Effect of substance P on respiratory rhythm and pre-inspiratory neurons in the ventrolateral structure of rostral medulla oblongata: an in vitro study

doi:10.1016/0006-8993(92)90401-T

Brain Research

Volume 599, Issue 2, 25 December 1992, Pages 272-276

https://doi.org/10.1016/0006-8993(92)90401-T Get rights and content

Abstract

The pre-inspiratory (Pre-I) neurons which fire in the pre- and usually also during the post-inspiratory phase are located in the ventrolateral structures of the rostral medulla. They are suggested as primary rhythm generating neurons for respiration. These have been studied in isolated brainstem-spinal cord preparations from newborn 0–5-day-old rats. We have found that application of substance P (SP) enhanced the respiratory rhythm as measured by C₄ ventral root and pre-I neuronal activities. Furthermore, the effect of SP was dependent on basal respiratory rate. An increase of the Pre-I and C₄ burst rate by SP was clearer when the basal respiratory rhythm was somewhat lower. Moreover, long lasting depression of respiratory rate after the application of the alpha 2-agonist clonidine was reversed by SP. On the other hand, an inhibitory effect appeared in preparations with a higher basal respiratory rate, while the Pre-I burst rate tended to increase during SP perfusion. During chemical synaptic transmission blockade by perfusion with low Ca²⁺, high Mg²⁺ solution, a pre-I burst retained or completely blocked was found to be enhanced or reactivated by SP perfusion. The results suggest a direct postsynaptic action of SP, which could strongly stimulate burst generating properties of Pre-I neurons.

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Intraventricular or local microinjections to medulla oblongata augmented tidal volume with variable effects on respiratory rate in rats (Hedner et al., 1984; Chen et al., 1990; Mazzone and Geraghty, 2000). The point to be mentioned here is that excitement of the respiratory rhythm was conclusively confirmed in brainstem spinal cord preparation of neonatal rats (Yamamoto et al., 1992; Ptak et al., 1999) as well as on rat medullary slices (Morgado-Valle and Feldman, 2004). This likely targeted pre-BötC, since Bötzinger one stands as the bradypnoeic site (Fong and Potts, 2006).
Numerous neurotransmitters identified in the central nervous system play role in ventilatory control. This mini-review focuses on the respiratory effects of two neurotransmitters: serotonin (5-HT) and substance P (SP). We discuss their co-localization in medullary raphe nuclei, expression of proper receptors within the specific regions of respiratory related structures and contribution to respiratory rhythmogenesis.
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Bath-application of high SubP concentrations (1000 nM) decreased respiratory burst frequency in neonatal rat brainstem-spinal cord preparations due to excessive depolarization of respiratory neurons (Sharev et al., 2002). Short duration (<6 min) and low concentration (0.1–100 nM) SubP applications increased burst frequency, but the effects were readily reversible during the washout period (Yamamoto et al., 1992; Monteau et al., 1996), suggesting that SubP application at these durations, concentrations, and timing are not sufficient to induce frequency plasticity. Another relevant observation is that SubP-induced increases in respiratory burst frequency were larger in brainstem-spinal cord preparations with a lower baseline frequency (Monteau et al., 1996; Ptak and Hilaire, 1999), suggesting that in vitro SubP effects may be related to the status of the respiratory control system prior to SubP applications.
Respiratory frequency plasticity is a long-lasting increase in breathing frequency due to a perturbation. Mechanisms underlying respiratory frequency are poorly understood, and there is little evidence of frequency plasticity in neonates. This hybrid review/research article discusses available literature regarding frequency plasticity and highlights potential research opportunities. Also, we include data demonstrating a model of frequency plasticity using isolated neonatal rat brainstem-spinal cord preparations. Specifically, substance P (SubP) application induced a long-lasting (>60 min) increase in spontaneous respiratory motor burst frequency, particularly in brainstem-spinal cords with the pons attached; there were no male/female differences. SubP-induced frequency plasticity is dependent on the application pattern, such that intermittent (rather than sustained) SubP applications induce more frequency plasticity. SubP-induced frequency plasticity was blocked by a neurokinin-1 receptor antagonist. Thus, the newborn rat respiratory control system has the capacity to express frequency plasticity. Identifying mechanisms that induce frequency plasticity may lead to novel methods to safely treat breathing disorders in premature and newborn infants.
The potential role of substance P in brainstem homeostatic control in the pathogenesis of sudden infant death syndrome (SIDS)
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Victims of sudden infant death syndrome (SIDS) are believed to have an underlying dysfunction in medullary homeostatic control that impairs critical responses to life threatening challenges such as hypoxia, hypercarbia and asphyxia, often during a sleep period. This failure is thought to result from abnormalities in a network of neural pathways in the medulla oblongata that control respiration, chemosensitivity, autonomic function and arousal. Studies have mainly focused on the role of serotonin, 5-hydroxytyptamine (5HT), although the neuropeptide substance P (SP) has also been shown to play an integral role in the modulation of medullary homeostatic function, often in conjunction with 5-HT. Actions of SP include regulation of respiratory rhythm generation, integration of cardiovascular control, modulation of the baroreceptor reflex and mediation of the chemoreceptor reflex in response to hypoxia. Abnormalities in SP neurotransmission may, therefore, also play a significant role in homeostatic dysfunction of the neurotransmitter network in SIDS. This review focuses on the pathways within the medulla involving SP and its tachykinin NK1 receptor, their potential relationship with the medullary 5-HT system, and possible involvement in the pathogenesis of SIDS.
Research progress of capsaicin responses to various pharmacological challenges
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In another experiment, it was found that capsaicin at the dose of 5 μg/kg induced immediate expiratory apnoea followed by stimulated breathing of increased tidal volume and respiratory rate [47]. Even though the specific role of Substance P (SP) in respiratory rhythm regulation is not clearly known, however, it was found that exogenously applied SP augments respiratory activity in vivo [48] and in vitro [49,50,51]. Medullary slices of neonatal rat generated respiratory-related rhythm, and capsaicin, dose dependently, caused termination of respiratory rhythm time accompanied by SP depletion and increased glutamate release.
Capsaicin, a well known vanilloid, has shown evidence of an ample variety of biological effects which make it the target of extensive research ever since its identification. In spite of the fact that capsaicin causes health hazards in quite a few ways, yet, the verity cannot be ignored that capsaicin has several therapeutic implications. In patients with hypersensitive bladders, vesical instillation of 1 mM capsaicin markedly improved urinary frequency and urge incontinence. Again, administration of capsaicin favors an augmentation in lipid mobilization and a decrease in adipose tissue mass. Topical capsaicin cream as well decreases postsurgical neuropathic pain and is preferred by patients over a placebo among other therapies. Several in vitro studies have revealed that capsaicin results in growth arrest in some transformed cell lines. Furthermore, capsaicin has been proven to be an undeniably exciting molecule and remains a valuable drug for alleviating pain and itch. It has been recognized that capsaicinoids are the most potential agonists of capsaicin receptor (TRPV1). However, vanilloids could exert the beneficial effects not only through the receptor-dependent pathway but also through the receptor-independent one. The involvement of serotonin, neuropeptide Substance P and somatostatin in the pharmacological actions of capsaicin has been expansively investigated. Better understanding of the established TRPV1 receptor mechanism as well as exploring other possible receptor mechanism may publicize other new clinical efficacies of capsaicin. Further, clinical studies are required in several of these conditions to establish the efficacy of capsaicin.
Role of neurokinin receptors and ionic mechanisms within the respiratory network of the lamprey
2010, Neuroscience
Citation Excerpt :
Stock solutions were diluted to final desired concentration in control solution immediately prior to application. The drug concentrations and the application time were selected in preliminary trials; they were similar to those employed in previous studies in mammalian brainstem-spinal cord preparations (e.g. Yamamoto et al., 1992; Monteau et al., 1996; Ptak and Hilaire, 1999; Ptak et al., 1999) or brain slice preparations (Stacey et al., 2002; Peña and Ramirez, 2004; Telgkamp et al., 2002; Pace et al., 2007b; Simmons et al., 2008). The brainstem was perfused with progressively increasing concentrations of each agonist, and at each concentration the drug was applied for 15 min before switching to the next concentration.
We have suggested that in the lamprey, a medullary region called the paratrigeminal respiratory group (pTRG), is essential for respiratory rhythm generation and could correspond to the pre-Bötzinger complex (pre-BötC), the hypothesized kernel of the inspiratory rhythm-generating network in mammals. The present study was performed on in vitro brainstem preparations of adult lampreys to investigate whether some functional characteristics of the respiratory network are retained throughout evolution and to get further insights into the recent debated hypotheses on respiratory rhythmogenesis in mammals, such as for instance the “group-pacemaker” hypothesis. Thus, we tried to ascertain the presence and role of neurokinins (NKs) and burst-generating ion currents, such as the persistent Na⁺ current (I_NaP) and the Ca²⁺-activated non-specific cation current (I_CAN), described in the pre-Bötzinger complex. Respiratory activity was monitored as vagal motor output. Substance P (SP) as well as NK1, NK2 and NK3 receptor agonists (400–800 nM) applied to the bath induced marked increases in respiratory frequency. Microinjections (0.5–1 nl) of SP as well as the other NK receptor agonists (1 μM) into the pTRG increased the frequency and amplitude of vagal bursts. Riluzole (RIL) and flufenamic acid (FFA) were used to block I_NaP and I_CAN, respectively. Bath application of either RIL or FFA (20–50 μM) depressed, but did not suppress respiratory activity. Coapplication of RIL and FFA at 50 μM abolished the respiratory rhythm that, however, was restarted by SP microinjected into the pTRG. The results show that NKs may have a modulatory role in the lamprey respiratory network through an action on the pTRG and that I_NaP and I_CAN may contribute to vagal burst generation. We suggest that the “group-pacemaker” hypothesis is tenable for the lamprey respiratory rhythm generation since respiratory activity is abolished by blocking both I_NaP and I_CAN, but is restored by enhancing network excitability.
Role of glutamate and substance P in the amphibian respiratory network during development
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This study tested the hypothesis that glutamatergic ionotropic (AMPA/kainate) receptors and neurokinin receptors (NKR) are important in the regulation of respiratory motor output during development in the bullfrog. The roles of these receptors were studied with in vitro brainstem preparations from pre-metamorphic tadpoles and post-metamorphic frogs. Brainstems were superfused with an artificial cerebrospinal fluid at 20–22 °C containing CNQX, a selective non-NMDA antagonist, or with substance P (SP), an agonist of NKR. Blockade of glutamate receptors with CNQX in both groups caused a reduction of lung burst frequency that was reversibly abolished at 5 μM (P < 0.01). CNQX, but not SP, application produced a significant increase (P < 0.05) in gill and buccal frequency in tadpoles and frogs, respectively. SP caused a significant increase (P < 0.05) in lung burst frequency at 5 μM in both groups. These results suggest that glutamatergic activation of AMPA/kainate receptors is necessary for generation of lung burst activity and that SP is an excitatory neurotransmitter for lung burst frequency generation. Both glutamate and SP provide excitatory input for lung burst generation throughout the aquatic to terrestrial developmental transition in bullfrogs.

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Effect of substance P on respiratory rhythm and pre-inspiratory neurons in the ventrolateral structure of rostral medulla oblongata: an in vitro study

Abstract

Brain Res.

Resp. Physiol.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Distribution of PNMT-immunoreactive neurons and effects of adrenaline on respiratory rhythm in the medulla of newborn rat

Neurosci. Res. Suppl.

A possible role of adrenaline on respiratory rhythm generation in the medulla of newborn rat in vitro

Neurosci. Res. Suppl.

Respiration-related neurons in the ventral medulla of newborn rats in vitro

Brain Res. Bull.

Involvement of cAMP in respiratory rhythm generation in the medulla of newborn rat in vitro

Neurosci. Res. Suppl.

Effects of graded focal cold block in rostral areas of the medulla

Acta Physiol. Scand.

Hypoventilation and apnoea induced by the substance P antagonist [d-Pro2,d-Trp7,9)-SP in the ventrolateral rat medulla

Acta Physiol. Scand.

Local effects of substance P on respiratory regulation in the medulla oblongata

Acta Physiol. Scand.

Hypoventilation and apnoea induced by the substance P antagonist [d-Pro²,d-Trp^7,9)-SP in the ventrolateral rat medulla