Gabapentin may inhibit synaptic transmission in the mouse spinal cord dorsal horn through a preferential block of P/Q-type Ca2+ channels.
Gabapentin is a lipophilic analog of gamma-amino butyric acid (GABA) with therapeutic activity against certain forms of epilepsy and neuropathic pain. Despite its structural similarity to GABA, it does not bind GABAA or GABAB receptors and the mechanism, especially of its analgesic action, has remained elusive. Here, we have studied its effects on synaptic transmission mediated by the major spinal fast excitatory and inhibitory neurotransmitters, L-glutamate and glycine, in the superficial layers of the spinal cord dorsal horn, a CNS area, which is critically involved in nociception. Gabapentin reversibly reduced evoked excitatory postsynaptic currents mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA-EPSCs) and inhibitory postsynaptic currents mediated by glycine (gly-IPSCs). Inhibition of AMPA-EPSCs and gly-IPSCs occurred with similar potencies (approximately 10-50 nM) and by about the same degree (approximately 40% at 1 microM). Gabapentin did not affect membrane currents elicited by exogenously applied glutamate or glycine arguing against a postsynaptic site of action. Selective blockade of N-type Ca2+ channels with omega-conotoxin GVIA dramatically increased and blockade of P/Q-type channels with omega-agatoxin IVA strongly attenuated inhibition of evoked synaptic transmission by gabapentin. These results show that gabapentin affects both excitatory and inhibitory spinal neurotransmission via a presynaptic mechanism which preferentially involves P/Q-type Ca2+ channels.
Bayer
Katharina
K
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Erlangen-Nürnberg, Fahrstrasse 17, D-91054 Erlangen, Germany.
Ahmadi
Seifollah
S
Zeilhofer
Hanns Ulrich
HU
D000085:Acetates / Q000494:pharmacology*; D000588:Amines; D000818:Animals; D020864:Calcium Channels, N-Type / Q000502:physiology*; D003509:Cyclohexanecarboxylic Acids; D004305:Dose-Response Relationship, Drug; D005260:Female; D000077206:Gabapentin; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D020864:Calcium Channels, N-Type; D003509:Cyclohexanecarboxylic Acids; D000077206:Gabapentin; D005680:gamma-Aminobutyric Acid