Comparison of the Antinociceptive Profiles of Gabapentin and 3-Methylgabapentin in Rat Models of Acute and Persistent Pain: Implications for Mechanism of Action
| العنوان: | Comparison of the Antinociceptive Profiles of Gabapentin and 3-Methylgabapentin in Rat Models of Acute and Persistent Pain: Implications for Mechanism of Action |
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| المؤلفون: | Kenneth T. Park, Kunkun Ren, Brian T. Campbell, Linda J. Bristow, Brian Andrew Stearns, Mark O. Urban, Charles J. Cohen, Michel Belley, Naomi Anker, Jayashree Aiyar |
| المصدر: | Journal of Pharmacology and Experimental Therapeutics. 313:1209-1216 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2005. |
| سنة النشر: | 2005 |
| مصطلحات موضوعية: | Male, Benzylamines, Cyclohexanecarboxylic Acids, Gabapentin, medicine.drug_class, medicine.medical_treatment, Pain, Acetates, Pharmacology, Rats, Sprague-Dawley, medicine, Animals, Amines, gamma-Aminobutyric Acid, Analgesics, Voltage-dependent calcium channel, business.industry, Receptor antagonist, Phosphinic Acids, Rats, Disease Models, Animal, Anticonvulsant, Nociception, Receptors, GABA-B, Mechanism of action, Hyperalgesia, Acute Disease, Chronic Disease, Neuropathic pain, Molecular Medicine, medicine.symptom, business, medicine.drug |
| الوصف: | 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. |
| تدمد: | 1521-0103 0022-3565 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::909b14cc05004ab7958d224b66f0bc69 https://doi.org/10.1124/jpet.104.081778 |
| رقم الأكسشن: | edsair.doi.dedup.....909b14cc05004ab7958d224b66f0bc69 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210103 00223565 |
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