The Experts below are selected from a list of 6378 Experts worldwide ranked by ideXlab platform
Philip J. Kadowitz - One of the best experts on this subject based on the ideXlab platform.
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opyright © American Society of Andrology [Tyr’]-Nociceptin and Nociceptin Have Similar Naloxone- Insensitive Erectile Activity in the Cat
2013Co-Authors: Hunter C. Champion, Trinity J. Bivalacqua, Run Wang, Wayne J. G. Hellstrom, Philip J. KadowitzAbstract:ABSTRACT: The heptadecapeptide Nociceptin, also known as Orphania FQ, is a newly discovered endogenous ligand for the opioidlike G-protein-coupled receptor ORL,. The present study was undertaken to investigate responses to intracavernosal injections of the Nociceptin analog [Tyr’]-Nociceptin and to investigate the effects of naloxone on erectile responses in anesthetized cats to [Tyr1]-Nociceptin and to Nociceptin. Intracavernosal injections of [Tyr1]-Nociceptin and of Nociceptin in doses of 0.3-30 nmol elicited dose-related increases in cavernosal pressure, which, at the highest dose studied, were comparable to increases induced by the triple-drug standard (papaverine, phentolamine, and prostaglandin E1), a preparation used in the treatment of erectile dysfunction. Responses to [Tyr1]-Nociceptin were rapid in onset and had a time course similar to responses to Nociceptin. Metenkephalin increased cavemosal pressure, whereas injections of Nociceptin-(2-17), dynorphin A, and 13-endorphin did not alter cavemosal pressure. Erectile responses to Nociceptin and to (Tyr1]-Nociceptin were not altered after administration of the opioid receptor antagonist naloxone at a time when erectile responses to metenkephalin were attenuated. These data show that [Tyr1]-Nociceptin and Nociceptin have similar naloxone-insensitive erectile activity in the cat
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[Tyr1]-Nociceptin and Nociceptin Have Similar Naloxone Insensitive Erectile Activity in the Cat
Journal of andrology, 1998Co-Authors: Hunter C. Champion, Trinity J. Bivalacqua, Run Wang, Wayne J. G. Hellstrom, Philip J. KadowitzAbstract:The heptadecapeptide Nociceptin, also known as Orphanin FQ, is a newly discovered endogenous ligand for the opioid-like G-protein-coupled receptor ORL 1 . The present study was undertaken to investigate responses to intracavernosal injections of the Nociceptin analog [Tyr 1 ]-Nociceptin and to investigate the effects of naloxone on erectile responses in anesthetized cats to [Tyr 1 ]-Nociceptin and to Nociceptin. Intracavernosal injections of [Tyr 1 ]-Nociceptin and of Nociceptin in doses of 0.3-30 nmol elicited dose-related increases in cavernosal pressure, which, at the highest dose studied, were comparable to increases induced by the triple-drug standard (papaverine, phentolamine, and prostaglandin E 1 ), a preparation used in the treatment of erectile dysfunction. Responses to [Tyr 1 ]-Nociceptin were rapid in onset and had a time course similar to responses to Nociceptin. Metenkephalin increased cavernosal pressure, whereas injections of Nociceptin-(2-17), dynorphin A, and β-endorphin did not alter cavernosal pressure. Erectile responses to Nociceptin and to [Tyr 1 ]-Nociceptin were not altered after administration of the opioid receptor antagonist naloxone at a time when erectile responses to metenkephalin were attenuated. These data show that [Tyr 1 ]-Nociceptin and Nociceptin have similar naloxone-insensitive erectile activity in the cat.
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Analysis of Vasodepressor Responses to Nociceptin and Nociceptin Analogs in the Systemic Vascular Bed of the Anesthetized Rabbit In Vivo
Journal of cardiovascular pharmacology and therapeutics, 1998Co-Authors: Hunter C. Champion, Trinity J. Bivalacqua, A. Rauchwarger, Sean M. Mcwilliams, Dennis B. Mcnamara, Philip J. KadowitzAbstract:Background: The heptadecapeptide Nociceptin, also known as Orphanin FQ, is a recently discovered endogenous ligand for the opioid-like G-protein-coupled receptor ORL(1). Methods and Results: In the present study, responses to Nociceptin, [Tyr(1)]-Nociceptin, Nociceptin-(2-17), Nociceptin-(1-11), and Nociceptin-(1-7) were compared in the systemic vascular bed of the rabbit. Nociceptin and [Tyr(1)]-Nociceptin induced dose related decreases in systemic arterial pressure (SAP) when injected in doses of 1-30 nmol/kg intravenous (IV); in terms of relative vasodepressor activity, [Tyr(1)]-Nociceptin and nocicpetin were similar in potency. However, nocicpetin-(2-17), nocicpetin-(1-11), and Nociceptin-(1-7) had no effect on SAP when injected in doses up to 30 nmol/kg IV. The decreases in SAP in response to Nociceptin and [Tyr(1)]-Nociceptin were not altered by the opioid receptor antagonist naloxone at a time when depressor responses to methionine-enkephalin were reduced significantly. Conclusions: The results of the present study show that vasodepressor responses to Nociceptin and [Tyr(1)]-nocicpetin are mediated by the activation of a naloxene-insensitive opioid receptor and are not dependent on the presence of Phe at the N-terminus of the Nociceptin sequence. Moreover, the present results show that Nociceptin-(2-17), Nociceptin-(1-11), and Nociceptin-(1-7) do not alter SAP in the rabbit, indicating that peptide chain length is important for the expression of vasodepressor activity.
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[Tyr1]-Nociceptin, a novel Nociceptin analog, decreases systemic arterial pressure by a naloxone-insensitive mechanism in the rat.
Biochemical and biophysical research communications, 1997Co-Authors: Hunter C. Champion, Philip J. KadowitzAbstract:The heptadecapeptide Nociceptin, also known as Orphanin FQ, is a newly discovered endogenous ligand for the opioid-like G-protein-coupled receptor ORL1. In the present study, responses to a novel Nociceptin analog, [Tyr1]-Nociceptin, were investigated in the systemic vascular bed of the rat. [Tyr1]-Nociceptin induced dose-related decrease in systemic arterial pressure when injected in doses of 1-30 nmol/kg i.v. In terms of relative vasodepressor activity, [Tyr1]-Nociceptin was comparable in potency to Nociceptin. The decreases in systemic arterial pressure in response to [Tyr1]-Nociceptin were not altered by the opioid receptor antagonist naloxone in a dose that reduced responses to Met-enkephalin. The results of the present study show that vasodepressor responses to [Tyr1]-Nociceptin are not mediated by the activation of a naloxone-sensitive opioid receptor and are not dependent on the presence of Phe at the N-terminus of the Nociceptin sequence.
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Nociceptin, an endogenous ligand for the ORL1 receptor, decreases cardiac output and total peripheral resistance in the rat.
Peptides, 1997Co-Authors: Hunter C. Champion, Marc A. Czapla, Philip J. KadowitzAbstract:Abstract Champion, H. C., M. A. Czapla and P. J. Kadowitz. Nociceptin, an endogenous ligand for the ORL1 receptor, decreases cardiac output and total peripheral resistance in the rat. Peptides 18 (5) 72–732, 1997.—The heptadecapeptide Nociceptin, also known as Orphanin FQ, is a newly discovered endogenous ligand for the opioid-like G-protein coupled receptor, ORL1. In the present study, responses to intravenous injections of Nociceptin were investigated in the systemic vascular bed of the rat. Nociceptin induced dose-related decreases in systemic arterial pressure and total peripheral resistance when injected in doses of 1–30 nmol/kg IV. Nociceptin decreased heart rate and in doses of 10 and 30 nmol/kg IV, significantly decreased cardiac output. In terms of relative vasodilator activity, Nociceptin was approximately 10-fold less potent than the beta-adrenergic receptor agonist isoproterenol. These data show that Nociceptin has novel vasodilator activity in the systemic vascular bed of the rat.
H. Ulrich Zeilhofer - One of the best experts on this subject based on the ideXlab platform.
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Selective Suppression of Inhibitory Synaptic Transmission by Nocistatin in the Rat Spinal Cord Dorsal Horn
2013Co-Authors: H. Ulrich Zeilhofer, Uta Muth-selbach, Hans Gühring, Katharina Erb, Seifollah AhmadiAbstract:Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) are two recently identified neuropeptides with opposing effects on several CNS functions, including spinal nociception. The cellular mechanisms that underlie this antagonism are not known. Here, we have investigated the effects of both peptides on synaptic transmission mediated by the three fast neurotransmitters L-glutamate, glycine, and GABA in the superficial layers of the rat spinal cord horn, which constitute the first important site of integration of nociceptive information in the pain pathway. NST selectively reduced transmitter release from inhibitory interneurons via a presynaptic Bordetella pertussis toxin-sensitive mechanism but left excitatory glutamatergic transmission unaffected. In contrast, N/OFQ only inhibited excitatory transmission. In the rat formalin test, an animal model of tonic pain in which N/OFQ exerts antinociceptive activity, NST induced profoun
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Modulation of synaptic transmission by Nociceptin/orphanin FQ and nocistatin in the spinal cord dorsal horn of mutant mice lacking the Nociceptin/orphanin FQ receptor.
Molecular pharmacology, 2001Co-Authors: Seifollah Ahmadi, Hiroshi Takeshima, Hans Gühring, Carolin E. Kotalla, Andreas Pahl, H. Ulrich ZeilhoferAbstract:Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) are two neuropeptides derived from the same precursor protein that exhibit opposing effects on spinal neurotransmission and nociception. Here, we have used whole-cell, patch-clamp recordings from visually identified neurons in spinal cord dorsal horn slices of genetically modified mice to investigate the role of the N/OFQ receptor (N/OFQ-R) in the modulatory action of both peptides on excitatory glutamatergic and inhibitory glycinergic and gamma-aminobutyric acid (GABA)-ergic synaptic transmission. In wild-type mice, N/OFQ selectively suppressed excitatory transmission in a concentration-dependent manner but left inhibitory synaptic transmission unaffected. In contrast, NST reduced only inhibitory but not alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated excitatory synaptic transmission. N/OFQ-mediated inhibition of excitatory transmission was completely absent in N/OFQ-R receptor-deficient (N/OFQ-R(-/-)) mice and significantly reduced in heterozygous (N/OFQ-R(+/-)) mice, whereas the action of NST on inhibitory neurotransmission was completely retained. To test for the relevance of these results for spinal nociception, we investigated the effects of intrathecally injected N/OFQ in the mouse formalin test, an animal model of tonic pain. N/OFQ (3 nmol/mouse) induced significant antinociception in wild-type mice, but had no antinociceptive effects in N/OFQ-R(-/-) mice. These results indicate that the inhibitory action of N/OFQ on excitatory glutamatergic synaptic transmission and its spinal antinociceptive action are mediated via the N/OFQ receptor, whereas the action of NST is independent of this receptor.
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modulation of synaptic transmission by Nociceptin orphanin fq and nocistatin in the spinal cord dorsal horn of mutant mice lacking the Nociceptin orphanin fq receptor
Molecular Pharmacology, 2001Co-Authors: Seifollah Ahmadi, Hiroshi Takeshima, H. Ulrich Zeilhofer, Hans Gühring, Carolin E. Kotalla, Andreas PahlAbstract:Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) are two neuropeptides derived from the same precursor protein that exhibit opposing effects on spinal neurotransmission and nociception. Here, we have used whole-cell, patch-clamp recordings from visually identified neurons in spinal cord dorsal horn slices of genetically modified mice to investigate the role of the N/OFQ receptor (N/OFQ-R) in the modulatory action of both peptides on excitatory glutamatergic and inhibitory glycinergic and gamma-aminobutyric acid (GABA)-ergic synaptic transmission. In wild-type mice, N/OFQ selectively suppressed excitatory transmission in a concentration-dependent manner but left inhibitory synaptic transmission unaffected. In contrast, NST reduced only inhibitory but not alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated excitatory synaptic transmission. N/OFQ-mediated inhibition of excitatory transmission was completely absent in N/OFQ-R receptor-deficient (N/OFQ-R(-/-)) mice and significantly reduced in heterozygous (N/OFQ-R(+/-)) mice, whereas the action of NST on inhibitory neurotransmission was completely retained. To test for the relevance of these results for spinal nociception, we investigated the effects of intrathecally injected N/OFQ in the mouse formalin test, an animal model of tonic pain. N/OFQ (3 nmol/mouse) induced significant antinociception in wild-type mice, but had no antinociceptive effects in N/OFQ-R(-/-) mice. These results indicate that the inhibitory action of N/OFQ on excitatory glutamatergic synaptic transmission and its spinal antinociceptive action are mediated via the N/OFQ receptor, whereas the action of NST is independent of this receptor.
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The role of the ORL1 receptor in the modulation of spinal neurotransmission by Nociceptin/orphanin FQ and nocistatin.
European journal of pharmacology, 2001Co-Authors: Seifollah Ahmadi, Jörg T. Liebel, H. Ulrich ZeilhoferAbstract:Nociceptin/orphanin FQ and nocistatin are two neuropeptides with opposing effects on spinal neurotransmission and nociception. Nociceptin/orphanin FQ selectively suppresses excitatory glutamatergic neurotransmission, while nocistatin selectively interferes with glycinergic and gamma-aminobutyric acid (GABA)-ergic transmission. Here, we performed whole-cell patch-clamp recordings from superficial rat spinal cord dorsal horn neurons to investigate the role of the opioid receptor-like (ORL)1 receptor for modulatory actions of these peptides. The partial ORL1 receptor antagonist [phe1psi(CH(2)-NH)Gly(2)]Nociceptin-(1-13)NH(2) competitively reversed the effects of Nociceptin/orphanin FQ on excitatory neurotransmission (estimated pA(2) 6.43), but left the suppression of inhibitory synaptic transmission by nocistatin unaffected. These results indicate that the inhibitory action of Nociceptin/orphanin FQ on glutamatergic transmission is mediated via ORL1 receptors, while nocistatin acts via a different so far unidentified receptor.
Hunter C. Champion - One of the best experts on this subject based on the ideXlab platform.
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opyright © American Society of Andrology [Tyr’]-Nociceptin and Nociceptin Have Similar Naloxone- Insensitive Erectile Activity in the Cat
2013Co-Authors: Hunter C. Champion, Trinity J. Bivalacqua, Run Wang, Wayne J. G. Hellstrom, Philip J. KadowitzAbstract:ABSTRACT: The heptadecapeptide Nociceptin, also known as Orphania FQ, is a newly discovered endogenous ligand for the opioidlike G-protein-coupled receptor ORL,. The present study was undertaken to investigate responses to intracavernosal injections of the Nociceptin analog [Tyr’]-Nociceptin and to investigate the effects of naloxone on erectile responses in anesthetized cats to [Tyr1]-Nociceptin and to Nociceptin. Intracavernosal injections of [Tyr1]-Nociceptin and of Nociceptin in doses of 0.3-30 nmol elicited dose-related increases in cavernosal pressure, which, at the highest dose studied, were comparable to increases induced by the triple-drug standard (papaverine, phentolamine, and prostaglandin E1), a preparation used in the treatment of erectile dysfunction. Responses to [Tyr1]-Nociceptin were rapid in onset and had a time course similar to responses to Nociceptin. Metenkephalin increased cavemosal pressure, whereas injections of Nociceptin-(2-17), dynorphin A, and 13-endorphin did not alter cavemosal pressure. Erectile responses to Nociceptin and to (Tyr1]-Nociceptin were not altered after administration of the opioid receptor antagonist naloxone at a time when erectile responses to metenkephalin were attenuated. These data show that [Tyr1]-Nociceptin and Nociceptin have similar naloxone-insensitive erectile activity in the cat
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[Tyr1]-Nociceptin and Nociceptin Have Similar Naloxone Insensitive Erectile Activity in the Cat
Journal of andrology, 1998Co-Authors: Hunter C. Champion, Trinity J. Bivalacqua, Run Wang, Wayne J. G. Hellstrom, Philip J. KadowitzAbstract:The heptadecapeptide Nociceptin, also known as Orphanin FQ, is a newly discovered endogenous ligand for the opioid-like G-protein-coupled receptor ORL 1 . The present study was undertaken to investigate responses to intracavernosal injections of the Nociceptin analog [Tyr 1 ]-Nociceptin and to investigate the effects of naloxone on erectile responses in anesthetized cats to [Tyr 1 ]-Nociceptin and to Nociceptin. Intracavernosal injections of [Tyr 1 ]-Nociceptin and of Nociceptin in doses of 0.3-30 nmol elicited dose-related increases in cavernosal pressure, which, at the highest dose studied, were comparable to increases induced by the triple-drug standard (papaverine, phentolamine, and prostaglandin E 1 ), a preparation used in the treatment of erectile dysfunction. Responses to [Tyr 1 ]-Nociceptin were rapid in onset and had a time course similar to responses to Nociceptin. Metenkephalin increased cavernosal pressure, whereas injections of Nociceptin-(2-17), dynorphin A, and β-endorphin did not alter cavernosal pressure. Erectile responses to Nociceptin and to [Tyr 1 ]-Nociceptin were not altered after administration of the opioid receptor antagonist naloxone at a time when erectile responses to metenkephalin were attenuated. These data show that [Tyr 1 ]-Nociceptin and Nociceptin have similar naloxone-insensitive erectile activity in the cat.
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Analysis of Vasodepressor Responses to Nociceptin and Nociceptin Analogs in the Systemic Vascular Bed of the Anesthetized Rabbit In Vivo
Journal of cardiovascular pharmacology and therapeutics, 1998Co-Authors: Hunter C. Champion, Trinity J. Bivalacqua, A. Rauchwarger, Sean M. Mcwilliams, Dennis B. Mcnamara, Philip J. KadowitzAbstract:Background: The heptadecapeptide Nociceptin, also known as Orphanin FQ, is a recently discovered endogenous ligand for the opioid-like G-protein-coupled receptor ORL(1). Methods and Results: In the present study, responses to Nociceptin, [Tyr(1)]-Nociceptin, Nociceptin-(2-17), Nociceptin-(1-11), and Nociceptin-(1-7) were compared in the systemic vascular bed of the rabbit. Nociceptin and [Tyr(1)]-Nociceptin induced dose related decreases in systemic arterial pressure (SAP) when injected in doses of 1-30 nmol/kg intravenous (IV); in terms of relative vasodepressor activity, [Tyr(1)]-Nociceptin and nocicpetin were similar in potency. However, nocicpetin-(2-17), nocicpetin-(1-11), and Nociceptin-(1-7) had no effect on SAP when injected in doses up to 30 nmol/kg IV. The decreases in SAP in response to Nociceptin and [Tyr(1)]-Nociceptin were not altered by the opioid receptor antagonist naloxone at a time when depressor responses to methionine-enkephalin were reduced significantly. Conclusions: The results of the present study show that vasodepressor responses to Nociceptin and [Tyr(1)]-nocicpetin are mediated by the activation of a naloxene-insensitive opioid receptor and are not dependent on the presence of Phe at the N-terminus of the Nociceptin sequence. Moreover, the present results show that Nociceptin-(2-17), Nociceptin-(1-11), and Nociceptin-(1-7) do not alter SAP in the rabbit, indicating that peptide chain length is important for the expression of vasodepressor activity.
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[Tyr1]-Nociceptin, a novel Nociceptin analog, decreases systemic arterial pressure by a naloxone-insensitive mechanism in the rat.
Biochemical and biophysical research communications, 1997Co-Authors: Hunter C. Champion, Philip J. KadowitzAbstract:The heptadecapeptide Nociceptin, also known as Orphanin FQ, is a newly discovered endogenous ligand for the opioid-like G-protein-coupled receptor ORL1. In the present study, responses to a novel Nociceptin analog, [Tyr1]-Nociceptin, were investigated in the systemic vascular bed of the rat. [Tyr1]-Nociceptin induced dose-related decrease in systemic arterial pressure when injected in doses of 1-30 nmol/kg i.v. In terms of relative vasodepressor activity, [Tyr1]-Nociceptin was comparable in potency to Nociceptin. The decreases in systemic arterial pressure in response to [Tyr1]-Nociceptin were not altered by the opioid receptor antagonist naloxone in a dose that reduced responses to Met-enkephalin. The results of the present study show that vasodepressor responses to [Tyr1]-Nociceptin are not mediated by the activation of a naloxone-sensitive opioid receptor and are not dependent on the presence of Phe at the N-terminus of the Nociceptin sequence.
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Nociceptin, an endogenous ligand for the ORL1 receptor, decreases cardiac output and total peripheral resistance in the rat.
Peptides, 1997Co-Authors: Hunter C. Champion, Marc A. Czapla, Philip J. KadowitzAbstract:Abstract Champion, H. C., M. A. Czapla and P. J. Kadowitz. Nociceptin, an endogenous ligand for the ORL1 receptor, decreases cardiac output and total peripheral resistance in the rat. Peptides 18 (5) 72–732, 1997.—The heptadecapeptide Nociceptin, also known as Orphanin FQ, is a newly discovered endogenous ligand for the opioid-like G-protein coupled receptor, ORL1. In the present study, responses to intravenous injections of Nociceptin were investigated in the systemic vascular bed of the rat. Nociceptin induced dose-related decreases in systemic arterial pressure and total peripheral resistance when injected in doses of 1–30 nmol/kg IV. Nociceptin decreased heart rate and in doses of 10 and 30 nmol/kg IV, significantly decreased cardiac output. In terms of relative vasodilator activity, Nociceptin was approximately 10-fold less potent than the beta-adrenergic receptor agonist isoproterenol. These data show that Nociceptin has novel vasodilator activity in the systemic vascular bed of the rat.
Seifollah Ahmadi - One of the best experts on this subject based on the ideXlab platform.
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Selective Suppression of Inhibitory Synaptic Transmission by Nocistatin in the Rat Spinal Cord Dorsal Horn
2013Co-Authors: H. Ulrich Zeilhofer, Uta Muth-selbach, Hans Gühring, Katharina Erb, Seifollah AhmadiAbstract:Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) are two recently identified neuropeptides with opposing effects on several CNS functions, including spinal nociception. The cellular mechanisms that underlie this antagonism are not known. Here, we have investigated the effects of both peptides on synaptic transmission mediated by the three fast neurotransmitters L-glutamate, glycine, and GABA in the superficial layers of the rat spinal cord horn, which constitute the first important site of integration of nociceptive information in the pain pathway. NST selectively reduced transmitter release from inhibitory interneurons via a presynaptic Bordetella pertussis toxin-sensitive mechanism but left excitatory glutamatergic transmission unaffected. In contrast, N/OFQ only inhibited excitatory transmission. In the rat formalin test, an animal model of tonic pain in which N/OFQ exerts antinociceptive activity, NST induced profoun
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Modulation of synaptic transmission by Nociceptin/orphanin FQ and nocistatin in the spinal cord dorsal horn of mutant mice lacking the Nociceptin/orphanin FQ receptor.
Molecular pharmacology, 2001Co-Authors: Seifollah Ahmadi, Hiroshi Takeshima, Hans Gühring, Carolin E. Kotalla, Andreas Pahl, H. Ulrich ZeilhoferAbstract:Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) are two neuropeptides derived from the same precursor protein that exhibit opposing effects on spinal neurotransmission and nociception. Here, we have used whole-cell, patch-clamp recordings from visually identified neurons in spinal cord dorsal horn slices of genetically modified mice to investigate the role of the N/OFQ receptor (N/OFQ-R) in the modulatory action of both peptides on excitatory glutamatergic and inhibitory glycinergic and gamma-aminobutyric acid (GABA)-ergic synaptic transmission. In wild-type mice, N/OFQ selectively suppressed excitatory transmission in a concentration-dependent manner but left inhibitory synaptic transmission unaffected. In contrast, NST reduced only inhibitory but not alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated excitatory synaptic transmission. N/OFQ-mediated inhibition of excitatory transmission was completely absent in N/OFQ-R receptor-deficient (N/OFQ-R(-/-)) mice and significantly reduced in heterozygous (N/OFQ-R(+/-)) mice, whereas the action of NST on inhibitory neurotransmission was completely retained. To test for the relevance of these results for spinal nociception, we investigated the effects of intrathecally injected N/OFQ in the mouse formalin test, an animal model of tonic pain. N/OFQ (3 nmol/mouse) induced significant antinociception in wild-type mice, but had no antinociceptive effects in N/OFQ-R(-/-) mice. These results indicate that the inhibitory action of N/OFQ on excitatory glutamatergic synaptic transmission and its spinal antinociceptive action are mediated via the N/OFQ receptor, whereas the action of NST is independent of this receptor.
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modulation of synaptic transmission by Nociceptin orphanin fq and nocistatin in the spinal cord dorsal horn of mutant mice lacking the Nociceptin orphanin fq receptor
Molecular Pharmacology, 2001Co-Authors: Seifollah Ahmadi, Hiroshi Takeshima, H. Ulrich Zeilhofer, Hans Gühring, Carolin E. Kotalla, Andreas PahlAbstract:Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) are two neuropeptides derived from the same precursor protein that exhibit opposing effects on spinal neurotransmission and nociception. Here, we have used whole-cell, patch-clamp recordings from visually identified neurons in spinal cord dorsal horn slices of genetically modified mice to investigate the role of the N/OFQ receptor (N/OFQ-R) in the modulatory action of both peptides on excitatory glutamatergic and inhibitory glycinergic and gamma-aminobutyric acid (GABA)-ergic synaptic transmission. In wild-type mice, N/OFQ selectively suppressed excitatory transmission in a concentration-dependent manner but left inhibitory synaptic transmission unaffected. In contrast, NST reduced only inhibitory but not alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated excitatory synaptic transmission. N/OFQ-mediated inhibition of excitatory transmission was completely absent in N/OFQ-R receptor-deficient (N/OFQ-R(-/-)) mice and significantly reduced in heterozygous (N/OFQ-R(+/-)) mice, whereas the action of NST on inhibitory neurotransmission was completely retained. To test for the relevance of these results for spinal nociception, we investigated the effects of intrathecally injected N/OFQ in the mouse formalin test, an animal model of tonic pain. N/OFQ (3 nmol/mouse) induced significant antinociception in wild-type mice, but had no antinociceptive effects in N/OFQ-R(-/-) mice. These results indicate that the inhibitory action of N/OFQ on excitatory glutamatergic synaptic transmission and its spinal antinociceptive action are mediated via the N/OFQ receptor, whereas the action of NST is independent of this receptor.
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The role of the ORL1 receptor in the modulation of spinal neurotransmission by Nociceptin/orphanin FQ and nocistatin.
European journal of pharmacology, 2001Co-Authors: Seifollah Ahmadi, Jörg T. Liebel, H. Ulrich ZeilhoferAbstract:Nociceptin/orphanin FQ and nocistatin are two neuropeptides with opposing effects on spinal neurotransmission and nociception. Nociceptin/orphanin FQ selectively suppresses excitatory glutamatergic neurotransmission, while nocistatin selectively interferes with glycinergic and gamma-aminobutyric acid (GABA)-ergic transmission. Here, we performed whole-cell patch-clamp recordings from superficial rat spinal cord dorsal horn neurons to investigate the role of the opioid receptor-like (ORL)1 receptor for modulatory actions of these peptides. The partial ORL1 receptor antagonist [phe1psi(CH(2)-NH)Gly(2)]Nociceptin-(1-13)NH(2) competitively reversed the effects of Nociceptin/orphanin FQ on excitatory neurotransmission (estimated pA(2) 6.43), but left the suppression of inhibitory synaptic transmission by nocistatin unaffected. These results indicate that the inhibitory action of Nociceptin/orphanin FQ on glutamatergic transmission is mediated via ORL1 receptors, while nocistatin acts via a different so far unidentified receptor.
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the role of the orl1 receptor in the modulation of spinal neurotransmission by Nociceptin orphanin fq and nocistatin
European Journal of Pharmacology, 2001Co-Authors: Seifollah Ahmadi, Jörg T. Liebel, Ulrich H ZeilhoferAbstract:Nociceptin/orphanin FQ and nocistatin are two neuropeptides with opposing effects on spinal neurotransmission and nociception. Nociceptin/orphanin FQ selectively suppresses excitatory glutamatergic neurotransmission, while nocistatin selectively interferes with glycinergic and gamma-aminobutyric acid (GABA)-ergic transmission. Here, we performed whole-cell patch-clamp recordings from superficial rat spinal cord dorsal horn neurons to investigate the role of the opioid receptor-like (ORL)1 receptor for modulatory actions of these peptides. The partial ORL1 receptor antagonist [phe1psi(CH(2)-NH)Gly(2)]Nociceptin-(1-13)NH(2) competitively reversed the effects of Nociceptin/orphanin FQ on excitatory neurotransmission (estimated pA(2) 6.43), but left the suppression of inhibitory synaptic transmission by nocistatin unaffected. These results indicate that the inhibitory action of Nociceptin/orphanin FQ on glutamatergic transmission is mediated via ORL1 receptors, while nocistatin acts via a different so far unidentified receptor.
Hiroshi Takeshima - One of the best experts on this subject based on the ideXlab platform.
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Nociceptin and its metabolite attenuate U0126-induced memory impairment through a Nociceptin opioid peptide (NOP) receptor-independent mechanism
Neurobiology of Learning and Memory, 2010Co-Authors: Masaya Miwa, Hiroshi Takeshima, Shogo Uchida, Fumika Horiba, Toshitaka Nabeshima, Masayuki HiramatsuAbstract:Nociceptin binds to Nociceptin opioid peptide (NOP) receptors. We reported that although high doses of Nociceptin impaired memory function and that these effects were mediated via NOP receptors, low doses of Nociceptin attenuated the memory impairment, and these attenuating effects were not mediated via NOP receptors. Even very low doses of Nociceptin were biologically active and suggested a certain binding site for this peptide, but the mechanism underlying this attenuating effect has not yet been elucidated. In the present study, we investigated the effect of an intrahippocampal injection (i.h.) of Nociceptin on memory impairment induced by U0126, a MEK inhibitor, and Rp-cAMPS, a PKA inhibitor in a step-down type passive avoidance test. U0126 (2.63 nmol/mouse, i.h.) impaired memory formation and training-dependent phosphorylation of ERK2 in the hippocampus. Co-administration of Nociceptin (10 fmol/mouse) significantly attenuated memory impairment, while it did not attenuate the inhibition of training-dependent phosphorylation of ERK2 induced by U0126. On the other hand, Nociceptin did not attenuate memory impairment induced by Rp-cAMPS (0.448 nmol/mouse, i.h.). Nociceptin (1 fmol/mouse) also attenuated U0126 (5.26 nmol/mouse)-induced memory impairment in NOP receptor knockout mice. Nociceptin was reported to metabolize into fragments (1-13) and (14-17) in vivo, which showed pharmacological activities without affecting NOP receptors. Our findings showed that Nociceptin (14-17) (1 fmol/mouse) also attenuated U0126-induced memory impairment, while Nociceptin (1-13) (0.1-10 fmol/mouse) did not attenuate memory impairment. These results suggest a novel action site or mechanism for the attenuating effects of Nociceptin and its metabolite, and the sequence of Nociceptin (14-17) is a critical structure.
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Intradermal Nociceptin Elicits Itch-Associated Responses Through Leukotriene B4 in Mice
Journal of Investigative Dermatology, 2004Co-Authors: Tsugunobu Andoh, Yuichi Yageta, Hiroshi Takeshima, Yasushi KuraishiAbstract:Nociceptin, the endogenous peptide ligand for opioid receptor like-1 (ORL1) receptor, has been implicated in the inflammation and pain in the skin. We examined whether Nociceptin is a pruritogen in mice. Intradermal injections of Nociceptin (1–100 nmol per site) concentration dependently increased scratching in ICR mice; the effect started within 1 min, peaked at 10–20 min, and almost subsided by 30 min. The Nociceptin action was absent in ORL1 receptor-deficient (ORL1-/-) mice. Systemic, but not local, treatment with naloxone significantly inhibited scratching induced by Nociceptin. The action of Nociceptin was inhibited by the leukotriene B4 receptor antagonist ONO-4057 and azelastine, which inhibits the action and production of leukotriene B4 in the skin. PreproNociceptin and ORL1 receptor mRNAs were substantially expressed in the skin, whereas their expression levels were very low in the dorsal root ganglia. In the skin, Nociceptin- and ORL1 receptor-like immunoreactivities were localized in the epidermis. Administration of Nociceptin to primary cultures of keratinocytes from ICR and C57BL/6 (ORL1+/+) mice, but not ORL1-/- mice, produced leukotriene B4. The results suggest that Nociceptin acts on ORL1 receptor on the keratinocytes to produce leukotriene B4, which induces itch-associated responses in mice.
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Exogenous, but not endogenous Nociceptin modulates mesolimbic dopamine release in mice
Journal of neurochemistry, 2004Co-Authors: Miwako Koizumi, Hiroshi Takeshima, Naoko Midorikawa, Niall P. MurphyAbstract:The effect of Nociceptin (an endogenous ligand of the ORL1 receptor) on mesolimbic dopamine release and simultaneous horizontal locomotion was studied in freely moving mice undergoing microdialysis of the nucleus accumbens. Intracerebroventricular (i.c.v.) administration of Nociceptin (7 nmol) induced a long-lasting suppression of mesolimbic dopamine release and horizontal locomotion in wild-type but not ORL1 knockout mice. I.c.v. administration of the recently reported peptide Nociceptin antagonist [Nphe1, Arg14, Lys15] Nociceptin-NH2 (known also as UFP-101, 5 nmol) completely abolished the suppressive effect of Nociceptin on mesolimbic dopamine release. However, UFP-101 administration alone induced a mild and lasting suppression of mesolimbic dopamine release in both wild-type and ORL1 knockout mice that was magnified in ORL1 knockout mice by coadministration of Nociceptin. UFP-101 administration alone suppressed locomotion in both genotypes. These results confirm that the suppressive action of Nociceptin on mesolimbic dopamine release is mediated entirely by the ORL1 receptor, and that UFP-101 effectively antagonizes this action. However, the lack of a stimulatory effect of UFP-101 in wild-type mice indicates that despite being sensitive to exogenous Nociceptin action, basal mesolimbic dopaminergic activity is not determined by endogenous Nociceptin in mice.
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Morphine tolerance and dependence in the Nociceptin receptor knockout mice.
Journal of neural transmission (Vienna Austria : 1996), 2001Co-Authors: Takayoshi Mamiya, Hiroshi Takeshima, Yukihiro Noda, Xiuhai Ren, Taku Nagai, Makoto Ukai, Toshitaka NabeshimaAbstract:Here we report the involvement of Nociceptin receptor in tolerance to morphine-induced antinociception and in morphine dependence. There was no different nociceptive perception and antinociceptive effects of morphine between wild-type and the Nociceptin receptor knockout mice. Tolerance to morphine (10 mg/kg)-induced antinociception was developed in both wild-type and the Nociceptin receptor knockout mice after administration of morphine (10 mg/kg) twice a day for 5 days. When naloxone (5 mg/kg) was administered to mice treated with morphine repeatedly on the 6th day, morphine withdrawal syndrome was observed in both wild-type and the Nociceptin receptor knockout mice, which were accompanied by the elevation of cyclic AMP levels. While naloxone benzoylhydrazone (1 mg/kg), a putative antagonist for Nociceptin receptor/naloxone benzoylhydrazone-sensitive sites, also induced the morphine withdrawal signs in both wild-type and the Nociceptin receptor knockout mice, the jumping signs in the Nociceptin receptor knockout mice were less severe than those in wild-type mice. Treatment with naloxone benzoylhydrazone in morphine-dependent wild-type mice caused a significant increase in cyclic AMP levels in the thalamus while it had no effect in the Nociceptin receptor knockout mice. The analysis of opioid mu-receptor binding showed no difference between wild-type and the Nociceptin receptor knockout mice. These results suggest that the Nociceptin receptor/naloxone benzoylhydrazone-sensitive sites contribute to the induction of morphine withdrawal syndrome in part. Furthermore, it is demonstrated that morphine withdrawal syndrome excepting jumping can be induced by naloxone benzoylhydrazone without any changes in the cyclic AMP levels in the thalamus.
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Modulation of synaptic transmission by Nociceptin/orphanin FQ and nocistatin in the spinal cord dorsal horn of mutant mice lacking the Nociceptin/orphanin FQ receptor.
Molecular pharmacology, 2001Co-Authors: Seifollah Ahmadi, Hiroshi Takeshima, Hans Gühring, Carolin E. Kotalla, Andreas Pahl, H. Ulrich ZeilhoferAbstract:Nociceptin/orphanin FQ (N/OFQ) and nocistatin (NST) are two neuropeptides derived from the same precursor protein that exhibit opposing effects on spinal neurotransmission and nociception. Here, we have used whole-cell, patch-clamp recordings from visually identified neurons in spinal cord dorsal horn slices of genetically modified mice to investigate the role of the N/OFQ receptor (N/OFQ-R) in the modulatory action of both peptides on excitatory glutamatergic and inhibitory glycinergic and gamma-aminobutyric acid (GABA)-ergic synaptic transmission. In wild-type mice, N/OFQ selectively suppressed excitatory transmission in a concentration-dependent manner but left inhibitory synaptic transmission unaffected. In contrast, NST reduced only inhibitory but not alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated excitatory synaptic transmission. N/OFQ-mediated inhibition of excitatory transmission was completely absent in N/OFQ-R receptor-deficient (N/OFQ-R(-/-)) mice and significantly reduced in heterozygous (N/OFQ-R(+/-)) mice, whereas the action of NST on inhibitory neurotransmission was completely retained. To test for the relevance of these results for spinal nociception, we investigated the effects of intrathecally injected N/OFQ in the mouse formalin test, an animal model of tonic pain. N/OFQ (3 nmol/mouse) induced significant antinociception in wild-type mice, but had no antinociceptive effects in N/OFQ-R(-/-) mice. These results indicate that the inhibitory action of N/OFQ on excitatory glutamatergic synaptic transmission and its spinal antinociceptive action are mediated via the N/OFQ receptor, whereas the action of NST is independent of this receptor.
