Effect of Endogenous Substance P on Visceral Afferent Signal Integration in the Nucleus Tractus Solitaries of Rat Brainstem Slices

Abstract

In the first synapse of the blood-pressure-regulating pathway, a neurokinin (NK) family peptide substance P (SP) is coreleased with an excitatory neurotransmitter, glutamate, to enhance the sensitivity of the baroreflex responses. However, the underlying mechanisms of action are not yet well understood. Effects of NK receptor antagonists and agonists on solitary tract stimulation-evoked excitatory postsynaptic responses were recorded using whole-cell patch-clamp recordings of neurons in the medial portion of the nucleus tractus solitarius in the brainstem. SP reduced the amplitude of the evoked excitatory postsynaptic currents (eEPSCs) and shifted the holding current inward, in a dose̶̶̶-dependent manner. The concentrations of SP needed to induce such responses were different between capsaicin-sensitive unmyelinated (C-type) and capsaicin-resistant myelinated (A-type) neurons. Perfusion of a NK1 receptor antagonist, reduced the amplitude of eEPSCs in all tested neurons but did not affect the levels of the holding current. A NK1R agonist, reduced the amplitude of the eEPSCs and shifted the holding current inward in capsaicin-resistant neurons; however, it failed to induce any significant changes in the capsaicin -sensitive neurons. Furthermore, a selective NK3 receptor antagonist, failed to induce any changes in any tested neuron. In current-clamp experiments, sendide reduced ST-stimulation evoked firing of action potentials in both A- and C-type neurons. [Sar9, Met(O2)11]-SP suppressed the firing of the action potentials in C-type but not A-type neurons. Our findings show that ST activation leads to the co-transmission of SP and glutamate and enhances baroreflex sensitivity by potentiating the amplitude of eEPSC in an NK1R activity-dependent manner.

Note:
Funding declaration: This work was supported by a grant from the NRF-2021R1F1A1060010 and KEITI-2022003310013.

Conflict of Interests: None.

Ethical Approval: All animal procedures were conducted with the approval of the institutional Animal Care and Use Committee of the Kyung Hee university.

Keywords: substance P, neurokinin receptor, baroreflex sensitivity, capsaicin (CAP)