Oral treatment with essential oil of Hyptis spicigera Lam. (Lamiaceae) reduces acute pain and inflammation in mice: Potential interactions with transient receptor potential (TRP) ion channels.

ETHNOPHARMACOLOGICAL RELEVANCE: The genus Hyptis comprehends almost 400 species widespread in tropical and temperate regions of America. The use of Hyptis spicigera Lam. (Lamiaceae) is reported in traditional medicine due to its gastroprotective, anti-inflammatory and analgesic properties. AIM OF THE STUDY: The rationale of this study was to investigate the potential use of the essential oil of H. spicigera (EOHs) as analgesic. MATERIAL AND METHODS: The antinociceptive effect of EOHs was verified analyzing acute nocifensive behavior of mice induced by chemical noxious stimuli [i.e., formalin and transient receptor potential (TRP) channels agonists]. We also verified the effects of EOHs on locomotor activity and motor performance in mice. Finally, we investigate the involvement of central afferent C-fibers with EOHs analgesic effect. RESULTS: EOHs presented antinociceptive effect at 300 and 1000mg/kg on formalin-induced pain behavior model, presenting 50% and 72% of inhibition during the first phase (ED50 =292mg/kg), and 85% and 100% during de second phase (ED50 =205mg/kg), respectively. Temperature of the hind paw was reduced by EOHs treatment in a dose-dependent manner; oedema was diminished only by EOHs 1000mg/kg. EOHs does not impaired locomotor activity or motor performance. For mice injected with capsaicin, a TRPV1 activator, EOHs (1000mg/kg, ED50 =660mg/kg) showed decreased (63%) nociceptive behavior. When injected with cinnamaldehyde (TRPA1 activator), mice treated with EOHs showed 23%, 43% and 66% inhibition on nociceptive behavior (100, 300 and 1000mg/kg, respectively; ED50 402mg/kg). When mice were injected with menthol (TRPM8 activator), EOHs showed 29%, 59% and 98% inhibition of nociceptive behavior (100, 300 and 1000mg/kg, respectively; with ED50 =198mg/kg. Finally, when desensitized mice were injected with menthol, EOHs (300mg/kg) does not show antinociceptive effect. CONCLUSIONS: This study demonstrated the efficacy of EOHs on experimental models of nociception. We have found the involvement of TRP channels V1, A1 and M8 with EOHs activity, which was remarkably potent and efficient in inhibiting pain evoked by menthol, a TRPM8 channel activator. TRPM8 channels from TRPV1+ C-fibers, but not TRPM8+ C-fibers nor TRPM8+ Aδ mechanosensory fibers, mediate EOHs analgesic effects.

Antidepressant-like effect of pramipexole in an inflammatory model of depression.

Pramipexole (PPX), a dopamine D2/3 receptor preferring agonist, is currently in use for the treatment of Parkinson's disease symptoms and restless legs syndrome. Recently, anti-inflammatory properties of PPX have been shown in an autoimmune model of multiple sclerosis, and case reports indicate PPX ameliorates depressive symptoms. Since peripheral inflammation is known to induce depression-like behavior in rodents, we assessed the potential antidepressant effect of PPX in an inflammatory model of depression induced by LPS. Repeated (daily for 7days, 1mg/kg, i.p.), but not acute (1h before LPS) treatment with PPX abolished the depression-like behavior induced by LPS (0.1mg/kg, i.p.) in the forced swim test, and the anhedonic behavior in the splash test. Interestingly, PPX per se decreased interleukin 1ß levels and reversed LPS-induced increase in its content in mice hippocampus⋅ Repeated PPX treatment also prevented the increase in hippocampal levels of the 3-nitrotyrosine protein adducts induced by LPS. Haloperidol (0.2mg/kg, i.p.) and sulpiride (50mg/kg, i.p.) were unable to prevent the antidepressant-like effect of PPX in LPS-treated mice. Altogether, these results suggest that the observed antidepressant-like effect of PPX in LPS-treated mice may be dependent on its anti-inflammatory properties and may not be related to dopamine D2 receptor activation.

The nociception induced by glutamate in mice is potentiated by protons released into the solution.

UNLABELLED: In this study we compare the effect of a glutamate solution with pH adjusted to 7 (3-30 micromol/paw), a non-pH-adjusted glutamate solution (.3-30 micromol/paw, pH range 2.24-1.14), and an acid solution (2% acetic acid, pH 1.4-7) in terms of causing licking behavior in mice. The sum of licking seconds was recorded in the first 15 minutes following the intraplantar (i.pl.) injection of the solutions. Protons potentiated the nociception induced by glutamate. The ED(50) values were 2.5 (1.5-4.2) and 15.1 (11.5-19.9) micromol/paw for the non-pH-adjusted and pH-adjusted glutamate solutions, respectively. The acid solutions at pH 1.4, 2 and 4 induced a similar nociception. The blocking of the acid-sensitive ion channels (ASICs) by amiloride and the antagonism of the transient receptor potential vanilloid subtype-1 (TRPV1) by capsazepine, injected via i.pl., significantly decreased the nociception mediated by acid and by non-pH-adjusted glutamate solutions, but did not affect the nociception caused by the pH-adjusted glutamate solution. The pretreatment with the NMDA-receptor antagonist (MK-801, i.pl.), with the cyclooxygenase inhibitor (indomethacin, i.pl.) or the disruption of the sensorial C fibers by capsaicin, decreased the nociceptive effect of the 3 algogen tested. In summary, the protons present in aqueous solution of glutamate can cause nociception per se or can potentiate the nociception caused by glutamate. These effects are related to the activation of ASICs, TRPV1 and NMDA receptors, inhibition of the synthesis of prostanoids, and disruption of the C fibers. PERSPECTIVE: The nociception induced by glutamate is a useful method for investigation of the mechanisms of nociception and the effects of new analgesic drugs. Our findings showed that the protons released from glutamic acid have to be removed from the solution to avoid misinterpretation of results in the search for new analgesic drugs.