Centrally-mediated antinociceptive actions of GABA(A) receptor agonists in the rat spared nerve injury model of neuropathic pain.
Gamma aminobutyric acid (GABA) plays a major role in the central hyperexcitabilty associated with nerve damage. The precise antinociceptive actions mediated by GABA(A) receptor agonists remain unclear as previous studies have shown mixed results in neuropathic pain models. Thus, various drugs which modulate GABA(A) receptor function were tested in the rat spared nerve injury (SNI) model of neuropathic pain. The selective GABA(A) receptor agonist gaboxadol dose-dependently (6 and 15 mg/kg, s.c.) reversed hindpaw mechanical allodynia and hyperalgesia for at least 150 min after administration. The GABA(A) receptor agonist muscimol (0.02-2 mg/kg, s.c.) also dose-dependently reversed mechanical allodynia, although the maximal effect achieved was less than that observed for gaboxadol. Mechanical hyperalgesia was attenuated only by the highest dose of muscimol. In contrast, the selective GABA(A) receptor agonist isoguvacine (20 mg/kg, s.c.) which has poor central nervous system penetration, and the benzodiazepine-site ligand zolpidem (20 mg/kg, s.c.) were ineffective against either nociceptive behaviour. In the rotarod test, both gaboxadol (15 mg/kg) and zolpidem impaired motor function for at least 60 min after injection; muscimol (2 mg/kg) and gaboxadol (6 mg/kg) were ineffective. Importantly, the ataxic effects induced by gaboxadol resolved 1-2 h after administration, a time point where clear antiallodynic and antihyperalgesic actions still occurred. Thus, systemic administration of blood-brain penetratable selective GABA(A) receptor agonists attenuate nociceptive behaviours in the SNI rat model of neuropathic pain that can be considered to occur independently of other effects on motor function.
Rode
Frederik
F
Danish University of Pharmaceutical Sciences, Department of Pharmacology, Jagtvej 120, Copenhagen, Denmark. FR@dfuni.dk
Jensen
Dorthe G
DG
Blackburn-Munro
Gordon
G
Bjerrum
Ole J
OJ
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D007539:Isonicotinic Acids / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D009437:Neuralgia / Q000209:etiology / Q000517:prevention & control*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000502:physiology; D013314:Stress, Mechanical; D013997:Time Factors; D020196:Trauma, Nervous System / Q000150:complications*; D000077334:Zolpidem
D000700:Analgesics; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D007539:Isonicotinic Acids; D007555:Isoxazoles; D011725:Pyridines; D011963:Receptors, GABA-A; D009118:Muscimol; D000077334:Zolpidem; C015542:gaboxadol; C015300:isoguvacine