ABSTRACT Orofacial pain is related to tissues of the head, face, neck and all the intraoral structures; it is rather debilitating to the patient and also difficult to treat. There are relatively few studies dedicated to the use of natural products to alleviate orofacial pain in preclinical experiment models (performed in experimental animals which provide support for clinical trials). Main objectives of the present systematic review summarize the studies on natural products assessed in animal models for orofacial pain seeking to give evidence to future development of new pharmaceutical products to manage the orofacial pain. Our review includes a thorough search of literature using the terms of orofacial pain, facial pain, medicinal plants and natural products. This search was performed using to retrieve English language articles in Medline-PubMed, Scopus and Web of Science. A total of eighteen studies were included in our survey for the inclusion criteria. Firstly, this review identified 210 citations from electronic search, after removal of duplicates and screening for relevant titles and abstracts, a total of eighteen articles were selected to the inclusion criteria established. Our findings suggest that natural products can be a promising or a trump tool for the development of new drugs to treat orofacial pain conditions, but the researchers that deal with experimental preclinical trials of new drugs (including natural products or synthetic drugs) for orofacial pain conditions urgently need to show translational evidence (with clinical approach) of these compounds.

The aim of this study was to investigate the wound healing activity of atranorin cream (Patent requested) on excision wounds. Seventy-two male rats were anesthetized and an excisional wound was performed. Then the rats were randomly assigned into three groups: untreated control group; atranorin 1 (group treated with 1% AT ointment); and atranorin 5 (group treated with 5% AT ointment). Six animals of each group were euthanized 3, 7, 14 or 21 days after surgical procedures and the wounded areas were analyzed and removed. Serial histological sections were obtained and stained by histochemical techniques (Hematoxilin-Eosin-HEand Sirius red) and immunohistochemical techniques. Topical application of atranorin reduced wound areas, induced earlier granulation tissue formation, increased cell proliferation, improved collagenization and modulated the myofibroblasts differentiation when compared to control animals. It is suggested that atranorin modulates the wound healing process. These data suggest that this formulation based on atranorin extracted from Cladina kalbii AHTI may be a new biotechnological product for wound healing clinical applications.

This study investigated the possible antinociceptive effect of p-cymene in different tests of orofacial nociception. The animals (mice) were pretreated (i.p.) with p-cymene (25, 50, 100 mg/kg), morphine (5 mg/kg), or vehicle (0.2% Tween 80+saline), and were then subsequently administered, subcutaneously into their upper lip: formalin, capsaicin, and glutamate. The nociceptive behavior response was characterized by the time in s that the mice remained rubbing the orofacial region, for a period of 40 min in the formalin test (first phase, 0-6 min; and second phase, 21-40 min), and for 42 and 15 min in the capsaicin and glutamate tests, respectively. To verify the possible opioid involvement in the antinociceptive effects, naloxone (i.p.) was administered into the mice 15 min prior to the pretreatment with p-cymene (100 mg/kg). Finally, whether or not the p-cymene evoked any change in motor performance in the Rota-rod test was evaluated. The results showed that the treatment with p-cymene, at all doses, reduced (p<0.001) the nociceptive behavior in all nociception tests. The antinociceptive effect of p-cymene was antagonized by naloxone (1.5 mg/kg). Additionally, mice treated with p-cymene did not show any change in motor performance. In conclusion, p-cymene attenuated orofacial nociception, suggesting an involvement of the opioid system in this effect. Thus, p-cymene might represent an important biomolecule for management and/or treatment of orofacial pain.

The monoterpenes are secondary metabolites of plants. They have various pharmacological properties including antifungal, antibacterial, antioxidant, anticancer, anti-spasmodic, hypotensive, and vasorelaxant. The purpose of this research was to review the cardiovascular effects of monoterpenes. The data in this resarch were collected using the Internet portals Pubmed, Scopus, and ISI Web of Knowledge between the years 1987 and 2010. In the study 33 monoterpenes were included, which were related to each of the thirteen individual words: artery, cardiovascular, heart, myocyte, vasorelaxant, vessel, hypotension, hypotensive, cardiomyocyte, ventricular, vasodilatory, aorta, and aortic. The research utilized 22 articles published mainly in the journals Phytomedicine, Fundamental Clinical Pharmacology, Planta Medica, Life Science, European Journal of Pharmacology, and Brazilian Journal of Medical and Biological Research. Of the 33 monoterpenes studied surveyed, sixteen of them had already been studied for their effects on the cardiovascular system: carvacrol, citronellol, p-cymene, eucalyptol (1,8-cineole), linalool, menthol, myrtenal, myrtenol, α-pinene, rotundifolone (piperitenone oxide), sobrerol, thymol, α-limonene, α-terpinen-4-ol, α-terpineol, and perillyl alcohol. The main effects observed were vasorelaxation, decreased heart rate and blood pressure. This review showed that the monoterpenes may be considered promising agents for prevention or treatment of diseases of the cardiovascular system.

The central nervous system (CNS) depressant and anticonvulsant activities of citronellal (CT) were investigated in animal models. The CT in doses of 100, 200 and 400 mg/kg injected by i.p. route in mice caused a significant decrease in the motor activity of animals when compared with the control group. The highest dose of CT significantly reduced the remaining time of the animals on the Rota-rod apparatus up to 2 h. Additionally, CT at doses 100, 200 and 400 mg/ kg (i.p.) was also capable to promote an increase of latency for development of convulsions induced by pentylenetetrazole (PTZ). It was efficient in prevents the tonic convulsions induced by maximal electroshock (MES) in doses of 200 and 400 mg/kg, resulting in 30 and 40% of protection, respectively. This compound was also capable to promote an increase of latency for development of convulsions induced by picrotoxin (PIC) at 400 mg/kg. In the same way, the anticonvulsant effect of CT was affected by pretreatment with flumazenil, a selective antagonist of benzodiazepine site of GABA A receptor. These results suggest a possible CNS depressant and anticonvulsant activities.

The present work investigated the antinociceptive and antiinflammatory activities of the Porophyllum ruderale (Jacq.) Cass., Asteraceae, aqueous extract (PRAE). For this purpose, acetic acid writhing, paw licking induced by formalin, hot-plate and pleurisy tests were performed. The doses of 100, 200 and 400 mg/kg (p.o.) significantly inhibited the writhing 63.4, 89.6 and 94.8%, respectively, in comparison with control group. The lick of the paw 1st phase was reduced at the dose of 400 mg/ kg (24.9%), while the 2nd phase had reduction at doses 200 and 400 mg/ kg (23.1 and 34.4%), respectively. The PRAE inhibited the carrageenaninduced neutrophil migration to the peritoneal cavity in a higher dose (p<0.05). Taken together, our results suggest that the PRAE can constitute target potential for use in therapies of the pain and inflammation.

Citral (CIT), which contains the chiral enantiomers, neral (cis) and geranial (trans), is the majority monoterpene from Lippia alba and Cymbopogon citratus. The present study aimed to evaluate CIT for antinociceptive and anti-inflammatory activities in rodents. Antinociceptive and anti-inflammatory effects were studied by measuring nociception through acetic acid and formalin tests, while inflammation was verified by inducing peritonitis and paw edema with carrageenan. All tested doses of CIT had significant protection (p<0.001) against acetic acid (0.8%) induced nociceptive behavior and the effects were also similar to morphine while formalin induced nociception was significantly protected (p<0.05) only at higher dose (200 mg/kg) of CIT in the first phase of the test. CIT significantly reduce (p<0.001) nociceptive behavior emanating from inflammation in second phase at all the doses.The pretreatment with CIT (100 and 200 mg/kg) significantly reduced the paw edema induced by carrageenan. Moreover, systemic treatment with CIT (100 and 200 mg/kg) significantly reduced (p<0.001) the leukocyte migration in the carrageenan-induced migration to the peritoneal cavity. Our investigation shows that CIT possess significant central and peripheral antinociceptive effects. It was also verified an anti-inflammatory activity. All together these results suggest that CIT might represent important tool for treatment of painful conditions.

The aims of the present study were to assess the influence of: a) trait anxiety on orofacial pain; and b) orofacial pain on state anxiety. Forty-four rats were initially exposed to the free-exploratory paradigm for the evaluation of their anxiety profiles. In accordance to the parameter "Percentage of time in the novel side", the animals were considered as presenting high or low levels of trait anxiety when presenting values below the 1st quartile, or above the 3rd quartile, respectively. A week later, formalin-1.5% was injected into the upper lip of each animal. The behavioural nociceptive response, characterized by increased orofacial rubbing (OR), was quantified for 30 minutes, as follows: Total time OR (0-30 minutes: total pain), 1st phase OR (0-6 minutes: neurogenic pain), and 2nd phase OR (12-30 minutes: inflammatory pain). Immediately after this test, but still under the effect of formalin, the rats were submitted to the Elevated Plus-maze test (EPM). The results showed that the high trait anxiety individuals presented higher frequency of OR than the low trait anxiety ones, except during the neurogenic pain period. However, no correlation was found between OR frequency and levels of state anxiety presented on the EPM. In conclusion, the animals presenting higher anxiety profiles were the most susceptible to orofacial pain, nevertheless, orofacial pain did not influence state anxiety.