Pharmacological Profiles of the Novel Analgesic M58996 in Rat Models of Persistent and Neuropathic Pain

• Main Authors: Yasushige Akada (Author), Reiko Mori (Author), Kazuyuki Matsuura (Author), Kazuhiro Suzuki (Author), Kazuo Kato (Author), Masatsugu Kamiya (Author), Hiroyasu Naba (Author), Misao Kurokawa (Author), Takuo Ogihara (Author), Yutaka Kato (Author), Fumiaki Yamasaki (Author), Ichiro Yamamoto (Author)
• Format: Book
• Published: Elsevier, 2006-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 (Gi/o protein), but not by subcutaneous naloxone, an opioid-receptor antagonist. This effect was also reversed by intracerebroventricular or intrathecal tropisetron, a 5-hydroxytryptamine3 (5-HT3)-receptor antagonist, and intraperitoneal bicuculline, a γ-aminobutyric acidA (GABAA)-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-HT3 receptors is likely to contribute to the M58996-induced antinociception. Keywords:: neuropathic pain, allodynia, formalin test, 5-HT3 receptor, GABAA receptor

Item Description

1347-8613
10.1254/jphs.FP0060621