N-antipyrine-3, 4-dichloromaleimide, an effective cyclic imide for the treatment of chronic pain: the role of the glutamatergic system.
BACKGROUND
In recent years, cyclic imides have attracted the attention of the scientific community because of their promising therapeutic potential. Studies with the compound N-antipyrine-3,4-dichloromaleimide (NA-3,4-DCM) also demonstrated an antinociceptive effect in formalin or capsaicin models of nociception, and that it reduced acetic acid-induced abdominal writhing in mice.


METHODS
In this study, we examined the effects of NA-3,4-DCM on mechanical hypernociception in persistent pain-like behavioral models in mice. We also investigated the peripheral, topical, spinal, and supraspinal antinociceptive properties of NA-3,4-DCM and evaluated the involvement of the glutamatergic system on the antinociceptive effects of NA-3,4-DCM in mice.


RESULTS
NA-3,4-DCM, dosed systemically (intraperitoneally or per os), was capable of interfering with the development of mechanical hypernociception induced by intraplantar injection of carrageenan and complete Freund adjuvant in mice. Interestingly, repeated intraperitoneal or per os treatment with NA-3,4-DCM, administered after the induction of hypernociception, also reversed the mechanical sensitization induced by complete Freund adjuvant injection or partial ligation of the sciatic nerve in mice, with lower doses than gabapentin, a drug used clinically to treat chronic pain. When administered systemically, locally, spinally, or supraspinally, NA-3,4-DCM was able to inhibit the overt nociception of both phases of the formalin test. The systemic administration of NA-3,4-DCM also reduced the nociception induced by intraplantar or intrathecal injection of glutamate in mice. Furthermore, NA-3,4-DCM caused marked inhibition of the nociceptive response induced by intrathecal injection of a group I metabotropic glutamate receptors agonist (1S,3R)-aminocyclopentane-trans-1,3-dicardboxylic acid (ACPD) or N-methyl-d-aspartate (NMDA), without interfering with nociception induced by other non-NMDA receptor agonists (alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid and kainate) or by substance P. Notably, in the same range of doses, the antinociception caused by the compound NA-3,4-DCM was not associated with nonspecific effects such as changes in locomotor activity or motor coordination.


CONCLUSIONS
These results provide strong evidence that NA-3,4-DCM produces antihypernociception in mice at peripheral, spinal, and supraspinal sites, and that interaction with the group I metabotropic glutamate receptors and NMDA receptors contributes to the mechanisms underlying its effect.
Quintão
Nara L M
NL
Programa de Mestrado em Ciências Farmacêuticas, Universidade do Vale do Itajaí, Rua Uruguai, n 458, Bloco 27, CCS, Sala 314, CEP 88202-302, Itajaí, Santa Catarina, Brazil. nara.quintao@univali.br
da Silva
Gislaine F
GF
Antonialli
Carla S
CS
de Campos-Buzzi
Fátima
F
Corrêa
Rogerio
R
Filho
Valdir Cechinel
VC
D000284:Administration, Oral; D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000983:Antipyrine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D002351:Carrageenan; D002908:Chronic Disease; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005557:Formaldehyde; D005620:Freund's Adjuvant; D018698:Glutamic Acid / Q000378:metabolism*; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D011930:Reaction Time; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism; D012584:Sciatic Nerve / Q000601:surgery; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D000700:Analgesics; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C547867:N-antipyrine-3,4-dichloromaleimide; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D005557:Formaldehyde; D018698:Glutamic Acid; D002351:Carrageenan; D005620:Freund's Adjuvant; D000983:Antipyrine