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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on February 25, 2005; DOI: 10.1124/jpet.104.081778

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Received for publication December 7, 2004.
Revised January 14, 2005.
Accepted for publication January 18, 2005.

Comparison of the Antinociceptive Profiles of Gabapentin and 3-Methylgabapentin in Rat Models of Acute and Persistent Pain: Implications for Mechanism of Action

Mark O. Urban 1*, Kunkun Ren 1, Kenneth T Park 1, Brian Campbell 1, Naomi Anker 1, Brian Stearns 1, Jayashree Aiyar 1, Michel Belley 1, Charles Cohen 1, Linda Bristow 1

1 Merck Research Laboratories

* Address correspondence to: E-mail: mark_urban{at}merck.com

Abstract

The anticonvulsant gabapentin (GBP) has been shown to be effective for the treatment of neuropathic pain, although its mechanism of action remains unclear. A recent report has suggested that binding to the {alpha}2{sigma} subunit of voltage gated calcium channels contributes to its antinociceptive effect, based on the stereoselective efficacy of two analogs: (1S,3R)3-MeGBP (IC50=42 nM) which is effective in neuropathic pain models, and (1R,3R)3-MeGBP (IC50>10000 nM) which is ineffective (Field et al., 2000). The present study was designed to further examine the profiles of GBP and 3-MeGBP in rat models of acute and persistent pain. Systemic administration of GBP or (1S,3R)3-MeGBP inhibited tactile allodynia in the spinal nerve ligation model of neuropathic pain, whereas (1R,3R)3-MeGBP was ineffective. The antiallodynic effect of GBP, but not (1S,3R)3-MeGBP, was blocked by i.t. injection of the GABAB receptor antagonist CGP52432. Systemic GBP or (1S,3R)3-MeGBP also inhibited the second phase of formalin-evoked nociceptive behaviors, whereas (1R,3R)3-MeGBP was ineffective. However, both (1S,3R)3-MeGBP and (1R,3R)3-MeGBP, but not GBP, inhibited first phase behaviors. In the carrageenan model of inflammatory pain, systemic GBP or (1R,3R)3-MeGBP failed to inhibit thermal hyperalgesia, whereas (1S,3R)3-MeGBP had a significant albeit transient effect. Systemic (1S,3R)3-MeGBP, but not GBP or (1R,3R)3-MeGBP, also produced an antinociceptive effect in the warm water tail withdrawal test of acute pain. These data demonstrate that GBP and 3-MeGBP display different antinociceptive profiles, suggesting dissimilar mechanisms of antinociceptive action. Thus, the stereoselective efficacy of 3-MeGBP, presumably related to {alpha}2{sigma}binding, likely does not completely account for the mechanism of action of GBP.


Key words: 3-methylgabapentin, allodynia, gabapentin, hyperalgesia, inflammation, neuropathy


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