scholarly journals Serotonin 5-HT2 Receptors Induce a Long-Lasting Facilitation of Spinal Reflexes Independent of Ionotropic Receptor Activity

2005 ◽  
Vol 94 (4) ◽  
pp. 2867-2877 ◽  
Author(s):  
Barbara L. Shay ◽  
Michael Sawchuk ◽  
David W. Machacek ◽  
Shawn Hochman
Keyword(s):  
Afferent Fiber ◽  
Receptor Activation ◽  
Receptor Expression ◽  
Spinal Reflexes ◽  
Field Size ◽  
Sprague Dawley ◽  
Ionotropic Receptor ◽  
Sensory Afferents ◽  
Selective Blockade

Dorsal root-evoked stimulation of sensory afferents in the hemisected in vitro rat spinal cord produces reflex output, recorded on the ventral roots. Transient spinal 5-HT2C receptor activation induces a long-lasting facilitation of these reflexes (LLFR) by largely unknown mechanisms. Two Sprague–Dawley substrains were used to characterize network properties involved in this serotonin (5-HT) receptor–mediated reflex plasticity. Serotonin more easily produced LLFR in one substrain and a long-lasting depression of reflexes (LLDR) in the other. Interestingly, LLFR and LLDR were bidirectionally interconvertible using 5-HT2A/2C and 5-HT1A receptor agonists, respectively, regardless of substrain. LLFR was predominantly Aβ afferent fiber mediated, consistent with prominent 5-HT2C receptor expression in the Aβ fiber projection territories (deeper spinal laminae). Reflex facilitation involved an unmasking of polysynaptic pathways and an increased receptive field size. LLFR emerged even when reflexes were evoked three to five times/h, indicating an activity independent induction. Both the NMDA and AMPA/kainate receptor–mediated components of the reflex could be facilitated, and facilitation was dependent on 5-HT receptor activation alone, not on coincident reflex activation in the presence of 5-HT. Selective blockade of GABAA and/or glycine receptors also did not prevent reflex amplification and so are not required for LLFR. Indeed, a more robust response was seen after blockade of spinal inhibition, indicating that inhibitory processes serve to limit reflex amplification. Overall we demonstrate that the serotonergic system has the capacity to induce long-lasting bidirectional changes in reflex strength in a manner that is nonassociative and independent of evoked activity or activation of ionotropic excitatory and inhibitory receptors.

scholarly journals AT1a influences GABAA-mediated inhibition through regulation of KCC2 expression

2018 ◽  
Vol 315 (5) ◽  
pp. R972-R982 ◽  
Author(s):  
George E. Farmer ◽  
Kirthikaa Balapattabi ◽  
Martha E. Bachelor ◽  
Joel T. Little ◽  
J. Thomas Cunningham
Keyword(s):  
Protein Expression ◽  
Body Fluid ◽  
Neuronal Excitability ◽  
Receptor Activation ◽  
Cardiovascular Control ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Fluid Homeostasis ◽  
Body Fluid Homeostasis

The median preoptic nucleus (MnPO) is an integrative site involved in body fluid homeostasis, cardiovascular control, thermoregulation, and sleep homeostasis. Angiotensin II (ANG II), a neuropeptide shown to have excitatory effects on MnPO neurons, is of particular interest with regard to its role in body fluid homeostasis and cardiovascular control. The present study investigated the role of angiotensin type 1a (AT1a) receptor activation on neuronal excitability in the MnPO. Male Sprague-Dawley rats were infused with an adeno-associated virus with an shRNA against the AT1a receptor or a scrambled control. In vitro loose-patch voltage-clamp recordings of spontaneous action potential activity were made from labeled MnPO neurons in response to brief focal application of ANG II or the GABAA receptor agonist muscimol. Additionally, tissue punches from MnPO were taken to asses mRNA and protein expression. AT1a receptor knockdown neurons were insensitive to ANG II and showed a marked reduction in GABAA-mediated inhibition. The reduction in GABAA-mediated inhibition was not associated with reductions in mRNA or protein expression of GABAA β-subunits. Knockdown of the AT1a receptor was associated with a reduction in the potassium-chloride cotransporter KCC2 mRNA as well as a reduction in pS940 KCC2 protein. The impaired GABAA-mediated inhibition in AT1a knockdown neurons was recovered by bath application of phospholipase C and protein kinase C activators. The following study indicates that AT1a receptor activation mediates the excitability of MnPO neurons, in part, through the regulation of KCC2. The regulation of KCC2 influences the intracellular [Cl−] and the subsequent efficacy of GABAA-mediated currents.

scholarly journals Modulation of phrenic motoneuron excitability by ATP: consequences for respiratory-related output in vitro

2002 ◽  
Vol 92 (5) ◽  
pp. 1899-1910 ◽  
Author(s):  
Gareth B. Miles ◽  
Marjorie A. Parkis ◽  
Janusz Lipski ◽  
Gregory D. Funk
Keyword(s):  
Pyridoxal Phosphate ◽  
Rapid Onset ◽  
Receptor Activation ◽  
Receptor Expression ◽  
P2x Receptor ◽  
Repetitive Firing ◽  
Burst Amplitude ◽  
Inward Currents ◽  
High Level

On the basis of the high level of P2X receptor expression found in phrenic motoneurons (MN) in rats (Kanjhan et al., J Comp Neurol407: 11–32, 1999) and potentiation of hypoglossal MN inspiratory activity by ATP (Funk et al., J Neurosci 17: 6325–6337, 1997), we tested the hypothesis that ATP receptor activation also modulates phrenic MN activity. This question was examined in rhythmically active brain stem-spinal cord preparations from neonatal rats by monitoring effects of ATP on the activity of spinal C4 nerve roots and phrenic MNs. ATP produced a rapid-onset, dose-dependent, suramin- and pyridoxal-phosphate-6-azophenyl-2′,4′-disulphonic acid 4-sodium-sensitive increase in C4 root tonic discharge and a 22 ± 7% potentiation of inspiratory burst amplitude. This was followed by a slower, 10 ± 5% reduction in burst amplitude. ATPγS, the hydrolysis-resistant analog, evoked only the excitatory response. ATP induced inward currents (57 ± 39 pA) and increased repetitive firing of phrenic MNs. These data, combined with persistence of ATP currents in TTX and immunolabeling for P2X2 receptors in Fluoro-Gold-labeled C4 MNs, implicate postsynaptic P2 receptors in the excitation. Inspiratory synaptic currents, however, were inhibited by ATP. This inhibition differed from that seen in root recordings; it did not follow an excitation, had a faster onset, and was induced by ATPγS. Thus ATP inhibited activity through at least two mechanisms: 1) a rapid P2 receptor-mediated inhibition and 2) a delayed P1 receptor-mediated inhibition associated with hydrolysis of ATP to adenosine. The complex effects of ATP on phrenic MNs highlight the importance of ATP as a modulator of central motor outflows.

scholarly journals Leukotriene Receptors: Crucial Components in Vascular Inflammation

2007 ◽  
Vol 7 ◽  
pp. 1422-1439 ◽  
Author(s):  
Magnus Bäck
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Vascular Inflammation ◽  
Vascular Wall ◽  
Receptor Activation ◽  
Receptor Expression ◽  
Surface Receptors ◽  
Beneficial Effects

The accumulation of immune cells during vascular inflammation leads to formation of leukotrienes (LTs). While macrophages represent a major source of LT biosynthesis in the proximity of the vascular wall, activated T lymphocytes may, in addition, play a key regulatory role on macrophage expression of LT-forming enzymes. Within the vascular wall, LTs activate cell surface receptors of the BLT and CysLT subtypes expressed on vascular smooth muscle and endothelial cells. The LT receptor expression on those cells is highly dependent on transcriptional regulation by pro- and anti-inflammatory mediators. LT receptor activation on vascular smooth muscle cells is associated with both directly and indirectly induced vasoconstriction, as well as intimal hyperplasia through stimulation of migration and proliferation. On the other hand, endothelial LT receptors induce vasorelaxation and leukocyte recruitment and adhesion. Results fromin vitroandin vivostudies of LT receptor antagonists indicate potential beneficial effects in atherosclerosis and other inflammatory cardiovascular diseases.

scholarly journals Afferent arteriolar vasodilator effect of adenosine predominantly involves adenosine A2B receptor activation

2010 ◽  
Vol 299 (2) ◽  
pp. F310-F315 ◽  
Author(s):  
Ming-Guo Feng ◽  
L. Gabriel Navar
Keyword(s):  
Receptor Activation ◽  
Receptor Blocker ◽  
Maximum Effect ◽  
Sprague Dawley ◽  
Afferent Arterioles ◽  
Vasodilator Action ◽  
Renal Vascular ◽  
Arteriolar Diameter

Adenosine is an important paracrine agent regulating renal vascular tone via adenosine A1 and A2 receptors. While A2B receptor message and protein have been localized to preglomerular vessels, functional evidence on the role of A2B receptors in mediating the vasodilator action of adenosine on afferent arterioles is not available. The present study determined the role of A2B receptors in mediating the afferent arteriolar dilation and compared the effects of A2B and A2A receptor blockade on afferent arterioles. We used the rat in vitro blood-perfused juxtamedullary nephron technique combined with videomicroscopy. Single afferent arterioles of Sprague-Dawley rats were visualized and superfused with solutions containing adenosine or adenosine A2 receptor agonist (CV-1808) along with adenosine A2B and A2A receptor blockers. Adenosine (10 μmol/l) caused modest constriction and subsequent superfusion with SCH-58261 (SCH), an A2A receptor blocker, at concentrations up 10 μmol/l elicited only slight additional decreases in afferent arteriolar diameter with maximum effect at a concentration of 1 μmol/l (−11.0 ± 2.5%, n = 6, P < 0.05). However, superfusion of adenosine-treated vessels with MRS-1754 (MRS), an A2B receptor blocker, elicited greater decreases in afferent arteriolar diameter (−26.0 ± 4.7%, n = 5, P < 0.01). SCH did not significantly augment the adenosine-mediated afferent constriction elicited by MRS; however, adding MRS after SCH caused further significant vasoconstriction. Superfusion with CV-1808 dilated afferent arterioles (17.2 ± 2.4%, n = 6, P < 0.01). This effect was markedly attenuated by MRS (−22.6 ± 2.0%, n = 5, P < 0.01) but only slightly reduced by SCH (−9.0 ± 1.1%, n = 5, P < 0.05) and completely prevented by adding MRS after SCH (−24.7 ± 1.8%, n = 5, P < 0.01). These results indicate that, while both A2A and A2B receptors are functionally expressed in juxtamedullary afferent arterioles, the powerful vasodilating action of adenosine predominantly involves A2B receptor activation, which counteracts A1 receptor-mediated vasoconstriction.

scholarly journals Potential involvement of P2Y2 receptor in diuresis of postobstructive uropathy in rats

2010 ◽  
Vol 298 (3) ◽  
pp. F634-F642 ◽  
Author(s):  
Yue Zhang ◽  
Donald E. Kohan ◽  
Raoul D. Nelson ◽  
Noel G. Carlson ◽  
Bellamkonda K. Kishore
Keyword(s):  
Mrna Expression ◽  
Collecting Duct ◽  
Receptor Activation ◽  
Receptor Expression ◽  
Urinary Concentration ◽  
Sham Operation ◽  
Protein Abundance ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Relative Mrna Expression

AVP resistance of the medullary collecting duct (mCD) in postobstructive uropathy (POU) has been attributed to increased production of PGE2. P2Y2 receptor activation causes production of PGE2 by the mCD. We hypothesize that increased P2Y2 receptor expression and/or activity may contribute to the diuresis of POU. Sprague-Dawley rats were subjected to bilateral ureteral obstruction for 24 h followed by release (BUO/R, n = 17) or sham operation (SHM/O, n = 15) and euthanized after 1 wk or 12 days. BUO/R rats developed significant polydipsia, polyuria, urinary concentration defect, and increased urinary PGE2 and decreased aquaporin-2 protein abundance in the inner medulla compared with SHM/O rats. After BUO/R, the relative mRNA expression of P2Y2 and P2Y6 receptors was increased by 2.7- and 4.9-fold, respectively, without significant changes in mRNA expression of P2Y1 or P2Y4 receptor. This was associated with a significant 3.5-fold higher protein abundance of the P2Y2 receptor in BUO/R than SHM/O rats. When freshly isolated mCD fractions were challenged with different types of nucleotides (ATPγS, ADP, UTP, or UDP), BUO/R and SHM/O rats responded to only ATPγS and UTP and released PGE2, consistent with involvement of the P2Y2, but not P2Y6, receptor. ATPγS- or UTP-stimulated increases in PGE2 were much higher in BUO/R (3.20- and 2.28-fold, respectively, vs. vehicle controls) than SHM/O (1.68- and 1.30-fold, respectively, vs. vehicle controls) rats. In addition, there were significant 2.4- and 2.1-fold increases in relative mRNA expression of prostanoid EP1 and EP3 receptors, respectively, in the inner medulla of BUO/R vs. SHM/O rats. Taken together, these data suggest that increased production of PGE2 by the mCD in POU may be due to increased expression and activity of the P2Y2 receptor. Increased mRNA expression of EP1 and EP3 receptors in POU may also help accentuate PGE2-induced signaling in the mCD.

scholarly journals AT1a dependent GABAA inhibition in the MnPO following chronic intermittent hypoxia

2021 ◽  
Author(s):  
George E. Farmer ◽  
Joel T. Little ◽  
Alexandria B. Marciante ◽  
J. Thomas Cunningham
Keyword(s):  
Intermittent Hypoxia ◽  
Receptor Expression ◽  
Chronic Intermittent Hypoxia ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Spontaneous Action ◽  
Potential Activity ◽  
At1a Receptor

Chronic intermittent hypoxia (CIH) is associated with diurnal hypertension, increased sympathetic nerve activity (SNA), and increases in circulating angiotensin II (ANG II). In rats, CIH increases angiotensin type 1 (AT1a) receptor expression in the median preoptic nucleus (MnPO), and pharmacological blockade or viral knockdown of this receptor prevents CIH dependent increases in diurnal blood pressure. The current study investigates the role of AT1a receptor in modulating the activity of MnPO neurons following 7 days of CIH. Male Sprague-Dawley rats received MnPO injections of an adeno-associated virus with a shRNA against the AT1a receptor or a scrambled control. Rats were then exposed to CIH 8 h a day for 7 days. In vitro loose patch recordings of spontaneous action potential activity were made from labeled MnPO neurons in response to brief focal application of ANG II or the GABAA receptor agonist muscimol. Additionally, MnPO KCC2 protein expression was assessed using Western blot. CIH impaired the duration but not the magnitude of ANG II mediated excitation in the MnPO. Both CIH and AT1a knockdown also impaired GABAA mediated inhibition and CIH with AT1a knockdown produced GABAA mediated excitation. Recordings using the ratiometric Cl- indicator ClopHensorN showed CIH was associated with Cl- efflux in MnPO neurons that was associated with decreased KCC2 phosphorylation. The combination of CIH and AT1a knockdown attenuated reduced KCC2 phosphorylation seen with CIH alone. The current study shows that CIH, through the activity of AT1a receptors, can impair GABAA mediated inhibition in the MnPO contributing sustained hypertension.

scholarly journals P2X1 receptor blockade inhibits whole kidney autoregulation of renal blood flow in vivo

2010 ◽  
Vol 298 (6) ◽  
pp. F1360-F1368 ◽  
Author(s):  
David A. Osmond ◽  
Edward W. Inscho
Keyword(s):  
Blood Flow ◽  
Renal Blood Flow ◽  
Renal Perfusion ◽  
Receptor Activation ◽  
Receptor Blockade ◽  
Sprague Dawley ◽  
Receptor Stimulation ◽  
Kidney Blood Flow

In vitro experiments demonstrate that P2X1 receptor activation is important for normal afferent arteriolar autoregulatory behavior, but direct in vivo evidence for this relationship occurring in the whole kidney is unavailable. Experiments were performed to test the hypothesis that P2X1 receptors are important for autoregulation of whole kidney blood flow. Renal blood flow (RBF) was measured in anesthetized male Sprague-Dawley rats before and during P2 receptor blockade with PPADS, P2X1 receptor blockade with IP5I, or A1 receptor blockade with DPCPX. Both P2X1 and A1 receptor stimulation with α,β-methylene ATP and CPA, respectively, caused dose-dependent decreases in RBF. Administration of either PPADS or IP5I significantly blocked P2X1 receptor stimulation. Likewise, administration of DPCPX significantly blocked A1 receptor activation to CPA. Autoregulatory behavior was assessed by measuring RBF responses to reductions in renal perfusion pressure. In vehicle-infused rats, as pressure was decreased from 120 to 100 mmHg, there was no decrease in RBF. However, in either PPADS- or IP5I-infused rats, each decrease in pressure resulted in a significant decrease in RBF, demonstrating loss of autoregulatory ability. In DPCPX-infused rats, reductions in pressure did not cause significant reductions in RBF over the pressure range of 100–120 mmHg, but the autoregulatory curve tended to be steeper than vehicle-infused rats over the range of 80–100 mmHg, suggesting that A1 receptors may influence RBF at lower pressures. These findings are consistent with in vitro data from afferent arterioles and support the hypothesis that P2X1 receptor activation is important for whole kidney autoregulation in vivo.

scholarly journals Renal medullary ETB receptors produce diuresis and natriuresis via NOS1

2008 ◽  
Vol 294 (5) ◽  
pp. F1205-F1211 ◽  
Author(s):  
Daisuke Nakano ◽  
Jennifer S. Pollock ◽  
David M. Pollock
Keyword(s):  
Renal Medulla ◽  
Urinary Sodium Excretion ◽  
Receptor Activation ◽  
No Production ◽  
Sprague Dawley ◽  
Receptor Stimulation ◽  
Water Excretion ◽  
Sprague Dawley Rats

Endothelin-1 (ET-1) plays an important role in the regulation of salt and water excretion in the kidney. Considerable in vitro evidence suggests that the renal medullary ETB receptor mediates ET-1-induced inhibition of electrolyte reabsorption by stimulating nitric oxide (NO) production. The present study was conducted to test the hypothesis that NO synthase 1 (NOS1) and protein kinase G (PKG) mediate the diuretic and natriuretic effects of ETB receptor stimulation in vivo. Infusion of the ETB receptor agonist sarafotoxin S6c (S6c: 0.45 μg·kg−1·h−1) in the renal medulla of anesthetized, male Sprague-Dawley rats markedly increased the urine flow (UV) and urinary sodium excretion (UNaV) by 67 and 120%, respectively. This was associated with an increase in medullary cGMP content but did not affect blood pressure. In addition, S6c-induced diuretic and natriuretic responses were absent in ETB receptor-deficient rats. Coinfusion of NG-propyl-l-arginine (10 μg·kg−1·h−1), a selective NOS1 inhibitor, suppressed S6c-induced increases in UV, UNaV, and medullary cGMP concentrations. Rp-8-Br-PET-cGMPS (10 μg·kg−1·h−1) or RQIKIWFQNRRMKWKK-LRK5H-amide (18 μg·kg−1·h−1), a PKG inhibitor, also inhibited S6c-induced increases in UV and UNaV. These results demonstrate that renal medullary ETB receptor activation induces diuretic and natriuretic responses through a NOS1, cGMP, and PKG pathway.

scholarly journals Tissue-nonspecific alkaline phosphatase promotes axonal growth of hippocampal neurons

2011 ◽  
Vol 22 (7) ◽  
pp. 1014-1024 ◽  
Author(s):  
M. Díez-Zaera ◽  
J. I. Díaz-Hernández ◽  
E. Hernández-Álvarez ◽  
H. Zimmermann ◽  
M. Díaz-Hernández ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Hippocampal Neurons ◽  
Hydrolysis Product ◽  
Axonal Growth ◽  
Receptor Activation ◽  
Extracellular Atp ◽  
Adult Brain ◽  
Receptor Expression ◽  
Selective Blockade ◽  
Tissue Nonspecific Alkaline Phosphatase

Axonal growth is essential for establishing neuronal circuits during brain development and for regenerative processes in the adult brain. Unfortunately, the extracellular signals controlling axonal growth are poorly understood. Here we report that a reduction in extracellular ATP levels by tissue-nonspecific alkaline phosphatase (TNAP) is essential for the development of neuritic processes by cultured hippocampal neurons. Selective blockade of TNAP activity with levamisole or specific TNAP knockdown with short hairpin RNA interference inhibited the growth and branching of principal axons, whereas addition of alkaline phosphatase (ALP) promoted axonal growth. Neither activation nor inhibition of adenosine receptors affected the axonal growth, excluding the contribution of extracellular adenosine as a potential hydrolysis product of extracellular ATP to the TNAP-mediated effects. TNAP was colocalized at axonal growth cones with ionotropic ATP receptors (P2X7 receptor), whose activation inhibited axonal growth. Additional analyses suggested a close functional interrelation of TNAP and P2X7 receptors whereby TNAP prevents P2X7 receptor activation by hydrolyzing ATP in the immediate environment of the receptor. Furthermore inhibition of P2X7 receptor reduced TNAP expression, whereas addition of ALP enhanced P2X7 receptor expression. Our results demonstrate that TNAP, regulating both ligand availability and protein expression of P2X7 receptor, is essential for axonal development.

α-2 And β-adrenergic receptors mediate NE's biphasic effects on rat thick ascending limb chloride flux

2001 ◽  
Vol 281 (3) ◽  
pp. R979-R986 ◽  
Author(s):  
Craig F. Plato
Keyword(s):  
Adrenergic Receptors ◽  
Receptor Activation ◽  
Thick Ascending Limb ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Chloride Flux ◽  
Concentration Dependent Manner ◽  
Β Adrenergic Receptors ◽  
Isolated Rat

The sympathetic neurotransmitter norepinephrine (NE) influences renal sodium excretion via activation of adrenergic receptors. The thick ascending limb (THAL) possesses both α-2 and β-adrenergic receptors. However, the role(s) different adrenergic receptors play in how isolated THALs respond to NE are unclear. We tested the hypothesis that both α-2 and β-adrenergic receptors are responsive to NE in the isolated THAL, with α-2 receptors inhibiting and β-receptors stimulating chloride flux ( J Cl). THALs from male Sprague-Dawley rats were perfused in vitro, and the effects of 1) incremental NE, 2) the α-2 agonist clonidine, and 3) the β-agonist isoproterenol on J Cl were measured. Low concentrations (0.1 nM) of NE decreased J Clfrom a rate of 114.2 ± 8.1 to 93.5 ± 14.6 pmol · mm−1 · min−1( P < 0.05), with the nadir occurring at 1 nM (67.7 ± 8.8 pmol · mm−1 · min−1; P < 0.05). In contrast, greater concentrations of NE significantly increased J Cl from the nadir to a maximal rate of 131.0 ± 28.5 pmol · mm−1 · min−1 at 10 μM ( P < 0.05). To evaluate the adrenergic receptors mediating these responses, the THAL J Cl response to NE was measured in the presence of selective antagonists of β- and α-2 receptors. A concentration of NE (1 μM), which alone tended to increase J Cl, decreased THAL J Cl (from 148.9 ± 16.4 to 76.2 ± 13.6 pmol · mm−1 · min−1; P < 0.01) in the presence of the β-antagonist propranolol. In contrast, a concentration of NE (0.1 μM), which alone tended to decrease J Cl, increased THAL J Cl (from 85.5 ± 20.1 to 111.8 ± 20.1 pmol · mm−1 · min−1; P < 0.05) in the presence of the α-2 antagonist rauwolscine. To further clarify the role of different adrenergic receptors, selective adrenergic agonists were used. The α-2 agonist clonidine decreased J Cl from 102.4 ± 9.9 to 54.0 ± 15.7 pmol · mm−1 · min−1, a reduction of 49.1 ± 11.0% ( P < 0.02). In contrast, the β-agonist isoproterenol stimulated J Cl from 95.3 ± 11.6 to 144.1 ± 15.0 pmol · mm−1 · min−1, an increase of 56 ± 14% ( P < 0.01). We conclude that 1) the sympathetic neurotransmitter NE exerts concentration-dependent effects on J Cl in the isolated rat THAL, 2) selective α-2 receptor activation inhibits THAL J Cl, and 3) selective β-receptor activation stimulates THAL J Cl. These data indicate the response elicited by the isolated rat THAL to NE is dependent on the neurotransmitter concentration, such that application of NE in vitro biphasically modulates J Cl via differential activation of α-2 and β-adrenergic receptors in a concentration-dependent manner.

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