Ketamine differentially blocks sensory afferent synaptic transmission in medial nucleus tractus solitarius (mNTS).
BACKGROUND
Ketamine increases blood pressure and heart rate by unknown mechanisms, but studies suggest that an intact central nervous system and arterial baroreceptors are required. In the brain stem, medial nucleus tractus solitarius receives afferents from nodose neurons that initiate cardiovascular autonomic reflexes. Here, the authors assessed ketamine actions on afferent medial nucleus tractus solitarius synaptic transmission.


METHODS
Ketamine was applied to horizontally sliced brain stems. Solitary tract (ST) stimulation evoked excitatory postsynaptic currents (eEPSCs) in medial nucleus tractus solitarius neurons. Capsaicin (200 nm) block of ST eEPSCs sorted neurons into sensitive (n = 19) and resistant (n = 23). In nodose ganglion slices, shocks to the peripheral vagal trunk activated afferent action potentials in sensory neurons classified by conduction velocities and capsaicin.


RESULTS
Ketamine potently (10-100 mciro m) blocked small, ST-evoked -methyl-d-aspartate synaptic currents found only in a subset of capsaicin-resistant neurons (6 of 12). Surprisingly, ketamine reversibly inhibited ST eEPSC amplitudes and induced synaptic failure at lower concentrations in capsaicin-sensitive than in capsaicin-resistant neurons (P < 0.005; n = 11 and 11). Spontaneous EPSCs using non- -methyl-d-aspartate receptors were insensitive even to 1-3 mm ketamine, suggesting that ST responses were blocked presynaptically. Similarly, ketamine blocked C-type action potential conduction at lower concentrations than A-type nodose sensory neurons.


CONCLUSIONS
The authors conclude that ketamine inhibits postsynaptic -methyl-d-aspartate receptors and presynaptic afferent processes in medial nucleus tractus solitarius. Unexpectedly, capsaicin-sensitive (C-type), unmyelinated afferents are significantly more susceptible to block than capsaicin-resistant (A-type), myelinated afferents. This differentiation may be related to tetrodotoxin-resistant sodium currents. Since C-type afferents mediate powerful arterial baroreflexes effects, these differential actions may contribute to ketamine-induced cardiovascular dysfunction.
Jin
Young-Ho
YH
Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon 97201-3098, USA.
Bailey
Timothy W
TW
Doyle
Mark W
MW
Li
Bai-Yan
BY
Chang
Kyoung S K
KS
Schild
John H
JH
Mendelowitz
David
D
Andresen
Michael C
MC
D000200:Action Potentials / Q000187:drug effects; D000778:Anesthetics, Dissociative / Q000494:pharmacology*; D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects; D001933:Brain Stem / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D004594:Electrophysiology; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects*; D009620:Nodose Ganglion / Q000166:cytology / Q000187:drug effects; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D017552:Solitary Nucleus / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects
D000778:Anesthetics, Dissociative; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D002211:Capsaicin