Gabapentin fails to alter P/Q-type Ca2+ channel-mediated synaptic transmission in the hippocampus in vitro.
Gabapentin (Neurontin) has been successfully used in the treatment of both epilepsy and neuropathic pain. Despite its widespread clinical use, its mechanism of action is very poorly understood. Indeed, the only protein it is known to interact with is the alpha2delta subunit of the voltage-gated Ca(2+) channel complex. In a recent article, gabapentin was reported to inhibit synaptic transmission in the spinal cord through an inhibitory effect on presynaptic P/Q-type Ca(2+) channels in both glutamatergic primary afferents and glycinergic interneuones. To examine if such inhibition of P/Q-channel-mediated synaptic transmission by gabapentin generalised to other synaptic pathways, we tested the actions of gabapentin of P/Q-type Ca(2+) channel-mediated synaptic responses in the CA1 subfield of the hippocampus. We found that gabapentin was completely inactive on such synaptic responses even at 10 times the maximally effective concentration used in the spinal cord. A small ( approximately 10%) but consistent depression of control synaptic responses was elicited by 10 microM gabapentin. No greater response was observed at a 10 times higher concentration. From these data we conclude that gabapentin is not a generic inhibitor of presynaptic P/Q-type channels and its actions at the spinal level must represent a feature of the P/Q-type channel not present in the hippocampus. Given the known interactions of this compound, the best candidate for this is the presence, subtype, or state of the alpha2delta subunit.
Brown
Jon T
JT
Neurology and Gastrointestinal CEDD, GlaxoSmithKline, Harlow, Essex, CM19 5AW, UK.
Randall
Andrew
A
D000588:Amines / Q000494:pharmacology*; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020865:Calcium Channels, P-Type / Q000187:drug effects* / Q000378:metabolism; D020907:Calcium Channels, Q-Type / Q000187:drug effects / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000077206:Gabapentin; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects* / Q000378:metabolism; D009924:Organ Culture Techniques; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D021122:Protein Subunits / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*; D020866:omega-Conotoxin GVIA / Q000494:pharmacology; D020960:omega-Conotoxins / Q000494:pharmacology
D000588:Amines; D002121:Calcium Channel Blockers; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D003509:Cyclohexanecarboxylic Acids; D021122:Protein Subunits; D020960:omega-Conotoxins; C075851:omega-conotoxin-MVIIC; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D020866:omega-Conotoxin GVIA