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

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.

Abnormalities in substance P neurokinin-1 receptor binding in key brainstem nuclei in sudden infant death syndrome related to prematurity and sex

“…SP and the NK1R have been shown to play an integral role in the modulation of homeostatic function in the medulla, including regulation of respiratory rhythm generation [ 14 – 16 ], integration of cardiovascular control [ 17 ], modulation of the baroreceptor reflex [ 18 ] and mediation of the chemoreceptor reflex in response to hypoxia [ 19 , 20 , 28 ]. In this study, we observed abnormalities related to development and sex in NK1R binding within multiple nuclei of the medullary homeostatic network in SIDS cases incuding absolute reductions in binding in the NTS and and all sub-divisions of IO nuclei (PIO, MAO, DAO).…”

“…The NTS houses the primary relay station for brainstem transmission of important respiratory and cardiovascular reflexes and is enriched with a high density of SP containing axon terminals [ 29 , 30 ]. Evidence from animal studies indicates a functional role for SP in the NTS as a central integrator of cardiovascular control [ 17 ], modulator of baroreceptor reflex sensitivity [ 18 ] and a primary excitatory mediator of the chemoreceptor reflex in response to hypoxia [ 19 , 20 ]. In rodent models, activation of NK1R by SP in the NTS stimulates respiration, while loss of NK1R reduces the respiratory response, severely impairing the chemoreceptor reflex and selective lesion of NK1R expressing neurons in the NTS blunts cardiovascular reflexes [ 31 , 32 ].…”

“…The neuropeptide SP has been shown to play an integral role in the modulation of homeostatic function in the medulla, in conjunction with other neurochemicals such as 5-HT, including regulation of respiratory rhythm generation [ 14 – 16 ], integration of cardiovascular control [ 17 ], modulation of the baroreceptor reflex [ 18 ] and mediation of the chemoreceptor reflex in response to hypoxia [ 19 , 20 ]. Abnormalities in SP neurotransmission may play, therefore, a role in homeostatic dysfunction in conjunction with other neurotransmitter network deficits in SIDS.…”

Investigating genetic variants in microRNA regulators of Neurokinin‐1 receptor in sudden infant death syndrome

“…The altered expression and/or function of the neuropeptide Substance P and its receptor, the Neurokinin‐1 receptor (NK1R), have also been suggested to play a role in the pathogenesis of SIDS 8–11 . They play key roles in mechanisms thought to contribute to SIDS including the modulation of homeostatic function in the medulla, involving regulation of respiratory rhythm generation, 12,13 integration of cardiovascular control, 14 modulation of the baroreceptor reflex 15 and mediation of the chemoreceptor reflex in response to hypoxia 16,17 . Furthermore, in rodent models the activation of NK1R by Substance P in the nucleus tractus solitarii (NTS) stimulates respiration, while loss of NK1R reduces the respiratory response, severely impairing the chemoreceptor reflex.…”

“… 8 , 9 , 10 , 11 They play key roles in mechanisms thought to contribute to SIDS including the modulation of homeostatic function in the medulla, involving regulation of respiratory rhythm generation, 12 , 13 integration of cardiovascular control, 14 modulation of the baroreceptor reflex 15 and mediation of the chemoreceptor reflex in response to hypoxia. 16 , 17 Furthermore, in rodent models the activation of NK1R by Substance P in the nucleus tractus solitarii (NTS) stimulates respiration, while loss of NK1R reduces the respiratory response, severely impairing the chemoreceptor reflex. The selective disruption of NK1R expressing neurons in the NTS reduces cardiovascular reflexes.…”