The possible mechanisms of protocatechuic acid-induced central analgesia

Abstract

It is aimed to investigate the central antinociceptive effect of protocatechuic acid and the involvement of stimulation of opioidergic, serotonin 5-HT, α2-adrenergic and muscarinic receptors in protocatechuic acid-induced central analgesia in mice. Time-dependent antinociceptive effects of protocatechuic acid at the oral doses of 75, 150 and 300 mg/kg were tested in hot-plate (integrated supraspinal response) and tail-immersion (spinal reflex) tests in mice. To investigate the mechanisms of action; the mice administered 300 mg/kg protocatechuic acid (p.o.) were pre-treated with non-specific opioid antagonist naloxone (5 mg/kg, i.p.), serotonin 5-HT receptor antagonist ketanserin (1 mg/kg, i.p.), α2-adrenoceptor antagonist yohimbine (1 mg/kg, i.p.) and non-specific muscarinic antagonist atropine (5 mg/kg, i.p.), respectively. The antinociceptive effect of protocatechuic acid was observed at the doses of 75, 150 and 300 mg/kg in tail-immersion test, at the doses of 150 and 300 mg/kg in hot-plate test at different time interval. The enhancement in the latency of protocatechuic acid-induced response to thermal stimuli was antagonized by yohimbine, naloxone and atropine in tail-immersion test, while it was antagonized only by yohimbine and naloxone pretreatments in hot-plate test. These results indicated that protocatechuic acid has the central antinociceptive action that is probably organized by spinal mediated cholinergic and opiodiergic, also spinal and supraspinal mediated noradrenergic modulation. However, further studies are required to understand how protocatechuic acid organizes the interactions of these modulatory systems. As a whole, these findings reinforce that protocatechuic acid is a potential agent that might be used for pain relief. Additionally, the clarification of the effect and mechanisms of action of protocatechuic acid will contribute to new therapeutic approaches and provide guidance for new drug development studies.

Methanol Extract of Dicranopteris linearis Leaves Attenuate Pain via the Modulation of Opioid/NO-Mediated Pathway

“…As part of an attempt to establish the antinociceptive potential of D. linearis and to promote the use of medicinal plants as pain-relieving agent, MEDL was also subjected to phytoconstituents analyses using the UHPLC-ESI-HRMS and GC-MS methods to determine the presence of polyphenolics or any volatile bioactive compounds with potential antinociceptive activity, respectively. The UHPLC-ESI-HRMS analysis of MEDL leads to identification of approximately 30 polyphenolic compounds of which several of them, such as gallic acid [60,61], ferulic acid [62], protocatechuic acid [63], caffeic acid [64,65], p-coumaric acid [66], rutin [67,68], isoquercitrin [69], astragalin [70], catechin [71], quercetin [72,73], apigenin [74] and kaempferol [75], have been reported to show antinociceptive activity. These reports also revealed that: (i) gallic acid was reported to show low antinociceptive activity against the acetic acid-induced nociception [60] while its derivative (gallic acid ethyl ester) was reported to attenuate bradykininand formalin-induced nociception [61].…”

“…These reports also revealed that: (i) gallic acid was reported to show low antinociceptive activity against the acetic acid-induced nociception [60] while its derivative (gallic acid ethyl ester) was reported to attenuate bradykininand formalin-induced nociception [61]. In addition, gallic acid ethyl ester was ineffective in the hot-plate test and demonstrated partly the opioid/NO-independent action; (ii) ferulic acid exerts an opioid-mediated antinociceptive activity when assessed using the hot plate test [62]; (iii) protocatechuic acid also exerts an opioid-mediated antinociceptive activity when assessed using the hot plate test [63]; (iv) caffeic acid demonstrated the antinociceptive activity against the abdominal constriction test and the late phase of the formalin-induced nociception, but not the hot plate test [64] whereas the dodecyl ester derivative of caffeic acid were reported to produce antinociceptive activity against the abdominal constriction test as well as the formalin-, capsaicin-and glutamate-induced nociceptive model [65]; (v) rutin exerts antinociceptive activity when assessed using the abdominal constriction test and the formalin-induced nociception, respectively [66,67] with Hernandez-Leon et al [67] also showed that rutin produces an opioid-mediated antinociceptive activity only in the late phase of the formalin-induced test; (vi) isoquercitrin exhibits antinociceptive activity against the abdominal constriction and formalin tests [68]; (vii) astragalin demonstrates an opioid-mediated antinociceptive activity when assessed using the hot plate test and the formalin-induced nociception [69]; (viii) catechin produces antinociceptive activity against the abdominal constriction, hot plate and formalin-induced paw licking tests with an opioid-independent activity shown using the hot plate test [70]; (ix) quercetin was earlier reported to show an opioid-mediated antinociceptive activity when assessed using the hot plate test [71] while later study demonstrates that quercetin produces antinociceptive activity against the abdominal constriction test, as well as the formalin-, capsaicin-and glutamate-induced nociceptive tests that involves an interaction with l-arginine/NO pathway [72]; (x) apigenin was found to show antinociceptive activity against the abdominal constriction, hot plate and formalin-induced paw licking tests with the centrally-mediated opioid activity proven using the hot plate test [73]; and (xi) kaempferol derivatives (i.e., kaempferol 3-O-rutinoside, kaempferol 3-O-glucoside and kaempferol-3,7-di-O-α-l-rhamnopyranoside) was reported to exert antinociceptive activity against the abdominal constriction and formalin-induced paw licking tests [74,75]. In addition, Ali et al [75] also...…”

Beta-Sitosterol and Its Antinociceptive Mechanism Action

“…The later formula was applied in order to calculate maximal possible effect (MPE%) according to the results obtained by the hot-plate and tail-flick assays [22,23]. The maximal possible effect percentage ascertained by the response latency against thermal stimulus: MPE% = [{(Post-drug latency)−(Pre-drug latency)} / {(Cut-off time)−(Pre-drug latency)}] X100…”

Mechanism of antinociceptive action of syringic acid

“…The 20s were chosen as cut-off time in order to minimize hind paw damage. Finally, the mice behavior was recorded before treatment and after treatment [44].…”