anti-inflammatory Agents', 'Cyclodextrins' and 'Drug effects' were used to retrieve articles in SCOPUS, PUBMED, MEDLINE and EMBASE. RESULTS: Forty-four papers were identified. In the in vivo and clinical studies, there was greater efficacy for complexed drugs when compared to control groups or uncomplexed drug, decreasing inflammation and inflammatory mediators. Through a meta-analysis, the preclinical studies demonstrated that the complexed drug had a significantly (p<0.001) greater anti-inflammatory effect than the non-CD-complexed drug. CONCLUSION: The use of CDs can improve the action of anti-inflammatory compounds and it can also be a way to reduce the side effects, therapeutic doses and toxicity.

Regular physical activity prevents development of chronic muscle pain through modulation of supraspinal opioid and serotonergic mechanisms.

INTRODUCTION: It is generally believed that exercise produces its effects by activating central opioid receptors; there are little data that support this claim. The periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) are key nuclei in opioid-induced analgesia, and opioids interact with serotonin to produce analgesia. OBJECTIVES: The purpose was to examine central inhibitory mechanisms involved in analgesia produced by wheel running. METHODS: C57/Black6 mice were given access to running wheels in their home cages before induction of chronic muscle hyperalgesia and compared with those without running wheels. Systemic, intra-PAG, and intra-RVM naloxone tested the role of central opioid receptors in the antinociceptive effects of wheel running in animals with muscle insult. Immunohistochemistry for the serotonin transporter (SERT) in the spinal cord and RVM, and pharmacological blockade of SERT, tested whether the serotonin system was modulated by muscle insult and wheel running. RESULTS: Wheel running prevented the development of muscle hyperalgesia. Systemic naloxone, intra-PAG naloxone, and intra-RVM naloxone reversed the antinociceptive effect of wheel running in animals that had received muscle insult. Induction of chronic muscle hyperalgesia increased SERT in the RVM, and blockade of SERT reversed the hyperalgesia in sedentary animals. Wheel running reduced SERT expression in animals with muscle insult. The serotonin transporter in the superficial dorsal horn of the spinal cord was unchanged after muscle insult, but increased after wheel running. CONCLUSION: These data support the hypothesis that wheel running produced analgesia through central inhibitory mechanisms involving opioidergic and serotonergic systems.

Docking, characterization and investigation of ß-cyclodextrin complexed with citronellal, a monoterpene present in the essential oil of Cymbopogon species, as an anti-hyperalgesic agent in chronic muscle pain model.

BACKGROUND: Citronellal (CT) is a monoterpene with antinociceptive acute effect. ß-Cyclodextrin (ßCD) has enhanced the analgesic effect of various substances. HYPOTHESIS/PURPOSE: To evaluate the effect of CT both complexed in ß-cyclodextrin (CT-ßCD) and non-complexed, in a chronic muscle pain model (CMP) in mice. STUDY DESIGN: The complex containing CT in ßCD was obtained and characterized in the laboratory. The anti-hyperalgesic effect of CT and CT-ßCD was evaluated in a pre-clinical in vivo study in a murine CMP. METHODS: The complex was characterized through differential scanning calorimetry, derivative thermogravimetry, moisture determination, infrared spectroscopy and scanning electron microscopy. Male Swiss mice were pre-treated with CT (50mg/kg, po), CT-ßCD (50mg/kg, po), vehicle (isotonic saline, po) or standard drug (tramadol4 mg/kg, ip). 60 min after the treatment and then each 1h, the mechanic hyperalgesia was evaluated to obtain the time effect. In addition, the muscle strength using grip strength meter and hyperalgesia were also performed daily, for 7 days. We assessed by immunofluorescence for Fos protein on brains and spinal cords of mice. The involvement of the CT with the glutamatergic system was studied with molecular docking. RESULTS: All characterization methods showed the CT-ßCD complexation. CT-induced anti-hyperalgesic effect lasted until 6h (p <0.001) while CT-ßCD lasted until 8h (p <0.001vs vehicle and p <0.001vs CT from the 6th h). CT-ßCD reduced mechanical hyperalgesia on all days of treatment (p <0.05), without changing muscle strength. Periaqueductal gray (p <0.01) and rostroventromedular area (p <0.05) showed significant increase in the Fos protein expression while in the spinal cord, there was a reduction (p <0.001). CT showed favorable energy binding (-5.6 and -6.1) to GluR2-S1S2J protein based in the docking score function. CONCLUSION: We can suggest that ßCD improved the anti-hyperalgesic effect of CT, and that effect seems to involve the descending pain-inhibitory mechanisms, with a possible interaction of the glutamate receptors, which are considered as promising molecules for the management of chronic pain such as CMP.

α-Terpineol, a monoterpene alcohol, complexed with ß-cyclodextrin exerts antihyperalgesic effect in animal model for fibromyalgia aided with docking study.

The anti-hyperalgesic effect of the complex containing α-terpineol (αTPN) and ß-cyclodextrin (ßCD) was analyzed in a non-inflammatory chronic muscle pain model, as well as its mechanism of action through docking study for a possible interaction with receptors. The αTPN-ßCD complex was prepared and characterized through the thermogravimetry/derivate thermogravimetry (TG/DTG), Fourier transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM). The model of chronic muscle pain was induced by two injections of pH 4.0 saline (20 µl) into the left gastrocnemius 5 days apart. After confirming hyperalgesia, male mice were treated with αTPN-ßCD (25, 50 or 100 mg/kg; p.o.) or vehicle (saline 0.9%, p.o.) daily for 10 days. 1 h after the mechanical hyperalgesia, motor performance was evaluated. In addition, the systemic administration of naloxone and ondansetron tested the analgesic effect on the active opioid and serotonin receptors, respectively. The characterization tests indicated that αTPN was efficiently incorporated into ßCD. The oral treatment with αTPN-ßCD, at all doses tested, produced a significant (p < 0.001) decrease in the mechanical hyperalgesia, without causing any alteration in the force and in motor performance. This analgesic effect was reversed by the systemic administration of naloxone or ondansetron. These findings are corroborated by the docking study described in the present study, which verified a possible interaction of αTPN-ßCD with opioid (MU, Kappa, Delta) and 5-HT receptors. Thus, it can be concluded that αTPN-ßCD reduced the hyperalgesia followed by the chronic muscle pain model, probably evoked by the descending inhibitory pain system, specifically by opioid and serotoninergic receptors.

ß-caryophyllene, a dietary cannabinoid, complexed with ß-cyclodextrin produced anti-hyperalgesic effect involving the inhibition of Fos expression in superficial dorsal horn.

AIMS: Evaluate the anti-hyperalgesic effect of the complex containing ß-caryophyllene (ßCP) and ß-cyclodextrin (ßCD) in a non-inflammatory chronic muscle pain mice model and investigated its action on superficial dorsal horn of the lumbar spinal cord. MAIN METHODS: The ßCP-ßCD complex were prepared and characterized through the DSC, TG/DTG, FTIR, XRD and SEM. The model of chronic muscle pain was induced by two injections of pH4.0 saline (20µL) into left gastrocnemius 5days apart. After confirming hyperalgesia, male mice were treated with ßCP-ßCD (10 or 20mg/kg; p.o.) or vehicle (saline 0.9%, p.o.) daily for 9days. 1h after, the mechanical hyperalgesia, muscle withdrawal thresholds and motor performance were evaluated. To evaluate the ßCP-ßCD action on spinal cord, animals induced with chronic muscle pain were treated with ßCP-ßCD (20mg/kg; p.o.) or vehicle (saline 0.9%, p.o.) and 90min. after, were perfused, the lumbar spinal cord collected, crioprotected, cut and submitted in an immunofluorescence protocol for Fos protein. KEY FINDINGS: The characterization tests indicated that ßCP were efficiently incorporated into ßCD. The oral treatment with ßCP-ßCD, at all doses tested, produced a significant (p<0.05) reduction on mechanical hyperalgesia and a significant (p<0.05) increase in muscle withdrawal thresholds, without produce any alteration in force. In addition, ßCP-ßCD was able to significantly (p<0.05) decrease Fos expression in the superficial dorsal horn. SIGNIFICANCE: Thus, ßCP-ßCD attenuates the non-inflammatory chronic muscle pain in mice and inhibits the Fos expression in the lumbar spinal cord.

ASIC3 Is Required for Development of Fatigue-Induced Hyperalgesia.

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.

Preparation, Characterization, and Pharmacological Activity of Cymbopogon winterianus Jowitt ex Bor (Poaceae) Leaf Essential Oil of ß-Cyclodextrin Inclusion Complexes.

This study aimed to evaluate the orofacial antinociceptive effect of the Cymbopogon winterianus essential oil (LEO) complexed in ß-cyclodextrin (LEO-CD) and to assess the possible involvement of the central nervous system (CNS). The LEO was extracted, chromatographed, and complexed in ß-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.

Citronellol, a natural acyclic monoterpene, attenuates mechanical hyperalgesia response in mice: Evidence of the spinal cord lamina I inhibition.

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.

Enhanced analgesic activity by cyclodextrins - a systematic review and meta-analysis.

INTRODUCTION: Analgesics can be ineffective in treating some types of pain, hence, improved drug delivery systems could optimize their efficacy. AREA COVERED: The authors conducted a systematic review to evaluate the analgesic activity of compounds complexed in cyclodextrins, analyzing whether these complexes improved analgesic efficacy. The search terms 'analgesics', 'cyclodextrins' and 'drug effects' were used to retrieve articles in SCOPUS, PUBMED and EMBASE. A total of 22 papers were identified. In the clinical studies, there was greater efficacy in the complexed drug when compared with control groups, with differences ranging from 25 to 83%. Through a meta-analysis, the preclinical studies showed that the complexed drug had a significantly (p < 0.01) greater effect than the non-complexed drug. EXPERT OPINION: The use of cyclodextrins can improve the efficacy of analgesic compounds, and they are an important tool in the search for greater analgesic effect. They may also be a way to reduce the therapeutic doses, and hence increasing the potential of the drug.

Evaluation of the anti-inflammatory and antinociceptive effects of the essential oil from leaves of Xylopia laevigata in experimental models.

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.

Antinociceptive activity of Syzygium cumini leaves ethanol extract on orofacial nociception protocols in rodents.

CONTEXT: Syzygium cumini (L.) Skeels (Myrtaceae) is a tree with dark purple fruits, popularly known as "jambolão" or "jambolan". In folk medicine, this plant is used for the treatment of diabetes and inflammatory conditions. OBJECTIVE: We investigated the antinociceptive effect of ethanol extract (EE) from S. cumini leaves on orofacial nociception. MATERIAL AND METHODS: The antinociceptive effects of the EE obtained from the leaves of S. cumini were evaluated in mice using formalin- and glutamate-induced orofacial nociception. RESULTS: ESI-MS/MS analyses demonstrated that major constituents in the analyzed samples coincided with the mass of the phenolic acids and flavonoids. In pharmacological approach, pre-treatment with EE (100, 200, or 400 mg/kg, p.o.) significantly reduced (p<0.05 or p<0.01) the percentage of paw licks time during phase 2 (43.2, 47.1, and 57.4%, respectively) of a formalin pain test when compared to control group animals. This effect was prevented by pretreatment with glibenclamide and N(G)-nitro-l-arginine (l-NOARG). The extract, all doses, also caused a marked inhibition (p<0.01 or p<0.001) of glutamate-induced orofacial nociception (38.8, 51.7, and 54.7%) when compared with the control group. No effect was observed with the rota-rod model. CONCLUSIONS: We can suggest that the antinociceptive effect of the EE is mediated by peripheral mechanisms, possibly involving KATP channels and the nitric oxide pathways. These effects appear to be related to the presence of flavonoids compounds, such as quercetin.

Cyclodextrin-complexed Ocimum basilicum leaves essential oil increases Fos protein expression in the central nervous system and produce an antihyperalgesic effect in animal models for fibromyalgia.

O. basilicum leaves produce essential oils (LEO) rich in monoterpenes. The short half-life and water insolubility are limitations for LEO medical uses. ß-Cyclodextrin (ß-CD) has been employed to improve the pharmacological properties of LEO. We assessed the antihyperalgesic profile of LEO, isolated or complexed in ß-CD (LEO/ß-CD), on an animal model for fibromyalgia. Behavioral tests: mice were treated every day with either LEO/ß-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-ßCD, 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 ß-CD, produces analgesic effects on chronic non-inflammatory pain as fibromyalgia.

Plants with anti-Leishmania activity: Integrative review from 2000 to 2011.

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.