Journal of pharmacological sciences
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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. ⋯ 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.