The potassium channel modulator flupirtine shifts the frequency-response function of hippocampal synapses to favour LTD in mice.
Flupirtine is a centrally acting nonopioid analgesic with muscle-relaxant properties. Flupirtine has been found to activate inwardly rectifying potassium conductances and hence to indirectly inhibit the activation of NMDA receptors. NMDA receptor activation is crucial for the induction of long-term potentiation (LTP) of synaptic transmission, which is considered as cellular correlate of learning and memory and of central sensitization in chronic pain states. Although flupirtine has been widely used for the management of pain, its effects on synaptic plasticity have not yet been investigated. We, therefore, performed extracellular and whole-cell patch-clamp recordings in hippocampal slices of mice to examine the effects of flupirtine on synaptic plasticity and neuronal membrane properties. Excitatory postsynaptic potentials (EPSPs) in the CA1 region were evoked alternately by stimulating two independent Schaffer collateral-commissural inputs. LTP and long-term depression (LTD) were induced by different stimulation paradigms (100 Hz, 10 Hz, 5 Hz, and 1 Hz). Flupirtine (30 microM) diminished the degree of LTP and enhanced LTD. This effect is most likely due to the hyperpolarization of CA1 pyramidal neurons and the reduction of their input resistance found after application of flupirtine. The observed effects on synaptic strength could underly the beneficial effects of flupirtine on different types of chronic pain.
Azad
Shahnaz Christina
SC
Max-Planck-Institute of Psychiatry, Clinical Neuropharmacology, Kraepelinstrasse 2, 80804 München, Germany. azad@mpipsykl.mpg.de
Eder
Matthias
M
Simon
Wanda
W
Hapfelmeier
Gerhard
G
Dodt
Hans-Ulrich
HU
Zieglgänsberger
Walter
W
Rammes
Gerhard
G
D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects / Q000528:radiation effects; D036881:Long-Term Synaptic Depression / Q000187:drug effects* / Q000528:radiation effects; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000528:radiation effects; D013569:Synapses / Q000187:drug effects* / Q000528:radiation effects; D009435:Synaptic Transmission / Q000187:drug effects / Q000528:radiation effects
D000631:Aminopyridines; C034161:flupirtine