Ketamine-mediated afferent-specific presynaptic transmission blocks in low-threshold and sex-specific subpopulation of myelinated Ah-type baroreceptor neurons of rats

• Published in: Oncotarget 2015-12, Vol.6 (42), p.44108-44122
• Main Authors: Wang, Lu-Qi, Liu, Sheng-Zhi, Wen, Xin, Wu, Di, Yin, Lei, Fan, Yao, Wang, Ye, Chen, Wei-Ran, Chen, Pei, Liu, Yang, Lu, Xiao-Long, Sun, Hong-Li, Shou, Weinian, Qiao, Guo-Fen, Li, Bai-Yan
• Format: Article
• Language: English
• Subjects: Action Potentials; Afferent Pathways - drug effects; Afferent Pathways - metabolism; Anesthetics, Dissociative - toxicity; Animals; Blood Pressure - drug effects; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists - toxicity; Excitatory Postsynaptic Potentials; Female; Ketamine - toxicity; Male; Nerve Fibers, Myelinated - drug effects; Nerve Fibers, Myelinated - metabolism; Neural Conduction - drug effects; Nodose Ganglion - cytology; Nodose Ganglion - drug effects; Nodose Ganglion - metabolism; Pressoreceptors - drug effects; Pressoreceptors - metabolism; Presynaptic Terminals - drug effects; Presynaptic Terminals - metabolism; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Research Paper: Pathology; Sex Characteristics; Sex Factors; Solitary Nucleus - cytology; Solitary Nucleus - drug effects; Solitary Nucleus - metabolism; Synaptic Transmission - drug effects; Time Factors
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.6586

Ketamine enhances autonomic activity, and unmyelinated C-type baroreceptor afferents are more susceptible to be blocked by ketamine than myelinated A-types. However, the presynaptic transmission block in low-threshold and sex-specific myelinated Ah-type baroreceptor neurons (BRNs) is not elucidated.  Action potentials (APs) and excitatory post-synaptic currents (EPSCs) were investigated in BRNs/barosensitive neurons identified by conduction velocity (CV), capsaicin-conjugated with Iberiotoxin-sensitivity and fluorescent dye using intact nodose slice and brainstem slice in adult female rats. The expression of mRNA and targeted protein for NMDAR1 was also evaluated.  Ketamine time-dependently blocked afferent CV in Ah-types in nodose slice with significant changes in AP discharge. The concentration-dependent inhibition of ketamine on AP discharge profiles were also assessed and observed using isolated Ah-type BRNs with dramatic reduction in neuroexcitability. In brainstem slice, the 2nd-order capsaicin-resistant EPSCs were identified and ~50% of them were blocked by ketamine concentration-dependently with IC50 estimated at 84.4 µM compared with the rest (708.2 µM). Interestingly, the peak, decay time constant, and area under curve of EPSCs were significantly enhanced by 100 nM iberiotoxin in ketamine-more sensitive myelinated NTS neurons (most likely Ah-types), rather than ketamine-less sensitive ones (A-types).  These data have demonstrated, for the first time, that low-threshold and sex-specific myelinated Ah-type BRNs in nodose and Ah-type barosensitive neurons in NTS are more susceptible to ketamine and may play crucial roles in not only mean blood pressure regulation but also buffering dynamic changes in pressure, as well as the ketamine-mediated cardiovascular dysfunction through sexual-dimorphic baroreflex afferent pathway.