GABA transporter type 1 (GAT-1) uptake inhibition reduces stimulated aspartate and glutamate release in the dorsal spinal cord in vivo via different GABAergic mechanisms.
Mechanisms through which the reported antinociceptive activity of GABA re-uptake inhibitors is mediated (and where on the sensory neuraxis) have not been defined. Here, microdialysis in the anaesthetised rat was used to examine the effect of selective GABA transporter type 1 (GAT-1) inhibition on basal and evoked amino acid release in the dorsal spinal cord. Reverse dialysis of the selective GAT-1 inhibitor NO-711 (10-300microM) induced a concentration-related increase in extracellular GABA (maximal approximately threefold of basal levels) without affecting other amino acids. Employing an S2/S1 paradigm, release evoked by brief high (45mM) K(+)-induced depolarisation of aspartate and glutamate, but not GABA or glycine, was found to be significantly reduced by reverse dialysis of NO-711 (300microM). Co-administration of selective antagonists for GABA(A) or GABA(B) receptors ((+)-bicuculline (100microM) or SCH 50911 (100microM), respectively) prevented the GAT-1 inhibition-induced reduction of evoked aspartate. In contrast, while (+)-bicuculline also antagonised the reduction of evoked glutamate, SCH 50911 (up to 1mM) was without effect. Inhibition of GAT-1 re-uptake was further found to play a permissive role in autoinhibitory effects on GABA release mediated through GABA(A) and GABA(B) receptors. These data demonstrate that augmentation of GABAergic neurotransmission by re-uptake inhibition activates pharmacologically distinguishable inhibitory influences on aspartate and glutamate release in the dorsal spinal cord. Thus, inhibition of spinal pro-nociceptive neurotransmitter release may contribute to the analgesic action of this drug class.
Smith
C G S
CG
Pain Signalling Group, Division of Neuroscience - Pharmacology, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Bowery
N G
NG
Whitehead
K J
KJ
D000704:Analysis of Variance; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D001640:Bicuculline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D050485:GABA Plasma Membrane Transport Proteins / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D017551:Microdialysis; D009025:Morpholines / Q000494:pharmacology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; D004338:Drug Combinations; D050485:GABA Plasma Membrane Transport Proteins; D009025:Morpholines; D014179:Neurotransmitter Uptake Inhibitors; D009557:Nipecotic Acids; D010091:Oximes; C078793:NNC 711; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D011189:Potassium Chloride; D001640:Bicuculline