Substance P Differentially Modulates Firing Rate of Solitary Complex (SC) Neurons from Control and Chronic Hypoxia-Adapted Adult Rats

Nicole L Nichols,Jay B Dean,Frank L Powell,Robert W Putnam,Mihai Covasa

doi:10.1371/journal.pone.0088161

Nicole L Nichols, Jay B Dean + Show 3 more

Open Access

https://doi.org/10.1371/journal.pone.0088161

Copy DOI

Abstract

NK1 receptors, which bind substance P, are present in the majority of brainstem regions that contain CO2/H+-sensitive neurons that play a role in central chemosensitivity. However, the effect of substance P on the chemosensitive response of neurons from these regions has not been studied. Hypoxia increases substance P release from peripheral afferents that terminate in the caudal nucleus tractus solitarius (NTS). Here we studied the effect of substance P on the chemosensitive responses of solitary complex (SC: NTS and dorsal motor nucleus) neurons from control and chronic hypoxia-adapted (CHx) adult rats. We simultaneously measured intracellular pH and electrical responses to hypercapnic acidosis in SC neurons from control and CHx adult rats using the blind whole cell patch clamp technique and fluorescence imaging microscopy. Substance P significantly increased the basal firing rate in SC neurons from control and CHx rats, although the increase was smaller in CHx rats. However, substance P did not affect the chemosensitive response of SC neurons from either group of rats. In conclusion, we found that substance P plays a role in modulating the basal firing rate of SC neurons but the magnitude of the effect is smaller for SC neurons from CHx adult rats, implying that NK1 receptors may be down regulated in CHx adult rats. Substance P does not appear to play a role in modulating the firing rate response to hypercapnic acidosis of SC neurons from either control or CHx adult rats.

Highlights

The neuropeptide substance P is involved in several physiological processes including cardiovascular, respiratory, gastrointestinal, and nociceptive processes and even modulation of the immune response [1,2,3,4]
The main findings of this study include: 1) substance P increases the basal firing rate of all solitary complex (SC) neurons in control rats, but only SC neurons activated by hypercapnia in chronic hypoxia-adapted (CHx) rats; 2) substance P has no effect on the firing rate response to acute hypercapnia of SC neurons from either control or CHx rats; and 3) when neurokinin receptor 1 (NK1) receptors are blocked we see no effect on the firing rate response of SC neurons to acute hypercapnia
We designed our experiments to employ the ability of hypoxia to modulate substance P levels and we studied the nucleus tractus solitaries (NTS) because it is known to have altered substance P levels and exhibit plasticity in response to hypoxia [29,30,31,35]

Summary

Introduction

The neuropeptide substance P is involved in several physiological processes including cardiovascular, respiratory, gastrointestinal, and nociceptive processes and even modulation of the immune response [1,2,3,4]. Substance P has been shown to affect ventilation as well. When saporin conjugated to substance P (which will lesion neurons expressing NK1 receptors) was microinjected into different chemoreceptor sites, including the retrotrapezoid nucleus (RTN) and medullary raphe, the hypercapnic ventilatory response (both frequency and tidal volume) was decreased [10,11,12]. This suggests that neurons expressing neurokinin receptor 1 (NK1) may play a role in modulating central chemosensitivity. Substance P has been shown to affect the hypoxic ventilatory response, where injections of an NK1 receptor antagonist into the ventricles of the brain decreased the hypoxic ventilatory response [13]

Objectives

Results

Discussion

Conclusion