Antinociceptive activity of a synthetic oxopyrrolidine-based compound, ASH21374, and determination of its possible mechanisms

This study was carried out to determine the antinociceptive activity of a novel synthetic oxopyrrolidine-based compound, (2R,3R,4S)-ethyl 4-hydroxy-1,2-dimethyl-5-oxopyrrolidine-3-carboxylate (ASH21374), and to elucidate the involvement of the opioid, vanilloid, glutamate, and nitric oxide – cyclic guanosine monophosphate (NO/cGMP) systems in modulating the observed antinociception. ASH21374, in the doses of 2, 10, and 100 mg/kg body mass, was administered orally to mice 60 mins prior to exposure to various antinociceptive assays. From the results obtained, ASH21374 exhibited significant (P < 0.05) antinociceptive activity in the abdominal constriction, hot-plate, and formalin tests that was comparable with 100 mg/kg acetylsalicylic acid or 5 mg/kg morphine, respectively. ASH21374 also attenuated capsaicin- and glutamate-induced paw licking. Pre-treatment with 5 mg/kg naloxone significantly (P < 0.05) inhibited the activity in all assays, while pretreatment with 10 mg/kg β-funaltraxamine, 1 mg/kg naltrindole, or 1 mg/kg nor-binaltorphimine significantly (P < 0.05) reversed the activity in the abdominal constriction test. l-Arginine, NG-nitro-l-arginine methyl esters (l-NAME), methylene blue, and their combinations, failed to inhibit the ASH21374 antinociceptive activity. In conclusion, ASH21374 demonstrated antinociceptive activities on the peripheral and central nervous systems, mediated through the activation of opioid receptors, inhibition of the glutamatergic system, and attenuation of vanilloid-mediated nociceptive transmission. Further studies have been planned to determine the pharmacological potential of ASH21374.

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Mechanisms of α-Mangostin-Induced Antinociception in a Rodent Model

Biological Research For Nursing ◽

10.1177/1099800414529648 ◽

2014 ◽

Vol 17 (1) ◽

pp. 68-77 ◽

Cited By ~ 8

Author(s):

Mohd. Hijaz Mohd. Sani ◽

Muhammad Taher ◽

Deny Susanti ◽

Teh Lay Kek ◽

Mohd. Zaki Salleh ◽

...

Keyword(s):

Methylene Blue ◽

Methyl Esters ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Glutamatergic System ◽

Vanilloid Receptors ◽

Hot Plate ◽

Hot Plate Test ◽

Plate Test ◽

Abdominal Constriction

Objective: Elucidate the antinociceptive mechanisms of α-mangostin isolated from Garcinia malaccensis Linn. Methods: Male mice/rats ( n = 6/group) were used in this between-group study. To determine α-mangostin’s antinociceptive profile, animals were given α-mangostin orally (3, 30, or 100 mg/kg) 60 min before the start of the abdominal constriction or formalin tests. In the hot plate test, the noxious stimulus was applied before and 60, 90, 120, 150, 180, and 210 min after treatment with test solutions. Positive controls received 100 mg/kg acetylsalicylic acid (ASA; oral) or 5 mg/kg morphine (intraperitoneal injection) for the abdominal constriction and hot plate tests, respectively, and either ASA or morphine for the formalin test. Negative controls received vehicle only. To explore α-mangostin’s mechanisms of action, we performed (i) the hot plate test with naloxone (5 mg/kg) pretreatment to verify involvement of opioid receptors; (ii) the abdominal constriction test with 20 mg/kg l-arginine, NG-nitro-l-arginine methyl esters (l-NAME), methylene blue (MB), l-arginine plus l-NAME, or l-arginine plus MB or 10 mg/kg glibenclamide pretreatment to verify involvement of the l-arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) and K+-ATP pathways; and (iii) the paw-licking test using capsaicin (1.6 μg capsaicin/paw), glutamate (10 μmol glutamate/paw), or phorbol 12-myristate 13-acetate (PMA; 0.05 µg/paw) to verify involvement of vanilloid receptors, the glutamatergic system, and protein kinase C (PKC). Results: α-mangostin significantly inhibited nociception ( p < .05) in all models. Only naloxone, l-arginine, methylene blue, PMA, and glibenclamide affected α-mangostin antinociception significantly ( p < .05). Conclusion: α-mangostin exhibits peripheral and central antinociception through modulation of opioid and vanilloid receptors, the glutamatergic system, and the l-arginine/NO/cGMP/PKC/K+-ATP pathways.

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Antinociceptive Activity of Methanol Extract ofMuntingia calaburaLeaves and the Mechanisms of Action Involved

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/890361 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 18

Author(s):

M. H. Mohd. Sani ◽

Z. A. Zakaria ◽

T. Balan ◽

L. K. Teh ◽

M. Z. Salleh

Keyword(s):

Methanol Extract ◽

Methyl Esters ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Antinociceptive Activity ◽

Opioid Antagonist ◽

Hot Plate Test ◽

No Donor ◽

Cgmp Pathway

Muntingia calaburaL. (family Elaeocarpaceae) has been traditionally used to relieve various pain-related ailments. The present study aimed to determine the antinociceptive activity of methanol extract ofM. calaburaleaves (MEMC) and to elucidate the possible mechanism of antinociception involved. Thein vivochemicals (acetic acid-induced abdominal constriction and formalin-, capsaicin-, glutamate-, serotonin-induced paw licking test) and thermal (hot plate test) models of nociception were used to evaluate the extract antinociceptive activity. The extract (100, 250, and 500 mg/kg) was administered orally 60 min prior to subjection to the respective test. The results obtained demonstrated that MEMC produced significant (P<0.05) antinociceptive response in all the chemical- and thermal-induced nociception models, which was reversed after pretreatment with 5 mg/kg naloxone, a non-selective opioid antagonist. Furthermore, pretreatment with L-arginine (a nitric oxide (NO) donor), NG-nitro-L-arginine methyl esters (L-NAME; an inhibitor of NO synthase (NOS)), methylene blue (MB; an inhibitor of cyclic-guanosine monophosphate (cGMP) pathway), or their combination also caused significant (P<0.05) change in the intensity of the MEMC antinociception. In conclusion, the MEMC antinociceptive activity involves activation of the peripheral and central mechanisms, and modulation via, partly, the opioid receptors and NO/cGMP pathway.

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Possible Participation of Ionotropic Glutamate Receptors and l-Arginine-Nitric Oxide-Cyclic Guanosine Monophosphate-ATP-Sensitive K+ Channel Pathway in the Antinociceptive Activity of Cardamonin in Acute Pain Animal Models

Molecules ◽

10.3390/molecules25225385 ◽

2020 ◽

Vol 25 (22) ◽

pp. 5385

Author(s):

Chung Pui Ping ◽

Muhammad Nadeem Akhtar ◽

Daud Ahmad Israf ◽

Enoch Kumar Perimal ◽

Mohd Roslan Sulaiman

Keyword(s):

Nitric Oxide ◽

Glutamate Receptors ◽

Cyclic Guanosine Monophosphate ◽

Nmda Receptor Antagonist ◽

Guanosine Monophosphate ◽

Antinociceptive Activity ◽

K Channel ◽

Kinase C ◽

Nmda Glutamate Receptors ◽

Pre Treatment

The perception of pain caused by inflammation serves as a warning sign to avoid further injury. The generation and transmission of pain impulses involves various pathways and receptors. Cardamonin isolated from Boesenbergia rotunda (L.) Mansf. has been reported to exert antinociceptive effects in thermal and mechanical pain models; however, the precise mechanism has yet to be examined. The present study investigated the possible mechanisms involved in the antinociceptive activity of cardamonin on protein kinase C, N-methyl-d-aspartate (NMDA) and non-NMDA glutamate receptors, l-arginine/cyclic guanosine monophosphate (cGMP) mechanism, as well as the ATP-sensitive potassium (K+) channel. Cardamonin was administered to the animals intra-peritoneally. Present findings showed that cardamonin significantly inhibited pain elicited by intraplantar injection of phorbol 12-myristate 13-acetate (PMA, a protein kinase C activator) with calculated mean ED50 of 2.0 mg/kg (0.9–4.5 mg/kg). The study presented that pre-treatment with MK-801 (NMDA receptor antagonist) and NBQX (non-NMDA receptor antagonist) significantly modulates the antinociceptive activity of cardamonin at 3 mg/kg when tested with glutamate-induced paw licking test. Pre-treatment with l-arginine (a nitric oxide precursor), ODQ (selective inhibitor of soluble guanylyl cyclase) and glibenclamide (ATP-sensitive K+ channel inhibitor) significantly enhanced the antinociception produced by cardamonin. In conclusion, the present findings showed that the antinociceptive activity of cardamonin might involve the modulation of PKC activity, NMDA and non-NMDA glutamate receptors, l-arginine/nitric oxide/cGMP pathway and ATP-sensitive K+ channel.

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Improved method for the determination of cyclic guanosine monophosphate (cGMP) in human plasma by LC–MS/MS

Journal of Chromatography B ◽

10.1016/j.jchromb.2009.12.009 ◽

2010 ◽

Vol 878 (3-4) ◽

pp. 487-491 ◽

Cited By ~ 13

Author(s):

Jens Martens-Lobenhoffer ◽

Christin Dautz ◽

Stefanie M. Bode-Böger

Keyword(s):

Human Plasma ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Improved Method

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Methanolic Extract ofClinacanthus nutansExerts Antinociceptive Activity via the Opioid/Nitric Oxide-Mediated, but cGMP-Independent, Pathways

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2016/1494981 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 15

Author(s):

Mohammad Hafiz Abdul Rahim ◽

Zainul Amiruddin Zakaria ◽

Mohd Hijaz Mohd Sani ◽

Maizatul Hasyima Omar ◽

Yusnita Yakob ◽

...

Keyword(s):

Nitric Oxide ◽

Antinociceptive Effect ◽

Soluble Guanylyl Cyclase ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Antinociceptive Activity ◽

Opioid Antagonist ◽

Clinacanthus Nutans ◽

Synthase Inhibitor

The objectives of the present study were to determine the mechanisms of antinociceptive effect of methanol extract ofClinacanthus nutans(Acanthaceae) leaves (MECN) using various animal nociceptive models. The antinociceptive activity of orally administered 10% DMSO, 100 mg/kg acetylsalicylic acid (ASA), 5 mg/kg morphine, or MECN (100, 250, and 500 mg/kg) was determined using the acetic acid-induced abdominal constriction (ACT), formalin-induced paw licking (FT), and hot plate tests (HPT). The role of opioid and nitric oxide/cyclic guanosine monophosphate (NO/cGMP) systems was also investigated. The results showed that MECN produced a significant (p<0.05) antinociceptive response in all nociceptive models with the recordedED50value of 279.3 mg/kg for the ACT, while, for the early and late phases of the FT, the value was >500 mg/kg or 227.7 mg/kg, respectively. This antinociceptive activity was fully antagonized by naloxone (a nonselective opioid antagonist) but was partially reversed byL-arginine (L-arg; a nitric oxide [NO] precursor), Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME; an NO synthase inhibitor), or their combinations thereof. In contrast, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ; a soluble guanylyl cyclase inhibitor) enhanced the extract’s antinociception. UHPLC analysis revealed the presence of several flavonoid-based compounds with antinociceptive action. In conclusion, MECN exerted the peripherally and centrally mediated antinociceptive activity via the modulation of the opioid/NO-mediated, but cGMP-independent, systems.

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