Jullyana de Souza Siqueira Quintans

Monoterpenes with Analgesic Activity—A Systematic Review

There is still the need for efficacious therapies for pain. In the search for new therapeutic options, plants are a major source of novel biomolecules. Monoterpenes constitute 90% of essential oils, and there is a growing interest in understanding the mechanisms underlying their pharmacological activity. This systematic review reports what is so far known about the analgesic activity of monoterpenes and also provides an overview of their mechanisms of action. The search terms analgesia, anti‐inflammatory, anaesthetic and antioxidant were used to retrieve English language articles in SCOPUS, PUBMED and EMBASE published between 1990 and 2012. Forty‐five papers were found concerning the potential analgesic activity of 27 monoterpenes. The data reviewed here suggest these compounds are possible candidates for the treatment of painful conditions. Copyright

Effect of low-level laser therapy on pain levels in patients with temporomandibular disorders: a systematic review

Temporomandibular disorders (TMD) are characterized by the presence of temporomandibular joint (TMJ) and/or masticatory muscle pain and dysfunction. Low-level laser is presented as an adjuvant therapeutic modality for the treatment of TMD, especially when the presence of inflammatory pain is suspected. Objective To systematically review studies that investigated the effect of low level laser therapy (LLLT) on the pain levels in individuals with TMD. Material and Methods The databases Scopus, embase, ebsco and PubMed were reviewed from January/2003 to October/2010 with the following keywords: laser therapy, low-level laser therapy, temporomandibular joint disorders, temporomandibular joint dysfunction syndrome, temporomandibular joint, temporomandibular, facial pain and arthralgia, with the inclusion criteria for intervention studies in humans. exclusion criteria adopted were intervention studies in animals, studies that were not written in english, Spanish or Portuguese, theses, monographs, and abstracts presented in scientific events. Results After a careful review, 14 studies fit the criteria for inclusion, of which, 12 used a placebo group. As for the protocol for laser application, the energy density used ranged from 0.9 to 105 J/cm2, while the power density ranged from 9.8 to 500 mW. The number of sessions varied from 1 to 20 and the frequency of applications ranged from daily for 10 days to 1 time per week for 4 weeks. A reduction in pain levels was reported in 13 studies, with 9 of these occurring only in the experimental group, and 4 studies reporting pain relief for both the experimental group and for the placebo. Conclusion Most papers showed that LLLT seemed to be effective in reducing pain from TMD. However, the heterogeneity of the standardization regarding the parameters of laser calls for caution in interpretation of these results. Thus, it is necessary to conduct further research in order to obtain a consensus regarding the best application protocol for pain relief in patients with TMD.

Improvement of p-cymene antinociceptive and anti-inflammatory effects by inclusion in β-cyclodextrin.

Previously, we have demonstrated the analgesic-like property of p-cymene in rodents. Short half-life is a limitation for p-cymene application and several approaches have been used to improve pharmaceutical properties of monoterpenes, including the employment of drug-delivery systems. Here, we used p-cymene/β-cyclodextrin (β-CD) complex and p-cymene (PC) isolated to evaluated whether the complex formulation is able to improve the antinociceptive activity of this monoterpene. Male mice (26-30g) were pretreated with PC/β-CD (20 or 40mg/kg, p.o.), PC (20 or 40mg/kg, p.o.) or vehicle (distilled water), 0.5h before painful tests and antinociceptive effect was evaluated at times: 0.5, 1, 2, 4, 8, and 16h after treatment. We evaluated the analgesic-like effect of PC/β-CD and PC in acetic acid-induced abdominal writhes, hot-plate, carrageenan-induced paw edema and in rota-rod apparatus. Our results demonstrated that acute treatment with complex PC/β-CD produced an antinocicepitve effect (p<0.01 or p<0.001) for 8h followed whereas isolated PC produced the same effect for 2h. Similar results were obtained in hot-plate test, PC/β-CD, in all doses, significantly reduces (p<0.01 or p<0.001) nociceptive behavior for 8h while isolated PC for 1h, did so only in higher dose. Such results were unlikely to be caused by motor abnormality. Systemic pretreatment with PC/β-CD and PC inhibited the development paw edema by carrageenan 1%, but PC/β-CD did so during a longer period when compared with isolated monoterpene alone. Our results provide evidence to propose that the complex with β-CD improved analgesic and anti-inflammatory effects of p-cymene.

Borneol, a Bicyclic Monoterpene Alcohol, Reduces Nociceptive Behavior and Inflammatory Response in Mice

Borneol, a bicyclic monoterpene, has been evaluated for antinociceptive and anti-inflammatory activities. Antinociceptive and anti-inflammatory activities were studied by measuring nociception by acetic acid, formalin, hot plate, and grip strength tests, while inflammation was prompted by carrageenan-induced peritonitis. The rotarod test was used to evaluate motor coordination. Borneol produced a significant (P < 0.01) reduction of the nociceptive behavior at the early and late phases of paw licking and reduced the writhing reflex in mice (formalin and writhing tests, resp.). When the hot plate test was conducted, borneol (in higher dose) produced an inhibition (P < 0.05) of the nociceptive behavior. Such results were unlikely to be provoked by motor abnormality. Additionally, borneol-treated mice reduced the carrageenan-induced leukocytes migration to the peritoneal cavity. Together, our results suggest that borneol possess significant central and peripheral antinociceptive activity; it has also anti-inflammatory activity. In addition, borneol did not impair motor coordination.

Antinociceptive Activity and Redox Profile of the Monoterpenes (+)-Camphene, p-Cymene, and Geranyl Acetate in Experimental Models

Objective. To evaluate antinocicpetive and redox properties of the monoterpenes (+)-camphene, p-cymene, and geranyl acetate in in vivo and in vitro experimental models. Methods. Evaluation of the in vitro antioxidant activity of (+)-camphene, p-cymene, and geranyl acetate using different free radical-generating systems and evaluation of antinociceptive actions by acetic acid-induced writhing and formalin-induced nociception tests in mice. Results. p-Cymene has the strongest antinociceptive effect, but (+)-camphene and geranyl acetate also present significant activity at high doses (200 mg/kg). (+)-Camphene had the strongest antioxidant effect in vitro at TBARS and TRAP/TAR assays and also had the highest scavenging activities against different free radicals, such as hydroxyl and superoxide radicals. Sodium nitroprussiate-derived NO production was enhanced by (+)-camphene. Geranyl acetate and p-cymene also presented some antioxidant effects, but with a varying profile according the free radical-generating system studied. Conclusion. (+)-Camphene, p-cymene, and geranyl acetate may present pharmacological properties related to inflammation and pain-related processes, being potentially useful for development of new therapeutic strategies, with limited possibilities for p-cymene and geranyl acetate.

β‐Cyclodextrin Complex Containing Lippia grata Leaf Essential Oil Reduces Orofacial Nociception in Mice – Evidence of Possible Involvement of Descending Inhibitory Pain Modulation Pathway

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.

Natural Products Evaluated in Neuropathic Pain Models - A Systematic Review

Chronic pain conditions, such as neuropathic pain, are a common problem that poses a major challenge to health‐care providers due to its complex natural history, unclear aetiology and poor response towards therapy. Despite the large number of drugs available, the adherence is limited by the large range of side effects and pharmacological ineffectiveness. Thus, the search for new chemical entities that can act as promising molecules to treat chronic pain conditions has emerged. The natural products remain as the most promising sources of new chemical entities with applicability for the medical approach. Hence, we performed a systematic review analysing pre‐clinical studies shown to be promising in a possible applicability in neuropathic pain. The search terms neuropathic pain, phytotherapy and medicinal plants were used to retrieve English language articles in LILACS, PUBMED and EMBASE published until 10 April 2013. From a total of 1529 articles surveyed, 28 met the inclusion and exclusion criteria established. The main chemical compounds studied were flavonoids (28%), terpenes (17%), alkaloids (14%), phenols (10%), carotenoids (10%) and others (21%). The mostly described animal models for the study of neuropathic pain included were chronic constriction injury (CCI – 32%), partial sciatic nerve ligation (PSNL – 28%), streptozotocin – induced diabetic (28%), alcoholic neuropathy (3.5%), sodium monoiodoacetate (MIA – 3.5%) and neuropathic pain induced by paclitaxel (3.5%). The opioids, serotonergic and cannabinoid systems are suggested as the most promising targets for the natural products described. Therefore, the data reviewed here suggest that these compounds are possible candidates for the treatment of chronic painful conditions, such as neuropathic pain.

Inclusion of terpenes in cyclodextrins: Preparation, characterization and pharmacological approaches

Terpenes constitute the largest class of natural products and are important resources for the pharmaceutical, food and cosmetics industries. However, due to their low water solubility and poor bioavailability there has been a search for compounds that could improve their physicochemical properties. Cyclodextrins (natural and derived) have been proposed for this role and have been complexed with different types of terpenes. This complexation has been demonstrated by using analytical techniques for characterizing complexes such as DSC, NMR, XRD, FTIR, and TGA. The formation of inclusion complexes has been able to improve drug characteristics such as bioavailability, solubility and stability; and to enhance biological activity and efficacy. This review shows strong experimental evidence that cyclodextrins improve the pharmacological properties of terpenes, and therefore need to be recognized as being possible targets for clinical use.

The Role of Flavonoids on Oxidative Stress in Epilepsy

Backgrounds. Oxidative stress can result from excessive free-radical production and it is likely implicated as a possible mechanism involved in the initiation and progression of epileptogenesis. Flavonoids can protect the brain from oxidative stress. In the central nervous system (CNS) several flavonoids bind to the benzodiazepine site on the GABAA-receptor resulting in anticonvulsive effects. Objective. This review provides an overview about the role of flavonoids in oxidative stress in epilepsy. The mechanism of action of flavonoids and its relation to the chemical structure is also discussed. Results/Conclusions. There is evidence that suggests that flavonoids have potential for neuroprotection in epilepsy.

Evidence for the Involvement of Descending Pain-Inhibitory Mechanisms in the Antinociceptive Effect of Hecogenin Acetate

Hecogenin is a sapogenin present in the leaves of species from the Agave genus, with a wide spectrum of reported pharmacological activities. The present study was undertaken to evaluate whether hecogenin acetate (1) has antinociceptive properties and to determine its mechanism of action. The nociceptive threshold was evaluated using the tail flick test in mice. Mice motor performance was evaluated in a Rotarod test. By using Fos expression as a marker of neural activation, the involvement of the periaqueductal gray in 1-induced antinociception was evaluated. Intraperitoneal administration of 1 (5-40 mg/kg) produced a dose-dependent increase in the tail flick latency time compared to vehicle-treated group (p < 0.01). Mice treated with 1 (40 mg/kg) did not show motor performance alterations. The antinociception of 1 (40 mg/kg) was prevented by naloxone (nonselective opioid receptor antagonist; 5 mg/kg), CTOP (μ-opioid receptor antagonist; 1 mg/kg), nor-BNI (κ-opioid receptor antagonist; 0.5 mg/kg), naltrindole (δ-opioid receptor antagonist; 3 mg/kg), or glibenclamide (ATP-sensitive K(+) channel blocker; 2 mg/kg). Systemic administration of 1 (5-40 mg/kg) increased the number of Fos positive cells in the periaqueductal gray. The present study has demonstrated for the first time that 1 produces consistent antinociception mediated by opioid receptors and endogenous analgesic mechanisms.