Acetic acid- and phenyl-p-benzoquinone-induced overt pain-like behavior depends on spinal activation of MAP kinases, PI(3)K and microglia in mice.
The acetic acid and phenyl-p-benzoquinone are easy and fast screening models to access the activity of novel candidates as analgesic drugs and their mechanisms. These models induce a characteristic and quantifiable overt pain-like behavior described as writhing response or abdominal contortions. The knowledge of the mechanisms involved in the chosen model is a crucial step forward demonstrating the mechanisms that the candidate drug would inhibit because the mechanisms triggered in that model will be addressed. Herein, it was investigated the role of spinal mitogen-activated protein (MAP) kinases ERK (extracellular signal-regulated kinase), JNK (Jun N-terminal Kinase) and p38, PI(3)K (phosphatidylinositol 3-kinase) and microglia in the writhing response induced by acetic acid and phenyl-p-benzoquinone, and flinch induced by formalin in mice. Acetic acid and phenyl-p-benzoquinone induced significant writhing response over 20 min. The nociceptive response in these models were significantly and in a dose-dependent manner reduced by intrathecal pre-treatment with ERK (PD98059), JNK (SB600125), p38 (SB202190) or PI(3)K (wortmannin) inhibitors. Furthermore, the co-treatment with MAP kinase and PI(3)K inhibitors, at doses that were ineffective as single treatment, significantly inhibited acetic acid- and phenyl-p-benzoquinone-induced nociception. The treatment with microglia inhibitors minocycline and fluorocitrate also diminished the nociceptive response. Similar results were obtained in the formalin test. Concluding, MAP kinases and PI(3)K are important spinal signaling kinases in acetic acid and phenyl-p-benzoquinone models of overt pain-like behavior and there is also activation of spinal microglia indicating that it is also important to determine whether drugs tested in these models also modulate such spinal mechanisms.
Departamento de Patologia, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rod. Celso Garcia Cid KM480 PR445, CEP 86051-990, Cx Postal 6001, Londrina, Paraná, Brazil.
Gabriela F
GF
Pavao-de-Souza
Ana C
AC
Zarpelon
Giovana C
GC
Tedeschi
Sandra S
SS
Mizokami
Joice S
JS
Sanson
Thiago M
TM
Cunha
Sérgio H
SH
Ferreira
Fernando Q
FQ
Cunha
Rubia
R
Casagrande
Waldiceu A
WA
Verri
D019342:Acetic Acid / Q000633:toxicity*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D016227:Benzoquinones / Q000633:toxicity*; D004195:Disease Models, Animal; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007278:Injections, Spinal; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D059225:Nociception / Q000187:drug effects / Q000502:physiology; D059226:Nociceptive Pain / Q000139:chemically induced / Q000503:physiopathology; D010146:Pain / Q000139:chemically induced* / Q000503:physiopathology*; D010147:Pain Measurement; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D000077191:Wortmannin
D019342:Acetic Acid; D000730:Androstadienes; D000873:Anthracenes; D016227:Benzoquinones; D005419:Flavonoids; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D000077191:Wortmannin; C432165:pyrazolanthrone; C029322:phenylbenzoquinone; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one