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.

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 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.

New insights into the antidepressant actions of substance P (NK1 receptor) antagonists

2002 ◽  
Vol 80 (5) ◽  
pp. 489-494 ◽  
Author(s):  
Nadia M.J Rupniak
Keyword(s):  
Substance P ◽  
Species Differences ◽  
Motor Impairment ◽  
Nk1 Receptor ◽  
Receptor Antagonists ◽  
Antidepressant Efficacy ◽  
Preclinical Species ◽  
Pharmacological Blockade ◽  
Nk1 Receptor Antagonists ◽  
Made In

Considerable progress has been made in understanding the neural circuits involved the antidepressant and anxiolytic efficacy of substance P (NK1 receptor) antagonists (SPAs). Progress has been hampered by species differences in the pharmacology of the NK1 receptor, and the availability of NK1R–/– mice has been a particularly useful resource in overcoming this difficulty. Using neuroanatomical, behavioural, and electrophysiological techniques, studies have now established that pharmacological blockade or deletion of the NK1 receptor produces an antidepressant and anxiolytic-like profile in a range of behavioural assays that is distinct from that of established drugs. There is evidence from focal injection studies that some of these effects may be mediated directly by blockade of NK1 receptors in the amygdala and its projections to the hypothalamus, periaqueductal gray, and reticulopontine nucleus. Substance P and NK1 receptors are also intimately associated with ascending 5-HT and norepinephrine projections to the forebrain, and alterations in the function of these systems are also likely to be related to the antidepressant efficacy of SPAs. Unlike some established drugs, SPAs are generally well tolerated and do not induce sedation or motor impairment in preclinical species. These findings are consistent with a novel antidepressant mechanism of action of SPAs.Key words: NK1 receptor, depression, anxiety.

scholarly journals Substance P (Neurokinin 1) Receptor Antagonists Enhance Dorsal Raphe Neuronal Activity

2002 ◽  
Vol 22 (17) ◽  
pp. 7730-7736 ◽  
Author(s):  
Rachel K. Conley ◽  
Michael J. Cumberbatch ◽  
Glenn S. Mason ◽  
David J. Williamson ◽  
Timothy Harrison ◽  
...  
Keyword(s):  
Substance P ◽  
Neuronal Activity ◽  
Dorsal Raphe ◽  
Receptor Antagonists ◽  
Neurokinin 1 Receptor ◽  
Neurokinin 1 ◽  
Dorsal Raphé

scholarly journals Lack of efficacy of L-759274, a novel neurokinin 1 (substance P) receptor antagonist, for the treatment of generalized anxiety disorder

2013 ◽  
Vol 16 (1) ◽  
pp. 1-11 ◽  
Author(s):  
David Michelson ◽  
Richard Hargreaves ◽  
Robert Alexander ◽  
Paulette Ceesay ◽  
Jarmo Hietala ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Anxiety Disorder ◽  
Substance P ◽  
Generalized Anxiety Disorder ◽  
Receptor Occupancy ◽  
Generalized Anxiety ◽  
Proof Of Concept ◽  
Nk1 Receptor ◽  
Neurokinin 1 ◽  
Nk1 Receptor Antagonists

Abstract Preclinical studies suggest that substance P acting at neurokinin 1 (NK1) receptors may be involved in stress responses and NK1 receptor antagonists show activity in tests of anxiety. These data raise the possibility that NK1 receptor antagonists could be potential anxiolytic treatments in humans. We evaluated this hypothesis clinically using the NK1 antagonist L-759274. This is a randomized, double-blind, placebo- and active-controlled, multicentre, proof-of-concept trial. Patients with generalized anxiety disorder were randomized 1:1:1 to 6 wk of treatment with 40 mg L-759274 (n = 73), 1–6 mg lorazepam (n = 69) or placebo (n = 71). Efficacy was assessed using the Hamilton Anxiety Scale (HAMA). A positron emission tomography (PET) study was also performed in 16 healthy subjects to determine the relationship between NK1 receptor occupancy and plasma levels of L-759274 to verify adequate target engagement by the doses tested during the clinical trial. No statistically significant difference in mean change from baseline HAMA score at 6 wk was seen for L-759274 vs. placebo [difference = 1.0 (95% confidence intervals (CI) −1.2 to 3.2), p = 0.359] whereas the lorazepam group did show a significant improvement vs. placebo (difference = −2.7, 95% CI −5.0 to −0.4, p = 0.020) and L-759274 (difference = 3.7, 95% CI 1.5–6.0, p = 0.001]. Results from the PET study indicated that the L-759274 dosing regimen used in the clinical trial likely provided high levels of NK1 receptor occupancy (>90%), supporting the view that it was an adequate proof-of-concept trial. The NK1 receptor antagonist L-759274 does not appear to be efficacious for the treatment of generalized anxiety disorder.

Chemotherapy-Induced Delayed Emesis: What is the Role of 5-HT3Antagonists?

2003 ◽  
Vol 19 (5) ◽  
pp. 287-297
Author(s):  
Kwong H Ng
Keyword(s):  
English Language ◽  
Current Data ◽  
Cytotoxic Agents ◽  
Delayed Emesis ◽  
Nk1 Receptor ◽  
Receptor Antagonists ◽  
Medline Search ◽  
Neurokinin 1 ◽  
Nk1 Receptor Antagonists

Objective: To review the current literature assessing the efficacy of different antiemetics, with a focus on comparison between serotonin (5-HT3) antagonists and other antiemetics, in the treatment of delayed emesis induced by either cisplatin or non-cisplatin cytotoxic agents. Data Sources: A MEDLINE search (1966–July 2002) was performed using delayed emesis, vomiting, nausea, chemotherapy, cisplatin, moderately emetogenic, selective serotonin subtype-3 (5-HT3) receptor antagonists, metoclopramide, domperidone, corticosteroids, dexamethasone, prognostic factors, risk factors, and neurokinin-1 (NK1) receptor antagonists as key words or subject headings. Only English-language articles were identified and included. Additional references were retrieved from selected articles. Data Synthesis: Various antiemetic consensus guidelines have recommended the use of different pharmacologic treatment, including the use of 5-HT3 antagonists, for the prevention of chemotherapy-induced delayed emesis. In some instances, it has been suggested that combinations containing a 5-HT3 antagonist may be superior to others. Current data have been synthesized in an attempt to demonstrate the efficacy of 5-HT3 antagonists in the treatment of chemotherapy-induced delayed emesis. Conclusions: Dexamethasone has consistently shown its antiemetic efficacy for delayed emesis induced by cisplatin and non-cisplatin agents, whereas the role of 5-HT3 antagonists alone remains controversial. Metoclopramide has been shown to be as efficacious as 5-HT3 antagonists when combined with dexamethasone for the prevention of delayed emesis. As a result, 5-HT3 antagonists should be reserved as second-line agents to metoclopramide in addition to dexamethasone. NK1 receptor antagonists have shown some early promising results. However, many questions need to be addressed before their extensive use in clinical practice.

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