Differential Effects of CRF1 and CRF2 Receptor Antagonists on Pain-Related Sensitization of Neurons in the Central Nucleus of the Amygdala

2007 ◽  
Vol 97 (6) ◽  
pp. 3893-3904 ◽  
Author(s):  
Guangchen Ji ◽  
Volker Neugebauer
Keyword(s):  
Receptor Antagonist ◽  
Hpa Axis ◽  
Stress Responses ◽  
Background Activity ◽  
Central Nucleus ◽  
Evoked Responses ◽  
Receptor Antagonists ◽  
Peripheral Tissues ◽  
Pain Model ◽  
Crf2 Receptor

As a hormone in the hypothalamic–pituitary–adrenocortical (HPA) axis corticotropin-releasing factor (CRF) mediates stress responses. CRF can also act as a neuromodulator of synaptic transmission outside the HPA axis. A major site of extrahypothalamic expression of CRF and its G-protein–coupled receptors is the amygdala, a key player in affect-related disorders such as anxiety. The laterocapsular division of the central nucleus of the amygdala (CeLC) is important for the modulation of pain affect. This study determined the effects of CRF1 and CRF2 receptor antagonists in CeLC neurons in an arthritis pain model. Extracellular single-unit recordings were made from CeLC neurons in anesthetized adult rats. All neurons responded more strongly to noxious than to innocuous mechanical stimulation (compression) of peripheral tissues, including the knee. Evoked responses and background activity were measured before and during the development of a kaolin/carrageenan-induced knee joint arthritis. Drugs were administered into the CeLC by microdialysis before and/or after arthritis induction. All CeLC neurons showed increased responses to mechanical stimuli (“sensitization”) 5–6 h postinduction of arthritis. A selective CRF1 receptor antagonist ( NBI27914 ; 1–100 μM, concentration in microdialysis probe; 15 min) inhibited evoked responses and background activity in arthritis ( n = 9) but had no effect under normal conditions before arthritis ( n = 9). In contrast, a selective CRF2 receptor antagonist (Astressin-2B; 1–100 μM, 15 min) had no effect in arthritis ( n = 7) but increased the neurons' responses under normal conditions ( n = 8). These data suggest that CRF1 receptors in the amygdala contribute to pain-related sensitization, whereas the normally inhibitory function of CRF2 receptors is lost in the arthritis pain model.

Pro- and Anti-Nociceptive Effects of Corticotropin-Releasing Factor (CRF) in Central Amygdala Neurons Are Mediated Through Different Receptors

2008 ◽  
Vol 99 (3) ◽  
pp. 1201-1212 ◽  
Author(s):  
Guangchen Ji ◽  
Volker Neugebauer
Keyword(s):  
Protein Kinase ◽  
Receptor Antagonist ◽  
Background Activity ◽  
Pain Modulation ◽  
Protein Kinase Inhibitors ◽  
Corticotropin Releasing Factor ◽  
Evoked Responses ◽  
Inhibitory Effects ◽  
Crf1 Receptor ◽  
Crf2 Receptor

Corticotropin-releasing factor (CRF) is not only a stress hormone but also acts as a neuromodulator outside the hypothalamic-pituitary-adrenocortical axis, playing an important role in anxiety, depression, and pain modulation. The underlying mechanisms remain to be determined. A major site of extra-hypothalamic expression of CRF and its receptors is the amygdala, a key player in affect-related disorders such as anxiety. The latero-capsular division of the central nucleus of the amygdala (CeLC) is also important for pain modulation and pain affect. This study analyzed the effects of CRF on nociceptive processing in CeLC neurons and the contribution of CRF1 and CRF2 receptors and protein kinases A and C. Extracellular single-unit recordings were made from CeLC neurons in anesthetized adult rats. All neurons responded more strongly to noxious than innocuous mechanical stimulation of the knee. Evoked responses and background activity were measured before and during administration of CRF into the CeLC by microdialysis. CRF was administered alone or together with receptor antagonists or protein kinase inhibitors. CRF (0.01–1 μM; concentrations in microdialysis probe; 15 min) facilitated the evoked responses more strongly than background activity; a higher concentration (10 μM) had inhibitory effects. Facilitation by CRF (0.1 μM) was reversed by a selective CRF1 receptor antagonist ( NBI27914 , 10 μM) but not a CRF2 receptor antagonist (astressin-2B, 100 μM) and by a protein kinase A (PKA) inhibitor (KT5720, 100 μM) but not a protein kinase C inhibitor (GF109203X, 100 μM). Inhibitory effects of CRF (10 μM) were reversed by astressin-2B. These data suggest that CRF has dual effects on amygdala neurons: CRF1 receptor-mediated PKA-dependent facilitation and CRF2 receptor-mediated inhibition.

scholarly journals Electro-Acupuncture Attenuates Chronic Stress Responses via Up-Regulated Central NPY and GABAA Receptors in Rats

2021 ◽  
Vol 14 ◽  
Author(s):  
Yu Yang ◽  
Haijie Yu ◽  
Reji Babygirija ◽  
Bei Shi ◽  
Weinan Sun ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Mrna Expression ◽  
Motor Function ◽  
Hpa Axis ◽  
Stress Responses ◽  
Corticosterone Level ◽  
Plasma Corticosterone ◽  
Gamma Aminobutyric Acid ◽  
Motor Functions ◽  
Gastric Motor Function

Stress can increase the release of corticotropin-releasing factor (CRF) in the hypothalamus, resulting in attenuation of gastric motor functions. In contrast, central neuropeptide Y (NPY) can reduce the biological actions of CRF, and in turn weaken stress responses. Although electroacupuncture (EA) at stomach 36 (ST-36) has been shown to have anti-stress effects, its mechanism has not yet been investigated. The effect of EA at ST-36 on the hypothalamus-pituitary-adrenal (HPA) axis and gastrointestinal motility in chronic complicated stress (CCS) conditions have not been studied and the inhibitory mechanism of NPY on CRF through the gamma-aminobutyric acid (GABA)A receptor need to be further investigated. A CCS rat model was set up, EA at ST-36 was applied to the bilateral hind limbs every day prior to the stress loading. Further, a GABAA receptor antagonist was intracerebroventricularly (ICV) injected daily. Central CRF and NPY expression levels were studied, serum corticosterone and NPY concentrations were analyzed, and gastric motor functions were assessed. CCS rats showed significantly elevated CRF expression and corticosterone levels, which resulted in inhibited gastric motor functions. EA at ST-36 significantly increased central NPY mRNA expression and reduced central CRF mRNA expression as well as the plasma corticosterone level, helping to restore gastric motor function. However, ICV administration of the GABAA receptor antagonist significantly abolished these effects. EA at ST-36 upregulates the hypothalamic NPY system. NPY may, through the GABAA receptor, significantly antagonize the overexpressed central CRF and attenuate the HPA axis activities in CCS conditions, exerting influences and helping to restore gastric motor function.

scholarly journals Intranasal Administration of Neuropeptide Y Significantly Antagonized Chronic Stress Responses via Central Gabaa Receptors in Male Rats

2021 ◽  
Author(s):  
Yu Yang ◽  
Haijie Yu ◽  
Reji Babygirija ◽  
Bei Shi ◽  
Weinan Sun ◽  
...  
Keyword(s):  
Neuropeptide Y ◽  
Receptor Antagonist ◽  
Mrna Expression ◽  
Hpa Axis ◽  
Stress Responses ◽  
Intranasal Administration ◽  
Male Rats ◽  
Invasive Technique ◽  
Motor Functions ◽  
Colonic Motor

Abstract Stress is widely believed to play a major role in the pathogenesis of many diseases. Central neuropeptide Y (NPY) counteracts the biological actions of corticotropin-releasing factor (CRF), and in turn attenuates stress responses. Administration (intracerebroventricular, ICV) of NPY, significantly antagonized the inhibitory effects of chronic complicated stress (CCS) on gastrointestinal (GI) dysmotility in rats. However, ICV administration is an invasive technique. The effect of intranasal administration of NPY on the hypothalamus-pituitary-adrenal (HPA) axis and GI motility in CCS conditions have not been studied, and the inhibitory mechanism of NPY on CRF through the gamma-aminobutyric acid (GABA)A receptor needs to be further investigated. A CCS rat model was set up, NPY was intranasal administered every day prior to the stress loading. Further, a GABAA receptor antagonist was ICV injected daily. Central CRF and NPY expression were evaluated, serum corticosterone and NPY levels were analyzed, and colonic motor functions was assessed. CCS rats showed significantly increased CRF expression and corticosterone levels, which resulted in enhanced colonic motor functions. Intranasal NPY significantly increased central NPY mRNA expression and reduced central CRF mRNA expression as well as the plasma corticosterone level, helping to restore colonic motor functions. However, ICV administration of the GABAA receptor antagonist significantly abolished these effects. Intranasal administration of NPY upregulates the hypothalamic NPY system. NPY may, through the GABAA receptor, significantly antagonize the overexpressed central CRF and attenuate the HPA axis activities in CCS conditions, exerting influences and helping to restore colonic motor function.

scholarly journals Nonselective and NR2B-selective N -methyl-d-aspartic Acid Receptor Antagonists Produce Antinociception and Long-term Relief of Allodynia in Acute and Neuropathic Pain

2011 ◽  
Vol 115 (1) ◽  
pp. 165-174 ◽  
Author(s):  
Maarten Swartjes ◽  
Aurora Morariu ◽  
Marieke Niesters ◽  
Leon Aarts ◽  
Albert Dahan
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Side Effects ◽  
Receptor Antagonist ◽  
Nerve Injury ◽  
Side Effect ◽  
Receptor Antagonists ◽  
Chronic Neuropathic Pain ◽  
Pain Model ◽  
Aspartate Receptor

Background At low dose, the nonselective N-methyl-D-aspartate receptor antagonist ketamine produces potent analgesia. In humans, psychedelic side effects limit its use. To assess whether other N-methyl-D-aspartate receptor antagonist have an improved therapeutic utility index, we compared antinociceptive, side effect, and locomotor activity of three N-methyl-D-aspartate receptor antagonists. Methods Ketamine, its active metabolite norketamine, and the NR2B-selective antagonist traxoprodil (CP-101,606) were tested in rat models of acute antinociception (paw-withdrawal response to heat) and chronic neuropathic pain (spared nerve injury). Side effects (stereotypical behavior, activity level) were scored and locomotor function of the nerve-injured paw was assessed using computerized gait analysis. In the chronic pain model, treatment was given 7 days after surgery, for 3 h on 5 consecutive days. Results All three N-methyl-D-aspartate receptor antagonists caused dose-dependent antinociception in the acute pain model and relief of mechanical and cold allodynia for 3-6 weeks after treatment in the chronic pain model (P < 0.05 vs. saline). In both tests, ketamine was most potent. Norketamine was as much as two times less potent and traxoprodil was up to 8 times less potent than ketamine (based on area under the curve measures). Nerve injury caused an inability to use the affected paw that either did not improve after treatment (ketamine, traxoprodil) or showed only a limited effect (norketamine). Traxoprodil, but not ketamine or norketamine, showed clear separation between effect and side effect. Conclusions The observation that traxoprodil causes relief of chronic pain outlasting the treatment period with no side effects makes it an attractive alternative to ketamine in the treatment of chronic neuropathic pain.

Cholecystokinin octapeptide analogues suppress food intake via central CCK-A receptors in mice

1993 ◽  
Vol 265 (3) ◽  
pp. R481-R486 ◽  
Author(s):  
Y. Hirosue ◽  
A. Inui ◽  
A. Teranishi ◽  
M. Miura ◽  
M. Nakajima ◽  
...  
Keyword(s):  
Food Intake ◽  
Receptor Antagonist ◽  
Rank Order ◽  
Peripheral Circulation ◽  
Inhibitory Effect ◽  
Peripheral Tissues ◽  
Cholecystokinin Octapeptide ◽  
The Central Nervous System ◽  
The Difference ◽  
The Brain

To examine the mechanism of the satiety-producing effect of cholecystokinin (CCK) in the central nervous system, we compared the potency of intraperitoneally (ip) or intracerebroventricularly (icv) administered CCK-8 and its analogues on food intake in fasted mice. The icv administration of a small dose of CCK-8 (0.03 nmol/brain) or of Suc-(Thr28, Leu29, MePhe33)-CCK-7 (0.001 nmol/brain) suppressed food intake for 20 min, whereas CCK-8 (1 nmol/kg, which is equivalent to 0.03 nmol/brain) or Suc-(Thr28, Leu29, MePhe33)-CCK-7 (1 nmol/kg) had satiety effect after ip administration. Dose-response studies indicated the following rank order of potency: Suc-CCK-7 > or = Suc-(Thr28, Leu29, MePhe33)-CCK-7 > or = CCK-8 > or = (Nle28,31)-CCK-8 >> desulfated CCK-8 = CCK-4 = 0 in the case of ip administration and Suc-(Thr28, Leu29, MePhe33)-CCK-7 >> Suc-CCK-7 > or = CCK-8 > or = (Nle28,31)-CCK-8 >> desulfated CCK-8 = CCK-4 = 0 in the case of icv administration. The selective CCK-A receptor antagonist MK-329 reversed the inhibitory effect of the centrally as well as peripherally administered CCK-8, or of Suc-(Thr28, Leu29, MePhe33)-CCK-7, whereas the selective CCK-B receptor antagonist L-365260 did not. The icv administered CCK-8 did not appear in the peripheral circulation. These findings suggest the participation of CCK-A receptors in the brain in mediating the satiety effect of CCK and the difference in CCK-A receptors in the brain and peripheral tissues.

scholarly journals Role of α1-adrenergic receptor subtypes in contractility of the rabbit abdominal aorta in vitro

2013 ◽  
Vol 82 (3) ◽  
pp. 331-336 ◽  
Author(s):  
Jan Gnus ◽  
Albert Czerski ◽  
Stanisław Ferenc ◽  
Wojciech Zawadzki ◽  
Wojciech Witkiewicz ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Receptor Antagonist ◽  
Abdominal Aorta ◽  
Adrenergic Receptor ◽  
Receptor Subtypes ◽  
Organ Bath ◽  
Dependent Manner ◽  
Receptor Antagonists ◽  
Selective Antagonists

Investigation of the effect of α1-adrenergic receptor subtypes on the contraction of the abdominal aorta will allow for more effective treatment of hypertension by use of selective antagonists. The aim of the study was to evaluate the participation of α1-adrenergic receptor subtypes in the contractility of the aortic smooth muscle cells in rabbits. The in vitro experiments were performed in isolated tissue preparations from 30 adult female New Zealand rabbits. The abdominal aortic sections were placed in organ bath chambers and contracted with increasing doses of non-selective α1-adrenergic receptor agonist phenylephrine without pre-incubation or after incubation in α1-adrenergic receptor subtype-selective or non-selective antagonists. Separate sections were incubated with increasing concentrations of antagonists. Phenylephrine caused maximal rise in arterial smooth muscle tone to 4.75 ± 0.47 mN. The most potent in blocking phenylephrine induced contraction was 5-metylurapidil (α1A-adrenergic receptor antagonist) followed by phentolamine and prazosin (non-selective α1-adrenergic receptor antagonists); BMY 7378 (α1D-adrenergic receptor antagonist), cyclazosin and L-765.314 (α1B-adrenergic receptor antagonists) were less effective. All antagonists, except BMY 7378 elicited relaxation of non-precontracted aorta in dose dependent manner. Our results indicate that postsynaptic α1A receptors are the most potent in producing rabbit abdominal aorta contraction, while α1B and α1D subtypes are less effective.

scholarly journals Adenosine A1receptor-mediated antiadrenergic effects are modulated by A2a receptor activation in rat heart

1999 ◽  
Vol 276 (2) ◽  
pp. H341-H349 ◽  
Author(s):  
Gavin R. Norton ◽  
Angela J. Woodiwiss ◽  
Robert J. McGinn ◽  
Mojca Lorbar ◽  
Eugene S. Chung ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Receptor Agonist ◽  
Ventricular Myocytes ◽  
Physiological Role ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Receptor Antagonists ◽  
Rat Hearts ◽  
Intracellular Ca ◽  
Perfused Rat Hearts

Presently, the physiological significance of myocardial adenosine A2a receptor stimulation is unclear. In this study, the influence of adenosine A2a receptor activation on A1 receptor-mediated antiadrenergic actions was studied using constant-flow perfused rat hearts and isolated rat ventricular myocytes. In isolated perfused hearts, the selective A2a receptor antagonists 8-(3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM-241385) potentiated adenosine-mediated decreases in isoproterenol (Iso; 10−8 M)-elicited contractile responses (+dP/d t max) in a dose-dependent manner. The effect of ZM-241385 on adenosine-induced antiadrenergic actions was abolished by the selective A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (10−7 M), but not the selective A3 receptor antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5-dicarboxylate (MRS-1191, 10−7 M). The A2a receptor agonist carboxyethylphenethyl-aminoethyl-carboxyamido-adenosine (CGS-21680) at 10−5 M attenuated the antiadrenergic effect of the selective A1 receptor agonist 2-chloro- N 6-cyclopentyladenosine (CCPA), whereas CSC did not influence the antiadrenergic action of this agonist. In isolated ventricular myocytes, CSC potentiated the inhibitory action of adenosine on Iso (2 × 10−7 M)-elicited increases in intracellular Ca2+concentration ([Ca2+]i) transients but did not influence Iso-induced changes in [Ca2+]itransients in the absence of exogenous adenosine. These results indicate that adenosine A2areceptor antagonists enhance A1-receptor-induced antiadrenergic responses and that A2a receptor agonists attenuate (albeit to a modest degree) the antiadrenergic actions of A1 receptor activation. In conclusion, the data in this study support the notion that an important physiological role of A2a receptors in the normal mammalian myocardium is to reduce A1 receptor-mediated antiadrenergic actions.

scholarly journals Angiotensin III Activates Nuclear Transcription Factor-κB in Cultured Mesangial Cells Mainly via AT2Receptors: Studies with AT1Receptor-Knockout Mice

2002 ◽  
Vol 13 (5) ◽  
pp. 1162-1171
Author(s):  
Óscar Lorenzo ◽  
Marta Ruiz-Ortega ◽  
Yusuke Suzuki ◽  
Mónica Rupérez ◽  
Vanesa Esteban ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Knockout Mice ◽  
Intracellular Signaling ◽  
Mesangial Cells ◽  
Renin Angiotensin System ◽  
Nuclear Factor Κb ◽  
Receptor Subtypes ◽  
Receptor Antagonists ◽  
Signaling Mechanism ◽  
Amino Terminal

ABSTRACT. Nuclear factor-κB (NF-κB) regulates many genes involved in renal pathophysiologic processes. It was previously demonstrated that angiotensin II (AngII) and its amino-terminal degradation product AngIII activate NF-κB in mesangial cells. However, which are the Ang receptor subtypes involved in the NF-κB pathway and whether these Ang peptides act through the same or different receptors in mesangial cells have not been evaluated. Under the culture conditions used, quiescent rat mesangial cells expressed both AT1and AT2receptors. To investigate the receptors involved in the NF-κB pathway, two different approaches were used,i.e., pharmacologic studies, using specific AT1and AT2receptor antagonists and agonists, and studies in AT1receptor-knockout mice. In cultured rat mesangial cells, both AT1and AT2receptor antagonists inhibited AngII-induced NF-κB DNA binding activity, whereas NF-κB activation elicited by AngIII was mainly blocked by the AT2receptor antagonist. Similar results were observed for cytosolic IκBα degradation. An AT2receptor agonist also activated NF-κB. In AT1receptor-knockout murine mesangial cells, AngIII and AngII increased NF-κB activity and degraded cytosolic IκBα; both processes were blocked by the AT2receptor antagonist. These data demonstrate that, in mesangial cells, NF-κB activation is mediated by AT1and AT2receptors, suggesting a novel intracellular signaling mechanism for AT2receptors in the kidney. Some differences in Ang peptide receptor-mediated responses were also observed. AngII activates NF-κB via AT1and AT2receptors, whereas AngIII acts mainly via AT2receptors. These results suggest the potential involvement of the AngIII/AT2receptor/NF-κB pathway in pathophysiologic processes in the kidney and provide a better understanding of the renin-angiotensin system.

Avermectin and avermectin derivatives are antagonists at the 4-aminobutyric acid (GABA) receptor on the somatic muscle cells of Ascaris; is this the site of anthelmintic action?

Parasitology ◽  
1990 ◽  
Vol 101 (2) ◽  
pp. 265-271 ◽  
Author(s):  
L. Dye-Holden ◽  
R. J. Walker
Keyword(s):  
Receptor Antagonist ◽  
Gaba Receptor ◽  
Parasitic Nematode ◽  
Anthelmintic Activity ◽  
Muscle Cells ◽  
Aminobutyric Acid ◽  
Electrophysiological Recording ◽  
Receptor Antagonists ◽  
Somatic Muscle

The mechanism underlying the ability of the anthelmintic avermectin to paralyse the nematode Ascaris is not yet fully understood. Using conventional two-electrode electrophysiological recording techniques we have demonstrated that micromolar concentrations of ivermectin block the inhibitory GABA response on the muscle cells of the parasitic nematode Ascaris. The ability of a number of avermectin derivatives to act as receptor antagonists for the Ascaris muscle GABA receptor has been determined. This provides useful information to compare with the in vivo anthelmintic potency of these compounds. Abamectin, the most potent anthelmintic, was the most potent compound at inhibiting the GABA response whilst octahydroavermectin, a compound which lacks anthelmintic activity, did not block the GABA receptor. This is consistent with the notion that the GABA receptor antagonist properties of the avermectins could contribute to their anthelmintic action.

Sign in / Sign up

Export Citation Format

Share Document