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 i...

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Bibliographic Details
Published in:	Journal of Pharmacological Sciences Vol. 102; no. 2; pp. 205 - 212
Main Authors:	Akada, Yasushige, Mori, Reiko, Matsuura, Kazuyuki, Suzuki, Kazuhiro, Kato, Kazuo, Kamiya, Masatsugu, Naba, Hiroyasu, Kurokawa, Misao, Ogihara, Takuo, Kato, Yutaka, Yamasaki, Fumiaki, Yamamoto, Ichiro
Format:	Journal Article
Language:	English
Published:	Japan Elsevier B.V 2006 The Japanese Pharmacological Society Elsevier
Subjects:	4-Aminobenzoic Acid - adverse effects 4-Aminobenzoic Acid - pharmacology 4-Aminobenzoic Acid - therapeutic use 5-HT3 receptor Administration, Oral allodynia Analgesics - adverse effects Analgesics - pharmacology Analgesics - therapeutic use Animals Behavior, Animal - drug effects Biogenic Monoamines - metabolism Disease Models, Animal Dose-Response Relationship, Drug formalin test GABAA receptor Male Motor Activity - drug effects neuropathic pain Pain - drug therapy Pain - metabolism Pain - physiopathology Pain Measurement para-Aminobenzoates Piperidines - adverse effects Piperidines - pharmacology Piperidines - therapeutic use Rats Rats, Wistar Receptors, GABA - metabolism Sciatic Neuropathy - drug therapy Sciatic Neuropathy - metabolism Sciatic Neuropathy - physiopathology neuropathic pain allodynia GABAA receptor formalin test 5-HT3 receptor
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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.
ISSN:	1347-8613 1347-8648
DOI:	10.1254/jphs.FP0060621