Antinociceptive esters of N-methylanthranilic acid: Mechanism of action in heat-mediated pain.
Recently, we identified a new natural antinociceptive alkaloid ternanthranin, isopropyl N-methylanthranilate (ISOAN), from the plant species Choisya ternata Kunth (Rutaceae). In this work we concentrated on the elucidation of its mechanism of action in comparison with two other esters of this acid (methyl (MAN) and propyl (PAN)). Mice orally pre-treated with ISOAN, MAN or PAN (at 0.3, 1 and 3mg/kg) were less sensitive to chemical or thermal stimuli in different nociception models (formalin-, capsaicin- and glutamate-induced licking response, tail flick and hot plate). All compounds (1 and 3mg/kg) showed significant activity in the peripheral nociception models, as well as a dose-dependent spinal antinociceptive effect in the tail flick model. We observed that glibenclamide was able to reverse the antinociceptive effect of ISOAN in the hot plate model suggesting the involvement of K(+)ATP channels. The antinociceptive effect of MAN and PAN may be related to adrenergic, nitrergic and serotoninergic pathways. In addition, the antinociception of PAN was reverted by naloxone implying that the opioid pathway participates in its activity. The cholinergic and cannabinoid systems were found not be involved in the onset of the antinociceptive effects of any of the esters. In conclusion, isopropyl, methyl and propyl N-methylanthranilates produced significant peripheral and central antinociception at doses lower than that of morphine, the classical opioid analgesic drug, without causing toxicity.
Universidade Federal do Rio de Janeiro, Instituto de Ciências Biomédicas, Laboratório de Farmacologia da Dor e da Inflamação, Rio de Janeiro, Brazil.
Mariana Martins Gomes
MM
Pinheiro
Department of Chemistry, Faculty of Science and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia.
Niko S
NS
Radulović
Department of Chemistry, Faculty of Science and Mathematics, University of Niš, Višegradska 33, 18000 Niš, Serbia.
Ana B
AB
Miltojević
School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
Fabio
F
Boylan
Universidade Federal do Rio de Janeiro, Instituto de Ciências Biomédicas, Laboratório de Farmacologia da Dor e da Inflamação, Rio de Janeiro, Brazil.
Patrícia
P
Dias Fernandes
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002211:Capsaicin; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005557:Formaldehyde; D018698:Glutamic Acid; D006358:Hot Temperature; D054086:KATP Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009292:Narcotic Antagonists / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010146:Pain / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control* / Q000523:psychology; D058748:Pain Perception / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D013997:Time Factors; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
D000700:Analgesics; D054086:KATP Channels; D009292:Narcotic Antagonists; D018377:Neurotransmitter Agents; D026902:Potassium Channel Blockers; C568549:isopropyl N-methylanthranilate; D062367:ortho-Aminobenzoates; D005557:Formaldehyde; D018698:Glutamic Acid; C412492:methyl N-methylanthranilate; D002211:Capsaicin
Analgesia; Antinociceptive activity; N-methylanthranilates; Pain; Ternanthranin