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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: (1 S,3 R)3-methylgabapentin (3-MeGBP) (IC50= 42 nM), which is effective in neuropathic pain models; and (1 R,3 R)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 (1 S,3 R)3-MeGBP inhibited tactile allodynia in the spinal nerve ligation model of neuropathic pain, whereas (1 R,3 R)3-MeGBP was ineffective. The antiallodynic effect of GBP, but not (1 S,3 R)3-MeGBP, was blocked by i.t. injection of the GABABreceptor antagonist [3-[[(3,4-dichlorophenyl)methyl]amino]propyl](diethoxymethyl)phosphinic acid (CGP52432). Systemic GBP or (1 S,3 R)3-MeGBP also inhibited the second phase of formalin-evoked nociceptive behaviors, whereas (1 R,3 R)3-MeGBP was ineffective. However, both (1 S,3 R)3-MeGBP and (1 R,3 R)3-MeGBP, but not GBP, inhibited first phase behaviors. In the carrageenan model of inflammatory pain, systemic GBP or (1 R,3 R)3-MeGBP failed to inhibit thermal hyperalgesia, whereas (1 S,3 R)3-MeGBP had a significant, albeit transient, effect. Systemic (1 S,3 R)3-MeGBP, but not GBP or (1 R,3 R)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 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) (IC(50) = 42 nM), which is effective in neuropathic pain models; and (1R,3R)3-MeGBP (IC(50) > 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 GABA(B) 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.

The anticonvulsive properties of pregnanolone (as an emulsion) were evaluated in mice and compared with similar properties of Althesin and thiopentone. Pregnanolone emulsion was found to antagonize convulsions induced by the GABA antagonists pentetrazole, bicuculline and picrotoxin and by the specific glycine receptor antagonist, strychnine. The drug was effective in all four convulsive tests at subanaesthetic doses with maximal activity appearing within less than 1 min. The anticonvulsive therapeutic indices of pregnanolone emulsion were superior when compared with the therapeutic indices of Althesin and thiopentone in all four tests. Pregnanolone emulsion might be a useful alternative drug in the management of convulsive states resistant to conventional therapy.