Pharmacological characterization of antiepileptic drugs and experimental analgesics on low magnesium-induced hyperexcitability in rat hippocampal slices.
Perfusion of acute hippocampal slices with stimulatory buffers has long been known to induce rhythmic, large amplitude, synchronized spontaneous neuronal bursting in areas CA1 and CA3. The characteristics of this model of neuronal hyperexcitability were investigated in this study, particularly with respect to the activity of antiepileptic drugs and compounds representing novel mechanisms of analgesic action. Toward that end, low Mg(2+)/high K(+)-induced spontaneous activity was quantified by a virtual instrument designed for the digitization and analysis of bursting activity. Uninterrupted streams of extracellular field potentials were digitized and analyzed in 10-s sweeps, yielding four quantified parameters of neuronal hyperexcitability. Following characterization of the temporal stability of low Mg(2+)/high K(+)-induced hyperexcitability, compounds representing a diversity of functional mechanisms were tested for their effectiveness in reversing this activity. Of the four antiepileptic drugs tested in this model, only phenytoin proved ineffective, while valproate, gabapentin and carbamazepine varied in their potencies, with only the latter drug proving to be completely efficacious. In addition, three investigational compounds having analgesic potential were examined: ZD-7288, a blocker of HCN channels; EAA-090, an NMDA antagonist; and WAY-132983, a muscarinic agonist. Each of these compounds showed strong efficacy by completely blocking spontaneous bursting activity, along with potency greater than that of the antiepileptic drugs. These data indicate that pharmacological agents with varying mechanisms of action are able to block low Mg(2+)/high K(+)-induced hyperexcitability, and thus this model may represent a useful tool for identifying novel agents and mechanisms involved in epilepsy and neuropathic pain.
Arias
Robert L
RL
Discovery Neuroscience, Wyeth Research, CN8000 Room 1513, Princeton, NJ 08543-8000, USA. ariasr@wyeth.com
Bowlby
Mark R
MR
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008274:Magnesium / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009924:Organ Culture Techniques; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000700:Analgesics; D000927:Anticonvulsants; D008274:Magnesium; D011188:Potassium