scholarly journals Neurokinin-1 receptor activation is sufficient to restore the hypercapnic ventilatory response in the Substance P-deficient naked mole-rat

2020 ◽  
Vol 318 (4) ◽  
pp. R712-R721 ◽  
Author(s):  
Maxwell S. Clayson ◽  
Maiah E. M. Devereaux ◽  
Matthew E. Pamenter
Keyword(s):  
Substance P ◽  
Network Architecture ◽  
Ventilatory Response ◽  
Receptor Activation ◽  
Whole Body ◽  
Hypercapnic Ventilatory Response ◽  
Exogenous Substance ◽  
Mole Rat ◽  
Freely Behaving ◽  
Neurokinin 1

Naked mole-rats (NMRs) live in large colonies within densely populated underground burrows. Their collective respiration generates significant metabolic carbon dioxide (CO2) that diffuses slowly out of the burrow network, creating a hypercapnic environment. Currently, the physiological mechanisms that underlie the ability of NMRs to tolerate environmental hypercapnia are largely unknown. To address this, we used whole-body plethysmography and respirometry to elucidate the hypercapnic ventilatory and metabolic responses of awake, freely behaving NMRs to 0%–10% CO2. We found that NMRs have a blunted hypercapnic ventilatory response (HCVR): ventilation increased only in 10% CO2. Conversely, metabolism was unaffected by hypercapnia. NMRs are insensitive to cutaneous acid-based pain caused by modified substance P (SP)-mediated peripheral neurotransmission, and SP is also an important neuromodulator of ventilation. Therefore, we re-evaluated physiological responses to hypercapnia in NMRs after an intraperitoneal injection of exogenous substance P (2 mg/kg) or a long-lived isoform of substance P {[pGlu5-MePhe8-MeGly9]SP(5-11), DiMe-C7; 40–400 μg/kg}. We found that both drugs restored hypercapnia sensitivity and unmasked an HCVR in animals breathing 2%–10% CO2. Taken together, our findings indicate that NMRs are remarkably tolerant of hypercapnic environments and have a blunted HCVR; however, the signaling network architecture required for a “normal” HCVR is retained but endogenously inactive. This muting of chemosensitivity likely suits the ecophysiology of this species, which presumably experiences hypercapnia regularly in their underground niche.

Action of substance P (neurokinin-1) receptor activation on rat neostriatal projection neurons

Synapse ◽  
1999 ◽  
Vol 33 (1) ◽  
pp. 26-35 ◽  
Author(s):  
Elvira Galarraga ◽  
Salvador Hern�ndez-L�pez ◽  
Dagoberto Tapia ◽  
Arturo Reyes ◽  
Jos� Bargas
Keyword(s):  
Substance P ◽  
Receptor Activation ◽  
Projection Neurons ◽  
Neurokinin 1 Receptor ◽  
Neurokinin 1

scholarly journals Lethal avian influenza A (H5N1) virus replicates in pontomedullary chemosensitive neurons and depresses hypercapnic ventilatory response in mice

2019 ◽  
Vol 316 (3) ◽  
pp. L525-L536 ◽  
Author(s):  
Jianguo Zhuang ◽  
Na Zang ◽  
Chunyan Ye ◽  
Fadi Xu
Keyword(s):  
Viral Infection ◽  
Carotid Body ◽  
Influenza A ◽  
Tryptophan Hydroxylase ◽  
Ventilatory Response ◽  
Severe Depression ◽  
Infection Period ◽  
Hypercapnic Ventilatory Response ◽  
H5n1 Influenza ◽  
Neurokinin 1

The highly pathogenic H5N1 (HK483) viral infection causes a depressed hypercapnic ventilatory response (dHCVR, 20%↓) at 2 days postinfection (dpi) and death at 7 dpi in mice, but the relevant mechanisms are not fully understood. Glomus cells in the carotid body and catecholaminergic neurons in locus coeruleus (LC), neurokinin 1 receptor (NK1R)-expressing neurons in the retrotrapezoid nucleus (RTN), and serotonergic neurons in the raphe are chemosensitive and responsible for HCVR. We asked whether the dHCVR became worse over the infection period with viral replication in these cells/neurons. Mice intranasally inoculated with saline or the HK483 virus were exposed to hypercapnia for 5 min at 0, 2, 4, or 6 dpi, followed by immunohistochemistry to determine the expression of nucleoprotein of H5N1 influenza A (NP) alone and coupled with 1) tyrosine hydroxylase (TH) in the carotid body and LC, 2) NK1R in the RTN, and 3) tryptophan hydroxylase (TPH) in the raphe. HK483 viral infection blunted HCVR by ∼20, 50, and 65% at 2, 4, and 6 dpi. The NP was observed in the pontomedullary respiratory-related nuclei (but not in the carotid body) at 4 and 6 dpi, especially in 20% of RTN NK1R, 35% of LC TH, and ∼10% raphe TPH neurons. The infection significantly reduced the local NK1R or TPH immunoreactivity and population of neurons expressing NK1R or TPH. We conclude that the HK483 virus infects the pontomedullary respiratory nuclei, particularly chemosensitive neurons in the RTN, LC, and raphe, contributing to the severe depression of HCVR and respiratory failure at 6 dpi.

Recent developments in tachykinin NK1 receptor antagonists: prospects for the treatment of migraine headache

1995 ◽  
Vol 73 (7) ◽  
pp. 871-877 ◽  
Author(s):  
D. T. Beattie ◽  
H. E. Connor ◽  
R. M. Hagan
Keyword(s):  
Substance P ◽  
Migraine Headache ◽  
Receptor Activation ◽  
Receptor Antagonists ◽  
Trigeminovascular System ◽  
Protein Extravasation ◽  
Recent Developments ◽  
Inhibit Substance ◽  
Neurokinin 1 ◽  
Nk1 Receptor Antagonists

The role of substance P and the influence of neurokinin 1 (NK1) receptor antagonists in the cranial circulation are described in the present review, particularly with respect to the mechanisms involved in the etiology of migraine headache. Substance P is distributed throughout the cranial vasculature, in the trigeminal sensory afferent nerve fibres, and its release can be demonstrated following activation of the trigeminovascular system in animals and humans. Following its release and NK1 receptor activation, dilatation and edema result, two events that are implicated in the pathogenesis of migraine headache. The recently developed selective NK1 receptor antagonists inhibit substance P mediated dilatation and plasma protein extravasation in the cranial circulation, suggesting that they may provide an effective and novel acute treatment for migraine.Key words: substance P, migraine, NK1 receptor antagonists.

scholarly journals Fossorial Damaraland mole rats do not exhibit a blunted hypercapnic ventilatory response

2019 ◽  
Vol 15 (3) ◽  
pp. 20190006 ◽  
Author(s):  
Sarah Y. Zhang ◽  
Matthew E. Pamenter
Keyword(s):  
Extraction Efficiency ◽  
Ventilatory Response ◽  
Natural Habitat ◽  
Metabolic Cost ◽  
Whole Body ◽  
Metabolic Responses ◽  
Gaseous Environment ◽  
Freely Behaving ◽  
Whole Body Plethysmography ◽  
Fossorial Species

Damaraland mole rats (DMRs, Fukomys damarensis ) are a eusocial fossorial species that spend the majority of their life in densely populated underground burrows, in which they likely experience intermittent periods of elevated CO 2 (i.e. hypercapnia). The primary physiological response to hypercapnia in most mammals is to increase depth and rate of breathing (i.e. hyperpnoea), but this response is often blunted in species that inhabit hypercapnic environments. In their natural habitat, DMRs putatively experience a gaseous environment ranging from normocapnic (0.1% CO 2 ) to hypercapnic (6.0% CO 2 ) conditions (Roper et al. 2001 J. Zool. 254 , 101–107). As such, we hypothesized that DMRs would exhibit blunted hypercapnic ventilatory and metabolic responses, relative to those of non-fossorial rodent species. To test this hypothesis, we exposed awake, freely behaving DMRs to normoxic normocapnia (21% O 2 , 0% CO 2 , balance N 2 ) or graded normoxic hypercapnia (21% O 2 , 0, 2, 5, 7 and 10% CO 2 , balance N 2 ), and measured ventilation and metabolism using whole-body plethysmography and indirect calorimetry, respectively. We found that ventilation and metabolism were unchanged during prolonged normocapnia, whereas during graded hypercapnia, ventilation was elevated at 2% CO 2 and above. As a result, O 2 extraction efficiency at the lungs decreased with increasing hyperpnoea. Conversely, metabolic rate did not increase until 10% CO 2 , presumably due to the metabolic cost of hyperpnoea. Taken together, our results suggest that despite their fossorial lifestyle, DMRs do not exhibit adaptations in their ventilatory or metabolic responses to environmental hypercapnia.

Substance P Neurokinin 1 Receptor Activation within the Dorsal Raphe Nucleus Controls Serotonin Release in the Mouse Frontal Cortex

2007 ◽  
Vol 72 (6) ◽  
pp. 1411-1418 ◽  
Author(s):  
Bruno P. Guiard ◽  
Jean-Philippe Guilloux ◽  
Christelle Reperant ◽  
Stephen P. Hunt ◽  
Miklos Toth ◽  
...  
Keyword(s):  
Substance P ◽  
Frontal Cortex ◽  
Dorsal Raphe Nucleus ◽  
Receptor Activation ◽  
Dorsal Raphe ◽  
Serotonin Release ◽  
Raphe Nucleus ◽  
Neurokinin 1 Receptor ◽  
Neurokinin 1 ◽  
Dorsal Raphé

Effects of temperature on ventilatory response to hypercapnia in newborn mice heterozygous for transcription factor Phox2b

2007 ◽  
Vol 293 (5) ◽  
pp. R2027-R2035 ◽  
Author(s):  
N. Ramanantsoa ◽  
V. Vaubourg ◽  
B. Matrot ◽  
G. Vardon ◽  
S. Dauger ◽  
...  
Keyword(s):  
Heart Rate ◽  
Transcription Factor ◽  
Temperature Regulation ◽  
Ventilatory Response ◽  
Whole Body ◽  
Wild Type ◽  
Newborn Mice ◽  
Phox2b Gene ◽  
Ambient Temperatures ◽  
Hypercapnic Ventilatory Response

Congenital central hypoventilation syndrome (CCHS) is a rare disease with variable severity, generally present from birth and chiefly characterized by impaired chemosensitivity to hypercapnia. The main cause of CCHS is a mutation in the PHOX2B gene, which encodes a transcription factor involved in the development of autonomic medullary reflex pathways. Temperature regulation is abnormal in many patients with CCHS. Here, we examined whether ambient temperature influenced CO2 sensitivity in a mouse model of CCHS. A weak response to CO2 at thermoneutrality (32°C) was noted previously in 2-day-old mice with an invalidated Phox2b allele ( Phox2b+/−), compared with wild-type littermates. We exposed Phox2b+/− pups to 8% CO2 at three ambient temperatures (TAs): 29°C, 32°C, and 35°C. We measured breathing variables and heart rate (HR) noninvasively using a novel whole body flow plethysmograph equipped with contact electrodes. Body temperature and baseline breathing increased similarly with TA in mutant and wild-type pups. The hypercapnic ventilatory response increased linearly with TA in both groups, while remaining smaller in mutant than in wild-type pups at all TAs. The differences between the absolute increases in ventilation in mutant and wild-type pups become more pronounced as temperature increased above 29°C. The ventilatory abnormalities in mutant pups were not associated with significant impairments of heart rate control. In both mutant and wild-type pups, baseline HR increased with TA. In conclusion, TA strongly influenced the hypercapnic ventilatory response in Phox2b+/− mutant mice. These findings suggest that abnormal temperature regulation may contribute to the severity of respiratory impairments in CCHS patients.

scholarly journals Need for Flexible Adjustment of the Treatment Schedule for Aprepitant Administration against Erlotinib-Induced Refractory Pruritus and Skin Rush

2019 ◽  
Vol 12 (1) ◽  
pp. 84-90 ◽  
Author(s):  
Nobuhiko Seki ◽  
Ryosuke Ochiai ◽  
Terunobu Haruyama ◽  
Masashi Ishihara ◽  
Maika Natsume ◽  
...  
Keyword(s):  
Substance P ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Subsequent Treatment ◽  
Treatment Schedule ◽  
Weekly Schedule ◽  
Patient Centered ◽  
Neurokinin 1 ◽  
Dermatological Side Effects

Common dermatological side-effects associated with erlotinib, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), include pruritus and skin rash, which are mediated by substance P, leading to the occasional discontinuation of cancer treatment. Aprepitant is an antagonist of neurokinin-1 receptor, through which substance P activates the pruritogens. Thus, aprepitant is expected to offer a promising option for the treatment of erlotinib-induced pruritus. However, the appropriate treatment schedule for aprepitant administration is under consideration. Here, we discuss the need for flexible adjustment of the treatment schedule for aprepitant administration against erlotinib-induced refractory pruritus and skin rush. A 71-year-old female smoker presented with stage IV EGFR-mutated lung adenocarcinoma. She was started on erlotinib at 150 mg/day. However, by 28 days, severe pruritus and acneiform skin rush resistant to standard therapies occurred, resulting in the interruption of erlotinib therapy. After recovery, she was restarted on erlotinib at 100 mg/day. However, severe pruritus and skin rush developed again within 2 weeks. Then, we started the first 3-day dose of aprepitant (125 mg on day 1, 80 mg on day 3, and 80 mg on day 5) based on the results of the previous prospective study, which showed the success rate of 100% with at least the second dose of aprepitant. However, the pruritus and skin rush exacerbated again within 4 weeks. Therefore, we started the second 3-day dose of aprepitant, but in vain. At this point, as the patient-centered medicine, bi-weekly schedule of the 3-day dose of aprepitant was considered and, then, adopted. As the results, the pruritus and skin rush remained well-controlled throughout the subsequent treatment with erlotinib.

Paradoxical effect of salbutamol in a model of acute organophosphates intoxication in guinea pigs: role of substance P release

2007 ◽  
Vol 292 (4) ◽  
pp. L915-L923 ◽  
Author(s):  
Jaime Chávez ◽  
Patricia Segura ◽  
Mario H. Vargas ◽  
José Luis Arreola ◽  
Edgar Flores-Soto ◽  
...  
Keyword(s):  
Substance P ◽  
Guinea Pigs ◽  
Smooth Muscle Contraction ◽  
In Vivo Experiments ◽  
Intracellular Ca ◽  
Neurokinin 1 ◽  
Substance P Release

Organophosphates induce bronchoobstruction in guinea pigs, and salbutamol only transiently reverses this effect, suggesting that it triggers additional obstructive mechanisms. To further explore this phenomenon, in vivo (barometric plethysmography) and in vitro (organ baths, including ACh and substance P concentration measurement by HPLC and immunoassay, respectively; intracellular Ca2+ measurement in single myocytes) experiments were performed. In in vivo experiments, parathion caused a progressive bronchoobstruction until a plateau was reached. Administration of salbutamol during this plateau decreased bronchoobstruction up to 22% in the first 5 min, but thereafter airway obstruction rose again as to reach the same intensity as before salbutamol. Aminophylline caused a sustained decrement (71%) of the parathion-induced bronchoobstruction. In in vitro studies, paraoxon produced a sustained contraction of tracheal rings, which was fully blocked by atropine but not by TTX, ω-conotoxin (CTX), or epithelium removal. During the paraoxon-induced contraction, salbutamol caused a temporary relaxation of ∼50%, followed by a partial recontraction. This paradoxical recontraction was avoided by the M2- or neurokinin-1 (NK1)-receptor antagonists (methoctramine or AF-DX 116, and L-732138, respectively), accompanied by a long-lasting relaxation. Forskolin caused full relaxation of the paraoxon response. Substance P and, to a lesser extent, ACh released from tracheal rings during 60-min incubation with paraoxon or physostigmine, respectively, were significantly increased when salbutamol was administered in the second half of this period. In myocytes, paraoxon did not produce any change in the intracellular Ca2+ basal levels. Our results suggested that: 1) organophosphates caused smooth muscle contraction by accumulation of ACh released through a TTX- and CTX-resistant mechanism; 2) during such contraction, salbutamol relaxation is functionally antagonized by the stimulation of M2 receptors; and 3) after this transient salbutamol-induced relaxation, a paradoxical contraction ensues due to the subsequent release of substance P.

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