title: Comparison of the antinociceptive profiles of gabapentin and 3-methylgabapentin in rat models of acute and persistent pain: implications for mechanism of action.
abstract: 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.
authors.affiliation: Department of Pharmacology and Chemistry, Merck Research Laboratories, San Diego, CA, USA. mark_urban@merck.com
authors.forename: M O
authors.initials: MO
authors.lastname: Urban
authors.forename: K
authors.initials: K
authors.lastname: Ren
authors.forename: K T
authors.initials: KT
authors.lastname: Park
authors.forename: B
authors.initials: B
authors.lastname: Campbell
authors.forename: N
authors.initials: N
authors.lastname: Anker
authors.forename: B
authors.initials: B
authors.lastname: Stearns
authors.forename: J
authors.initials: J
authors.lastname: Aiyar
authors.forename: M
authors.initials: M
authors.lastname: Belley
authors.forename: C
authors.initials: C
authors.lastname: Cohen
authors.forename: L
authors.initials: L
authors.lastname: Bristow
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000208:Acute Disease; D000588:Amines / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002908:Chronic Disease; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004195:Disease Models, Animal; D000077206:Gabapentin; D006930:Hyperalgesia / Q000188:drug therapy; D008297:Male; D010146:Pain / Q000188:drug therapy*; D010721:Phosphinic Acids / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018080:Receptors, GABA-B / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: C420103:3-methylgabapentin; D000085:Acetates; D000588:Amines; D000700:Analgesics; D001596:Benzylamines; D003509:Cyclohexanecarboxylic Acids; D010721:Phosphinic Acids; D018080:Receptors, GABA-B; C083008:CGP 52432; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin