Substance P-induced inflammation in the rat knee joint is mediated by neurokinin 1 (NK1) receptors

1. In anesthetized rats we studied the involvement of substance P and neurokinin-1 receptors in the generation and maintenance of hyperexcitability in spinal cord neurons, which develops in the course of an acute experimental inflammation in the knee. In all experiments one nociceptive neuron with knee input was identified, and the responses to mechanical stimuli and the receptive fields were monitored before and after induction of inflammation by the injections of kaolin and carrageenan into the knee joint. In 18 experiments either the specific antagonist at the neurokinin-1 receptor ionophoretically close to the neuron or intravenously during the injections of kaolin and carrageenan and in three periods of 15 min in the 95 min postkaolin (initial period of inflammation) to test their effects on the development of hyperexcitability. CP96,345 and CP96,344 were also administered after full development of inflammation to study their effects in hyperexcitable neurons. CP96,345 was ejected at currents that reduced or completely suppressed the effects of ionophoretically administered substance P but not those of neurokinin A, the agonist at neurokinin-2 receptors. 2. After the injections of kaolin and carrageenan into the knee joint, untreated control neurons (n = 8) developed hyperexcitability consisting of enhanced responses to noxious stimuli applied to the injected knee and the noninjected ankle, of an enhancement or induction of the responses to innocuous pressure applied to the joints and of an expansion of the receptive field. In eight neurons treated with ionophoretic administration of CP96,345 during the induction and initial period of inflammation, the development of hyperexcitability was not completely prevented but significantly attenuated. In comparison with the changes in the control neurons, the development of hyperexcitability was markedly reduced from the 2nd h up to 5 h postkaolin, but it was barely affected by CP96,345 within the 1st h postkaolin. Intravenous administration of CP96,345 in the initial period of inflammation produced a similar reduction of the development of hyperexcitability in another four neurons. The ionophoretic application of CP96,344 during and after induction of inflammation did not apparently impair the development of hyperexcitability (n = 6 neurons). 3. After development of inflammation and hyperexcitability, both the responses to innocuous and noxious pressure applied to the inflamed knee joint were reduced by the ionophoretic (n = 16 neurons) and intravenous administration (n = 9 neurons) of CP96,345 (tested 4.5-8 h postkaolin). Similarly, the responses to innocuous and noxious pressure applied to the noninflamed ankle were reduced by CP96,345 after inflammation had developed in the knee joint.(ABSTRACT TRUNCATED AT 400 WORDS)

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Direct observation of substance P-induced internalization of neurokinin 1 (NK1) receptors at sites of inflammation.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.91.19.8964 ◽

1994 ◽

Vol 91 (19) ◽

pp. 8964-8968 ◽

Cited By ~ 175

Author(s):

J. J. Bowden ◽

A. M. Garland ◽

P. Baluk ◽

P. Lefevre ◽

E. F. Grady ◽

...

Keyword(s):

Substance P ◽

Direct Observation ◽

Nk1 Receptors ◽

Neurokinin 1

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Upregulation of substance P receptors in angiogenesis associated with chronic airway inflammation in rats

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1997.273.3.l565 ◽

1997 ◽

Vol 273 (3) ◽

pp. L565-L571 ◽

Cited By ~ 8

Author(s):

P. Baluk ◽

J. J. Bowden ◽

P. M. Lefevre ◽

D. M. McDonald

Keyword(s):

Endothelial Cells ◽

Substance P ◽

Blood Vessels ◽

Sensory Nerves ◽

Mycoplasma Pulmonis ◽

Tracheal Mucosa ◽

Fischer 344 ◽

Nk1 Receptors ◽

Plasma Leakage ◽

Neurokinin 1

In rat airways, substance P released from sensory nerves induces plasma leakage via neurokinin-1 (NK1) receptors on endothelial cells. In pathogen-free rats, both leakage and endothelial NK1 receptors are most abundant in postcapillary venules. In Mycoplasma pulmonis-infected rats, extensive angiogenesis occurs in the tracheal mucosa. The capillary-sized (< 10 microns in diameter) angiogenic blood vessels are abnormally sensitive to substance P. The aim of this study was to determine whether increased expression of NK1 receptors contributes to this abnormal sensitivity. Fischer 344 rats were infected with M. pulmonis and were challenged with substance P (5 micrograms/kg i.v.), and then plasma leakage in the tracheal mucosa was measured by extravasation of Monastral blue (30 mg/kg i.v.). NK1 receptors on endothelial cells were localized by immunohistochemistry. Five minutes after substance P, NK1 receptor-immunoreactive endosomes were five times more abundant in endothelial cells of angiogenic capillaries in M. pulmonis-infected rats than in corresponding capillaries in pathogen-free controls (17.1 +/- 2.3 vs. 3.5 +/- 0.4 endosomes/100 micron 2 of endothelial surface). Endosomes were slightly more abundant in postcapillary venules 15-35 microns in diameter in infected rats (23.0 +/- 0.6 vs. 19.2 +/- 0.7 endosomes/100 micron 2). Similarly, after substance P, angiogenic capillaries had much more Monastral blue labeling (area density: 18.8 +/- 1.5 vs. 2.9 +/- 0.5% of vessel wall), whereas postcapillary venules had about the same amount of labeling (36.0 +/- 3.7 vs. 34.1 +/- 1.8%). We conclude that increased expression of NK1 receptors, which are internalized into endosomes after ligand binding, contributes to the abnormal sensitivity of endothelial cells of angiogenic blood vessels to substance P in the airways of M. pulmonis-infected rats.

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The involvement of substance P and neurokinin-1 receptors in the responses of rat dorsal horn neurons to noxious but not to innocuous mechanical stimuli applied to the knee joint

Brain Research ◽

10.1016/0006-8993(94)90774-9 ◽

1994 ◽

Vol 666 (2) ◽

pp. 207-215 ◽

Cited By ~ 28

Author(s):

Volker Neugebauer ◽

Hans-Georg Schaible ◽

Frank Weiretter ◽

Ulrike Freudenberger

Keyword(s):

Substance P ◽

Knee Joint ◽

Dorsal Horn ◽

Mechanical Stimuli ◽

Dorsal Horn Neurons ◽

Neurokinin 1

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NK1 receptors mediate neurogenic inflammatory increase in blood flow in rat airways

Journal of Applied Physiology ◽

10.1152/jappl.1993.74.5.2462 ◽

1993 ◽

Vol 74 (5) ◽

pp. 2462-2468 ◽

Cited By ~ 40

Author(s):

G. Piedimonte ◽

J. I. Hoffman ◽

W. K. Husseini ◽

R. M. Snider ◽

M. C. Desai ◽

...

Keyword(s):

Blood Flow ◽

Substance P ◽

Neurogenic Inflammation ◽

Sensory Nerves ◽

Nk1 Receptor ◽

Nk1 Receptors ◽

Calcitonin Gene ◽

Nk1 Receptor Antagonist ◽

Selective Agonists ◽

Neurokinin 1

We studied the effect of neurogenic inflammation on airway blood flow in anesthetized F-344 rats. Three successive determinations of blood flow were made by injecting radionuclide-labeled microspheres suspended in 70% dextrose into the left ventricle. A selective agonist of the tachykinin receptor neurokinin 1 (NK1) increased airway blood flow, but NK2- and NK3-selective agonists were without effect. The natural agonist of NK1 receptors, substance P (1 micrograms/kg), increased airway blood flow, an effect that was abolished by the selective NK1 receptor antagonist CP-99,994 [(+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine] but not by the (2R,3R)-enantiomer CP-100,263. Capsaicin (25 micrograms/kg), a drug that releases tachykinins and calcitonin gene-related peptide from sensory nerves, increased airway blood flow, and again this effect was abolished by CP-99,994. We also studied the effect of a selective inhibitor (captopril, 2.5 mg/kg) of the tachykinin-degrading enzyme kininase II [or angiotensin-converting enzyme (ACE)] on substance P-induced airway vasodilation. Captopril potentiated and prolonged the vasodilator effect of substance P. We conclude that neurogenic vasodilation in rat airways is due to the release of substance P, acts via NK1 receptors, and may be modulated by ACE.

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Frequency-Dependent Release of Substance P Mediates Heterosynaptic Potentiation of Glutamatergic Synaptic Responses in the Rat Visual Thalamus

Journal of Neurophysiology ◽

10.1152/jn.00010.2010 ◽

2010 ◽

Vol 104 (3) ◽

pp. 1758-1767 ◽

Cited By ~ 16

Author(s):

Sean P. Masterson ◽

Jianli Li ◽

Martha E. Bickford

Keyword(s):

Substance P ◽

High Frequency ◽

Input Resistance ◽

Resistance Change ◽

Frequency Dependent ◽

Dorsal Thalamus ◽

Nk1 Receptors ◽

Neurokinin 1 ◽

Synaptic Responses

To investigate the interaction between peptides and glutamatergic synapses in the dorsal thalamus, we compared the frequency-dependent plasticity of excitatory postsynaptic potentials (EPSPs) in the tectorecipient zone of rodent lateral posterior nucleus (LPN), which is densely innervated by axons that contain the neuromodulator substance P (SP). Immunocytochemistry and confocal and electron microscopy revealed that neurokinin 1 (NK1) receptors are distributed on the dendrites of LPN cells, whereas SP is contained in axons originating from the superior colliculus (SC) and is reduced following SC lesions. In vitro whole cell recordings in parasagittal slices revealed that stimulation of the SC or optic radiations (corticothalamic axons [CTXs]) evoked LPN EPSPs that increased in amplitude with increasing stimulation intensity, suggesting convergence. With 0.5- to 10-Hz stimulus trains, CTX EPSP amplitudes displayed frequency-dependent facilitation, whereas SC EPSP amplitudes were unchanged. High-frequency SC stimulation (100 Hz for 0.5 s), or bath application of SP, resulted in gradual increases in both SC and CTX EPSP amplitudes to twofold or greater above baseline within 15–20 min poststimulation/application. This enhancement correlated with increases in input resistance and both the potentiation and resistance change were abolished in the presence of the NK1 antagonist L-703,606. These results indicate that SP is released when SC-LPN neurons fire at high frequency and SP acts postsynaptically via NK1 receptors to potentiate subsequent LPN responses to both cortical and tectal inputs. We suggest that the SP-mediated potentiation of synaptic responses may serve to amplify responses to threatening objects that move across large regions of the visual field.

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Combined unilateral blockade of cholinergic, peptidergic, and serotonergic receptors in the ventral respiratory column does not affect breathing in awake or sleeping goats

Journal of Applied Physiology ◽

10.1152/japplphysiol.00145.2015 ◽

2015 ◽

Vol 119 (3) ◽

pp. 308-320 ◽

Cited By ~ 5

Author(s):

Clarissa Muere ◽

Suzanne Neumueller ◽

Samantha Olesiak ◽

Justin Miller ◽

Thomas Langer ◽

...

Keyword(s):

Substance P ◽

Eye Movement ◽

Large Degree ◽

Nrem Sleep ◽

Rapid Eye Movement ◽

Serotonergic Receptors ◽

Nk1 Receptors ◽

Effluent Concentration ◽

Past Data ◽

Neurokinin 1

Previous work in intact awake and sleeping goats has found that unilateral blockade of excitatory inputs in the ventral respiratory column (VRC) elicits changes in the concentrations of multiple neurochemicals, including serotonin (5-HT), substance P, glycine, and GABA, while increasing or having no effect on breathing. These findings are consistent with the concept of interdependence between neuromodulators, whereby attenuation of one modulator elicits compensatory changes in other modulators to maintain breathing. Because there is a large degree of redundancy and multiplicity of excitatory inputs to the VRC, we herein tested the hypothesis that combined unilateral blockade of muscarinic acetylcholine (mACh), neurokinin-1 (NK1, the receptor for substance P), and 5-HT2A receptors would elicit changes in multiple neurochemicals, but would not change breathing. We unilaterally reverse-dialyzed a cocktail of antagonists targeting these receptors into the VRC of intact adult goats. Breathing was continuously monitored while effluent fluid from dialysis was collected for quantification of neurochemicals. We found that neither double blockade of mACh and NK1 receptors, nor triple blockade of mACh, NK1, and 5-HT2A receptors significantly affected breathing ( P ≥ 0.05) in goats that were awake or in non-rapid eye movement (NREM) sleep. However, both double and triple blockade increased the effluent concentration of substance P ( P < 0.001) and decreased GABA concentrations. These findings support our hypothesis and, together with past data, suggest that both in wakefulness and NREM sleep, multiple neuromodulator systems collaborate to stabilize breathing when a deficit in one or multiple excitatory neuromodulators exists.

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

Case Reports in Oncology ◽

10.1159/000493256 ◽

2019 ◽

Vol 12 (1) ◽

pp. 84-90 ◽

Cited By ~ 2

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.

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00253.2005 ◽

2007 ◽

Vol 292 (4) ◽

pp. L915-L923 ◽

Cited By ~ 10

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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