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.

Antioxidant Activity, Molecular Docking, Quantum Studies and In Vivo Antinociceptive Activity of Sulfonamides Derived From Carvacrol

The synthesis and antioxidant, antinociceptive and antiedematogenic activities of sulfonamides derived from carvacrol—a druglike natural product—are reported. The compounds showed promising antioxidant activity, and sulfonamide derived from morpholine (S1) demonstrated excellent antinociceptive and antiedematogenic activities, with no sedation or motor impairment. The mechanism that underlies the carvacrol and derived sulfonamides’ relieving effects on pain has not yet been fully elucidated, however, this study shows that the antinociceptive activity can be partially mediated by the antagonism of glutamatergic signaling. Compound S1 presented promising efficacy and was predicted to have an appropriate medicinal chemistry profile. Thus, derivative S1 is an interesting starting point for the design of new leads for the treatment of pain and associated inflammation and prooxidative conditions.

Anti-oedematous and antinociceptive activities assessment of stem bark aqueous extract of Ficus exasperata Vahl. (Moraceae) in rat and mice.

Background: Ficus exasperata Vahl. (Moraceae) is widely used in African traditional medicine for the treatment of various diseases. The present study is undertaken to assess the anti-oedematous and antinociceptive activities of the stem bark aqueous extract of Ficus exasperata in mice and rats. Methods: The anti-oedematous activity was investigated following carrageenan or histamine-induced rat paw oedema models. Antinociceptive activity was evaluated using acetic acid induced writhing test (1 %, 10 ml/kg), capsaicin-induced neurogenic pain (32 µg/mL, 30 µL) and formalin-induced test (1%, 20 µL). Extract was administrated orally at 37.5, 75 and 150 mg/kg. Results: Pre-treatment of rats with Ficus exasperata stem bark aqueous extract exhibited significant inhibition of paw oedema during all the phases of both carrageenan and histamine induced edema in rat. The maximum inhibition percentages were 94.75 % (3 h) and 30.64 % after one hour at the dose of 37.5 mg/kg, respectively, in carrageenan or histamine models. Antinociceptive activity showed that aqueous extract reduced significantly (p < 0.001) the pain induced by acetic acid with an inhibition percentage of 70.8% (150 mg/kg). In the formalin-induced test, the extract also reduced significantly (p < 0.001) licking time during neurogenic phase and inflammatory phase with inhibition percentages of 44.75% and 52.78% respectively at the dose of 75 and 150 mg/kg. In addition, aqueous extract of F. exasperata reduced significantly (p < 0.001) neurogenic pain induced by capsaïcin by 71.28 % at the highest dose (150 mg/kg). Conclusion: This finding suggests that the stem bark aqueous extract of Ficus exasperata possess potent anti-oedematous and antinociceptive activities.

Synthesis and Antinociceptive Effect of Some Thiazole-Piperazine Derivatives: Involvement of Opioidergic System in the Activity

In this study, we aimed to design and synthesize novel molecules carrying both the thiazole and piperazine rings in their structures and to investigate their antinociceptive activity. Targeted compounds were obtained by reacting thiosemicarbazide derivative and appropriate 2-bromoacetophenone in ethanol. The structures of the obtained compounds were determined using data from various spectroscopic methods (IR, 1H-NMR, 13C-NMR, and LCMSMS). Experimental data from in vivo tests showed that test compounds 3a–3c, 3f, and 3g (50 mg/kg) significantly prolonged reaction times of animals in tail-clip and hot-plate tests compared to the controls, indicating that these compounds possess centrally mediated antinociceptive activities. Furthermore, these compounds reduced the number of writhing behaviors in the acetic acid-induced writhing tests, showing that the compounds also possess peripheral antinociceptive activity. In the mechanistic studies, naloxone pre-treatments abolished the antinociceptive activities of compounds 3a–3c, 3f, and 3g, indicating that opioidergic mechanisms were involved in their antinociceptive effects. Molecular docking studies demonstrating significant interactions between the active compounds and µ- and δ-opioid receptor proteins supported the pharmacological findings. This study is the first showing that molecules designed to bear thiazole and piperazine moieties together on their structure exert centrally and peripherally mediated antinociceptive effects by activating the opioid system.