GABA uptake inhibitors produce a greater antinociceptive response in the mouse tail-immersion assay than other types of GABAergic drugs.
Antinociception produced by the GABA uptake inhibitors d,l- SKF-89976A and SKF-100330A was characterized and compared to that produced by other types of GABAergic drugs. Using the mouse tail-immersion assay it was found that the antinociception produced by the uptake inhibitors was antagonized by scopolamine, a cholinergic muscarinic receptor antagonist. However, neither SKF compound demonstrated any significant affinity for muscarinic receptor binding sites suggesting that they are not direct-acting cholinomimetics. In vitro uptake experiments revealed that the SKF compounds selectively inhibit GABA transport, having no effect on the accumulation of aspartic acid, glutamic acid, beta-alanine or glycine. Moreover, antinociception and GABA uptake inhibition were stereoselective for SKF-89976A, with the d-isomer being more active in both tests. When comparing antinociceptive responses at maximally effective doses it was also found that the SKF compounds were substantially more efficacious than direct-acting GABA receptor agonists or a GABA transaminase inhibitor. These data suggest that uptake inhibitors may be facilitating GABA transmission in a system that is less affected by other types of GABAergic compounds.
D000700:Analgesics; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D018756:GABA Antagonists; D008297:Male; D051379:Mice; D009539:Nicotinic Acids / Q000494:pharmacology*; D009557:Nipecotic Acids / Q000494:pharmacology*; D010095:Oxotremorine / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology*; D013623:Tail; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000700:Analgesics; D018756:GABA Antagonists; D009539:Nicotinic Acids; D009557:Nipecotic Acids; D005680:gamma-Aminobutyric Acid; D010095:Oxotremorine; C045598:N-(4,4-diphenyl-3-butenyl)nipecotic acid; C045597:SK&F 100330-A