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

0022-3565/05/3133-1209-1216$20.00
JPET 313:1209-1216, 2005
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NEUROPHARMACOLOGY

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

M. O. Urban, K. Ren, K. T. Park, B. Campbell, N. Anker, B. Stearns, J. Aiyar, M. Belley, C. Cohen, and L. Bristow

Departments of Pharmacology and Chemistry, Merck Research Laboratories, San Diego, California (M.O.U., K.R., K.T.P., B.C., N.A., B.S., J.A., C.C., L.B.); and Department of Chemistry, Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada (M.B.)

The anticonvulsant gabapentin (GBP) has been shown 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{delta} subunit of voltage-gated calcium channels contributes to its antinociceptive effect, based on the stereoselective efficacy of two analogs: (1S,3R)3-methylgabapentin (3-MeGBP) (IC50 = 42 nM), which is effective in neuropathic pain models; and (1R,3R)3-MeGBP (IC50 > 10,000 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 [3-[[(3,4-dichlorophenyl)methyl]amino]propyl](diethoxymethyl)phosphinic acid (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{delta} binding, likely does not completely account for the mechanism of action of GBP.

Received for publication December 3, 2004
Accepted January 18, 2005.

Address correspondence to: Dr. Mark O. Urban, Merck Research Laboratories, WP46-300, West Point, PA 19486. E-mail: mark_urban{at}merck.com




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