Does gabapentin act as an agonist at native GABA(B) receptors?
Gabapentin, a novel anticonvulsant and analgesic, is a gamma-aminobutyric acid (GABA) analogue but was shown initially to have little affinity at GABA(A) or GABA(B) receptors. It was recently reported to be a selective agonist at GABA(B) receptors containing GABA(B1a)-GABA(B2) heterodimers, although several subsequent studies disproved that conclusion. In the present study, we examined whether gabapentin is an agonist at native GABA(B) receptors using a rat model of postoperative pain in vivo and periaqueductal gray (PAG) slices in vitro; PAG contains GABA(B) receptors, and their activation results in antinociception. An intrathecal injection of gabapentin or baclofen, a GABA(B) receptor agonist, induced antiallodynia in this postoperative pain model. Intrathecal injection of GABA(B) receptor antagonists CGP 35348 and CGP 55845 antagonized baclofen- but not gabapentin-induced antiallodynia. In ventrolateral PAG neurons, baclofen activated G-protein-coupled inwardly rectifying K(+) (GIRK) channels in a manner blocked by CGP 35348 or CGP 55845. However, gabapentin displayed no effect on the membrane current. In neurons unaffected by gabapentin, baclofen activated GIRK channels through GABA(B) receptors. It is concluded that gabapentin is not an agonist at GABA(B) receptors that are functional in baclofen-induced antiallodynia in the postoperative pain model in vivo and in GIRK channel activation in ventrolateral PAG neurons in vitro.
Cheng
Jen-Kun
JK
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
Lee
Sun-Zhi
SZ
Yang
Jia-Rung
JR
Wang
Chien-Hua
CH
Liao
Yan-Yu
YY
Chen
Chien-Chuan
CC
Chiou
Lih-Chu
LC
D000588:Amines / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D000077206:Gabapentin; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010721:Phosphinic Acids / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; D010721:Phosphinic Acids; D011412:Propanolamines; C085075:CGP 55845A; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; C066430:CGP 35348