Changes in spinal inhibitory networks induced by furosemide in humans.
During neural development in animals, GABAergic and glycinergic neurons are first excitatory, and then become inhibitory in the mature state. This developmental shift is due mainly to strong expression of the cation-chloride K-Cl cotransporter 2 (KCC2) and down-regulation of Na-K-Cl cotransporter 1 (NKCC1) during maturation. The down-regulation of co-transporter KCC2 after spinal cord transection in animals leads to the depolarising (excitatory) action of GABA and glycine and thus results in a reduction of inhibitory synaptic efficiency. Furosemide, a loop diuretic, has been shown to selectively and reversibly block inhibitory postsynaptic potentials without affecting excitatory postsynaptic potentials in animal spinal neurons. Moreover, this diuretic has been also demonstrated to block the cation-chloride co-transporters. Here, we used furosemide to demonstrate changes in spinal inhibitory networks in healthy human subjects. Non-invasive electrophysiological techniques were used to assess presynaptic inhibition, postsynaptic inhibition and the efficacy of synaptic transmission between muscle afferent terminals and soleus motoneurons in the spinal cord. Orally administered furosemide, at doses commonly used in the clinic (40 mg), significantly reduced spinal inhibitory interneuronal activity for at least 70 min from intake compared to control experiments in the same subjects while no changes were observed in the efficacy of synaptic transmission between muscle afferent terminals and soleus motoneurons. The reduction of inhibition was dose-dependent. Our results provide indirect evidence that reversible changes in the cation-chloride transport system induce modulations of inhibitory neuronal activity at spinal cord level in humans.
Sorbonne Universités UPMC Univ Paris 06, ER 6: Physiologie et physiopathologie de la motricité chez l'Homme, Médecine Physique et Réadaptation, Hôpital Pitié-Salpêtrière, 75013, Paris, France Faculty of Physical Therapy, Mahidol University, 73170, Nakonpathom, Thailand.
Wanalee
W
Klomjai
Sorbonne Universités UPMC Univ Paris 06, ER 6: Physiologie et physiopathologie de la motricité chez l'Homme, Médecine Physique et Réadaptation, Hôpital Pitié-Salpêtrière, 75013, Paris, France.
Alexandra
A
Lackmy-Vallée
Sorbonne Universités UPMC Univ Paris 06, ER 6: Physiologie et physiopathologie de la motricité chez l'Homme, Médecine Physique et Réadaptation, Hôpital Pitié-Salpêtrière, 75013, Paris, France APHP Service de Médicine Physique et Réadaptation, Hôpital Pitié-Salpêtrière, 75651, Paris, Cedex, 13, France rose.katz@upmc.fr.
Rose
R
Katz
APHP Service de Médecine Physique et Réadaptation, Hôpital Raymond Poincaré, 92380, Garches, France.
Bernard
B
Bussel
APHP Service de Médecine Physique et Réadaptation, Hôpital Raymond Poincaré, 92380, Garches, France.
Djamel
D
Bensmail
CESEM, CNRS UMR 8194, Université Paris Descartes, 75006, Paris, France.
Jean-Charles
JC
Lamy
APHP Service de Médecine Physique et Réadaptation, Hôpital Raymond Poincaré, 92380, Garches, France Université Versailles-Saint-Quentin, EA 4497, 92380, Garches, France.
Nicolas
N
Roche
D000328:Adult; D004232:Diuretics / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D005665:Furosemide / Q000494:pharmacology*; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials; D007395:Interneurons / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
D004232:Diuretics; D005665:Furosemide