TY - JOUR T1 - Comparison of the Antinociceptive Profiles of Gabapentin and 3-Methylgabapentin in Rat Models of Acute and Persistent Pain: Implications for Mechanism of Action JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 1209 LP - 1216 DO - 10.1124/jpet.104.081778 VL - 313 IS - 3 AU - M. O. Urban AU - K. Ren AU - K. T. Park AU - B. Campbell AU - N. Anker AU - B. Stearns AU - J. Aiyar AU - M. Belley AU - C. Cohen AU - L. Bristow Y1 - 2005/06/01 UR - http://jpet.aspetjournals.org/content/313/3/1209.abstract N2 - 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 α2δ 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 α2δ binding, likely does not completely account for the mechanism of action of GBP. The American Society for Pharmacology and Experimental Therapeutics ER -