Pharmacological profiles of the novel analgesic M58996 in rat models of persistent and neuropathic pain.
We investigated the effects of 4-(N-{1-[2-(4-cyanophenyl)ethyl]-4-hydroxypiperidin-4-ylmethyl}-N-methylamino)benzoic acid monohydrochloride (M58996), a novel analgesic, on persistent and neuropathic pain in rats. In the formalin test, oral M58996 (0.3 - 10 mg/kg) reduced nociceptive behaviors only in the late phase. In the neuropathic pain model, oral M58996 (1 - 10 mg/kg) attenuated mechanical allodynia and heat hyperalgesia in the nerve-injured paw without affecting normal responses of the uninjured paw. High doses (10 - 100 mg/kg) of oral M58996 did not influence normal motor function. Thus, M58996 had a wide dose range showing antinociceptive, antiallodynic, and antihyperalgesic effects without motor dysfunction. In addition, we studied the possible mechanisms involved in the M58996-induced antinociception. The antinociceptive effect of M58996 was reversed by intrathecal pertussis toxin, an inhibitor of the inhibitory- and other-GTP-binding protein (G(i/o) protein), but not by subcutaneous naloxone, an opioid-receptor antagonist. This effect was also reversed by intracerebroventricular or intrathecal tropisetron, a 5-hydroxytryptamine(3) (5-HT(3))-receptor antagonist, and intraperitoneal bicuculline, a gamma-aminobutyric acid(A) (GABA(A))-receptor antagonist. These results suggest that M58996 produces its antinociceptive effect by a pertussis toxin-sensitive G protein mechanism. In addition, the GABA released by the activation of supraspinal and/or spinal 5-HT(3) receptors is likely to contribute to the M58996-induced antinociception.
Akada
Yasushige
Y
Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd., Japan. yakada@mochida.co.jp
Mori
Reiko
R
Matsuura
Kazuyuki
K
Suzuki
Kazuhiro
K
Kato
Kazuo
K
Kamiya
Masatsugu
M
Naba
Hiroyasu
H
Kurokawa
Misao
M
Ogihara
Takuo
T
Kato
Yutaka
Y
Yamasaki
Fumiaki
F
Yamamoto
Ichiro
I
D010129:4-Aminobenzoic Acid / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000284:Administration, Oral; D000700:Analgesics / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015306:Biogenic Monoamines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010147:Pain Measurement; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D062366:para-Aminobenzoates
C515660:4-(N-(1-(2-(4-cyanophenyl)ethyl)-4-hydroxypiperidin-4-ylmethyl)-N-methylamino)benzoic acid; D000700:Analgesics; D015306:Biogenic Monoamines; D010880:Piperidines; D018079:Receptors, GABA; D062366:para-Aminobenzoates; D010129:4-Aminobenzoic Acid