Antinociceptive Effects of Aza-Bicyclic Isoxazoline-Acylhydrazone Derivatives in Different Models of Nociception in Mice

Background: In a study recently published by our research group, the compounds isoxazoline-acylhydrazone derivatives R-99 and R-123 presented promising antinociceptive activity. However, the mechanism of action of this compound is still unknown. Objective: This study aimed to assess the mechanisms involved in the antinociceptive activity of these compounds in chemical models of pain. Methods: Animals were orally pretreated and evaluated in the acetic acid-, formalin-, capsaicin-, carrageenan- and Complete Freund's Adjuvant (CFA)-induced pain models in mice. The effects of the compounds after pretreatment with naloxone, prazosin, yohimbine, atropine, L-arginine, or glibenclamide were studied, using the acetic acid-induced writhing test to verify the possible involvement of opioid, α1-adrenergic, α2-adrenergic or cholinergic receptors, and nitric oxide or potassium channels pathways, respectively. Results: R-99 and R-123 compounds showed significant antinociceptive activity on pain models induced by acetic acid, formalin, and capsaicin. Both compounds decreased the mechanical hyperalgesia induced by carrageenan or CFA in mice. The antinociceptive effects of R-99 and R-123 on the acetic acid-induced writhing test were significantly attenuated by pretreatment with naloxone, yohimbine or atropine. R-99 also showed an attenuated response after pretreatment with atropine and glibenclamide. However, on the pretreatment with prazosin, there was no change in the animals' response to both compounds. Conclusion: R-99 and R-123 showed antinociceptive effects related to mechanisms that involve, at least in part, interaction with the opioid and adrenergic systems and TRPV1 pathways. The compound R-99 also interacts with the cholinergic pathways and potassium channels.

Antidiarrheal Effect of Zornia brasiliensis Vogel (Leguminosae) on Mice Involves Adrenergic Pathway Activation

Several secondary metabolites have been isolated from Zornia brasiliensis (Leguminosae), mainly flavonoids. These compounds are known for many pharmacological actions, such as antispasmodic and antidiarrheal. Therefore, we evaluated the antidiarrheal effect of the ethanolic extract obtained from Zornia brasiliensis aerial parts (ZB-EtOHAP), as well as its underlying mechanisms. Castor-oil-induced diarrhea, fluid accumulation, and intestinal transit (normal and castor oil induced) were performed to assess the antidiarrheal, antisecretory, and antipropulsive activities of the extract. The involvement of opioid and adrenergic pathways was also investigated. ZB-EtOHAP inhibited, in a dose-dependent manner, both total defecation frequency and the number of watery stools. The extract showed no effect on fluid accumulation or normal intestinal transit. On the other hand, when the animals were pretreated with castor oil, the extract decreased the distance traveled by the marker in the small intestine. Investigation of the involvement of opioid and adrenergic systems showed that the pharmacological potency of the extract did not change in the presence of naloxone, but it was reduced in the presence of yohimbine. The data indicate that Zornia brasiliensis has an antidiarrheal effect due to inhibition of the intestinal motility through adrenergic pathway activation.

A mechanistic approach to anti-nociceptive potential of Nymphaea lotus Linn (Nymphaeaceae) in rodents

Background: Nymphaea lotus Linn. (Nymphaeaceae), commonly known as white water-lily, white lotus or Egyptian lotus, is an important and well-known medicinal plant, widely used in the Ayurveda and Siddha systems of medicine for the treatment of diabetes, inflammation, liver disorders, urinary disorders, fever, skin diseases, cancer, gonorrhoea, pain and bronchitis. Objective: The study was designed to explore anti-nociceptive potential of aqueous extract of Nymphaea lotus leaf, its possible mechanism of action, and antioxidant properties. Methods: The anti-nociceptive activity of Nymphaea lotus (50, 100 and 250 mg/kg) was explored using writhing, formalin, tail clip and hot plate tests, while formalin test was used to investigate the involvement of opioid, dopamine, serotonin, K+ channel blocker, α1-adrenergic and α2- adrenergic systems. The antioxidant effect was carried out using DPPH, nitric oxide free radical scavenging activity and the reducing power effect. Total phenolic and flavonoids contents were also explored. Results: Oral administration of N. lotus in doses of 50, 100 and 250 mg/kg recorded a significant (p<0.05) dose dependent obstruction of nociception. A remarkable effect was recorded with the writhing and formalin tests and a significant effect was also observed in the tail clip and hot plate test, which suggests peripheral and central anti-nociceptive activity of the extract. The anti-nociceptive effect produced by N. lotus was significantly reversed by naloxone and yohimbine, suggesting the possible involvement of opioid and α2–adrenergic systems in its anti-nociceptive activity. N. lotus also displayed a potent antioxidant activity. Conclusion: These findings justify the folkloric use of N. lotus in pain management.

An Update on the Neurochemistry of Essential Tremor

Background: The pathophysiology and neurochemical mechanisms of essential tremor (ET) are not fully understood, because only a few post-mortem studies have been reported, and there is a lack of good experimental model for this disease. Objective: The main aim of this review is to update data regarding the neurochemical features of ET. Alterations of certain catecholamine systems, the dopaminergic, serotonergic, GABAergic, noradrenergic, and adrenergic systems have been described, and are the object of this revision. Methods: For this purpose, we performed a literature review on alterations of the neurotransmitter or neuromodulator systems (catecholamines, gammaaminobutyric acid or GABA, excitatory amino acids, adenosine, T-type calcium channels) in ET patients (both post-mortem or in vivo) or in experimental models resembling ET. Results and Conclusion: The most consistent data regarding neurochemistry of ET are related with the GABAergic and glutamatergic systems, with a lesser contribution of adenosine and dopaminergic and adrenergic systems, while there is not enough evidence of a definite role of other neurotransmitter systems in ET. The improvement of harmaline-induced tremor in rodent models achieved with T-type calcium channel antagonists, cannabinoid 1 receptor, sphingosine-1-phosphate receptor agonists, and gap-junction blockers, suggests a potential role of these structures in the pathogenesis of ET.