Gabapentin produces PKA-dependent pre-synaptic inhibition of GABAergic synaptic transmission in LC neurons following partial nerve injury in mice.
We have previously demonstrated that gabapentin supraspinally activates the descending noradrenergic system to ameliorate pain hypersensitivity in mice with partial nerve ligation. To clarify the supraspinal mechanism of action of gabapentin, whole-cell patch-clamp recordings were performed on locus coeruleus (LC) neurons in brainstem slices prepared from mice after peripheral nerve injury or mice subjected to a sham-operation, and the effects of gabapentin in the modulation of synaptic transmission were studied. Bath application of gabapentin (10, 30 and 100 muM) in a concentration-dependent manner reduced the GABA(A) receptor-mediated inhibitory post-synaptic currents (IPSCs) in slices prepared from partially nerve-ligated mice, whereas glutamate-mediated excitatory post-synaptic currents were hardly affected. By contrast, gabapentin did not reduce IPSCs in slices taken from mice given a sham operation. Although gabapentin altered neither the amplitude nor the frequency of miniature IPSCs, it reduced IPSCs together with an increase in the paired-pulse ratio, suggesting that gabapentin acts on the pre-synaptic GABAergic nerve terminals in the LC. As the protein kinase A (PKA) inhibitor H-89 but not the protein kinase C inhibitor chelerythrine abolished the inhibitory action of gabapentin on IPSCs, PKA-mediated phosphorylation seems to be important for supraspinal gabapentin responsiveness in neuropathic conditions. Together, gabapentin generates PKA-dependent pre-synaptic inhibition of GABAergic synaptic transmission, and thereby removes the inhibitory influence on LC neurons only under neuropathic pain states. These findings provide crucial evidence of how supraspinally acting gabapentin recruits the descending noradrenergic system.
Takasu
Keiko
K
Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho-ku, Nagoya, Japan.
Ono
Hideki
H
Tanabe
Mitsuo
M
D000588:Amines / Q000494:pharmacology*; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004525:Efferent Pathways / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D000077206:Gabapentin; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008026:Ligation; D008125:Locus Coeruleus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009924:Organ Culture Techniques; D010146:Pain / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D020426:Sciatic Neuropathy / Q000150:complications; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D017868:Cyclic AMP-Dependent Protein Kinases