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James E. Zadina - One of the best experts on this subject based on the ideXlab platform.
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Differential antagonism of Endomorphin-1 and Endomorphin-2 supraspinal antinociception by naloxonazine and 3-methylnaltrexone.
Peptides, 2002Co-Authors: Shinobu Sakurada, Tsutomu Fujimura, Kimie Murayama, Takafumi Hayashi, Masayuki Yuhki, Akihiko Yonezawa, Chikai Sakurada, Mitsuhiro Takeshita, Takumi Sato, James E. ZadinaAbstract:Abstract To determine if different subtypes of μ-opioid receptors were involved in antinociception induced by Endomorphin-1 and Endomorphin-2, the effect of pretreatment with various μ-opioid receptor antagonists β-funaltrexamine, naloxonazine and 3-methylnaltrexone on the inhibition of the paw-withdrawal induced by Endomorphin-1 and Endomorphin-2 given intracerebroventricularly (i.c.v.) were studied in ddY male mice. The inhibition of the paw-withdrawal induced by i.c.v. administration of Endomorphin-1, Endomorphin-2 or DAMGO was completely blocked by the pretreatment with a selective μ-opioid receptor antagonist β-funaltrexamine (40 mg/kg), indicating that the antinociception induced by all these peptides are mediated by the stimulation of μ-opioid receptors. However, naloxonazine, a μ1-opioid receptor antagonist pretreated s.c. for 24 h was more effective in blocking the antinociception induced by Endomorphin-2, than by Endomorphin-1 or DAMGO given i.c.v. Pretreatment with a selective morphine-6β-glucuronide blocker 3-methylnaltrexone 0.25 mg/kg given s.c. for 25 min or co-administration of 3-methylnaltrexone 2.5 ng given i.c.v. effectively attenuated the antinociception induced by Endomorphin-2 given i.c.v. and co-administration of 3-methylnaltrexone shifted the dose–response curves for Endomorphin-2 induced antinociception to the right by 4-fold. The administration of 3-methylnaltrexone did not affect the antinociception induced by Endomorphin-1 or DAMGO given i.c.v. Our results indicate that the antinociception induced by Endomorphin-2 is mediated by the stimulation of subtypes of μ-opioid receptor, which is different from that of μ-opioid receptor subtype stimulation by Endomorphin-1 and DAMGO.
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Differential antinociceptive effects induced by intrathecally administered Endomorphin-1 and Endomorphin-2 in the mouse
European journal of pharmacology, 2001Co-Authors: Shinobu Sakurada, Tsutomu Fujimura, Kimie Murayama, James E. Zadina, Abba J. Kastin, Takafumi Hayashi, Masayuki Yuhki, Chikai Sakurada, Tohru Orito, Tsukasa SakuradaAbstract:Abstract Two highly selective μ-opioid receptor agonists, Endomorphin-1 and Endomorphin-2, have been identified and postulated to be endogenous ligands for μ-opioid receptors. Intrathecal (i.t.) administration of Endomorphin-1 and Endomorphin-2 at doses from 0.039 to 5 nmol dose-dependently produced antinociception with the paw-withdrawal test. The paw-withdrawal inhibition rapidly reached its peak at 1 min, rapidly declined and returned to the pre-injection levels in 20 min. The inhibition of the paw-withdrawal responses to Endomorphin-1 and Endomorphin-2 at a dose of 5 nmol observed at 1 and 5 min after injection was blocked by pretreatment with a non-selective opioid receptor antagonist naloxone (1 mg/kg, s.c.). The antinociceptive effect of Endomorphin-2 was more sensitive to the μ 1 -opioid receptor antagonist, naloxonazine than that of Endomorphin-1. The Endomorphin-2-induced paw-withdrawal inhibition at both 1 and 5 min after injection was blocked by pretreatment with κ-opioid receptor antagonist nor-binaltorphimine (10 mg/kg, s.c.) or the δ 2 -opioid receptor antagonist naltriben (0.6 mg/kg, s.c.) but not the δ 1 -opioid receptor antagonist 7-benzylidine naltrexone (BNTX) (0.6 mg/kg s.c.). In contrast, the paw-withdrawal inhibition induced by Endomorphin-1 observed at both 1 and 5 min after injection was not blocked by naloxonazine (35 mg/kg, s.c.), nor-binaltorphimine (10 mg/kg, s.c.), naltriben (0.6 mg/kg, s.c.) or BNTX (0.6 mg/kg s.c.). The Endomorphin-2-induced paw-withdrawal inhibition was blocked by the pretreatment with an antiserum against dynorphin A-(1-17) or [Met 5 ]enkephalin, but not by antiserum against dynorphin B-(1-13). Pretreatment with these antisera did not affect the Endomorphin-1-induced paw-withdrawal inhibition. Our results indicate that Endomorphin-2 given i.t. produces its antinociceptive effects via the stimulation of μ 1 -opioid receptors (naloxonazine-sensitive site) in the spinal cord. The antinociception induced by endomophin-2 contains additional components, which are mediated by the release of dynorphin A-(1-17) and [Met 5 ]enkephalin which subsequently act on κ-opioid receptors and δ 2 -opioid receptors to produce antinociception.
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Research report The effects of Endomorphin-1 on conditioned defeat in Syrian hamsters (Mesocricetus auratus)
2001Co-Authors: R D Whitten, James E. Zadina, A M Jasnow, H E Albers, S Martin-schild, K L HuhmanAbstract:The present study examined the effect of Endomorphin-1 (EM1), an endogenous opioid with a high affinity for the mu opiate receptor, on conditioned defeat. Conditioned defeat is a phenomenon in which hamsters that have been defeated subsequently fail to exhibit normal territorial aggression and instead display submissive / defensive behaviors even when paired with a non-aggressive intruder. In experiment 1, animals were placed in the home cage of a larger resident for 15 min and were defeated. After 24 h, animals received a 3-ml injection of EM1 (0.0, 0.3, 3.0, or 10 nmol) into the left lateral cerebral ventricle 5 min before a smaller non-aggressive intruder was placed in the home cage of the experimental animal. In experiment 2, animals were infused with EM1 immediately after the initial defeat and were paired with a non-aggressive intruder 24 h later as in experiment 1. EM1 reduced the duration of submissive / defensive behavior in experiment 1 (P,0.05) but not in experiment 2 (P.0.05). These data support the hypothesis that the highly selective mu receptor agonist Endomorphin-1 modulates the expression of conditioned defeat, but provides no support for the hypothesis that Endomorphin-1 modulates the consolidation of conditioned defeat. © 2001 Elsevier Science B.V. All rights reserved. Theme: Neurotransmitters, modulators, transporters, and receptors Topic: Behavioural pharmacology
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Differential antagonism of Endomorphin-1 and Endomorphin-2 spinal antinociception by naloxonazine and 3-methoxynaltrexone.
Brain research, 2000Co-Authors: Shinobu Sakurada, Tsutomu Fujimura, Kimie Murayama, James E. Zadina, Takafumi Hayashi, Masayuki Yuhki, Akihiko Yonezawa, Chikai Sakurada, Mitsuhiro Takeshita, Abba J. KastinAbstract:Abstract To determine the role of spinal mu-opioid receptor subtypes in antinociception induced by intrathecal (i.t.) injection of Endomorphin-1 and -2, we assessed the effects of β-funaltrexamine (a selective mu-opioid receptor antagonist) naloxonazine (a selective antagonist at the mu 1 -opioid receptor) and a novel receptor antagonist (3-methoxynaltrexone) using the paw-withdrawal test. Antinociception of i.t. Endomorphins and [ d -Ala 2 , MePhe 4 , Gly(ol) 5 ]enkephalin (DAMGO) was completely reversed by pretreatment with β-funaltrexamine (40 mg/kg s.c.). Pretreatment with a variety of doses of i.t. or s.c. naloxonazine 24 h before testing antagonized the antinociception of Endomorphin-1, -2 and DAMGO. Judging from the ID 50 values of naloxonazine, the antinociceptive effect of Endomorphin-2 was more sensitive to naloxonazine than that of Endomorphin-1 or DAMGO. The selective morphine-6β-glucuronide antagonist, 3-methoxynaltrexone, which blocked Endomorphin-2-induced antinociception at each dose (0.25 mg/kg s.c. or 2.5 ng i.t.) that was inactive against DAMGO, did not affect Endomorphin-1-induced antinociception but shifted the dose–response curve of Endomorphin-2 3-fold to the right. These findings may be interpreted as indicative of the existence of a novel mu-opioid receptor subtype in spinal sites, where antinociception of morphine-6β-glucuronide and Endomorphin-2 are antagonized by 3-methoxynaltrexone. The present results suggest that Endomorphin-1 and Endomorphin-2 may produce antinociception through different subtypes of mu-opioid receptor.
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Analgesic effects of Endomorphin-1 and Endomorphin-2 in the formalin test in mice.
Life sciences, 2000Co-Authors: R. Denis Soignier, Abba J. Kastin, Anthony L. Vaccarino, Angela M. Brennan, James E. ZadinaAbstract:Two recently isolated peptides, Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and Endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), are highly selective micro-opioid receptor agonists with analgesic actions in the tail-flick test. To further assess the analgesic properties of these peptides, the effects of Endomorphin-1, Endomorphin-2, and morphine were examined in the formalin test. Male Swiss Webster mice were injected i.c.v. with Endomorphin-1, Endomorphin-2, or morphine (0, 1, 3, 10 microg) 5 min before injection of 20 microl of 5% formalin s.c. into the plantar surface of one hind-paw. The mice were observed for 60 min after formalin injection. Endomorphin-1 and Endomorphin-2 produced dose-dependent analgesia that was shorter in duration than for morphine. Increased locomotion was observed after morphine, but not after Endomorphin-1 or Endomorphin-2. These findings extend previous results and suggest that Endomorphins may have therapeutic potential for the treatment of acute pain.
Abba J. Kastin - One of the best experts on this subject based on the ideXlab platform.
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Differential antinociceptive effects induced by intrathecally administered Endomorphin-1 and Endomorphin-2 in the mouse
European journal of pharmacology, 2001Co-Authors: Shinobu Sakurada, Tsutomu Fujimura, Kimie Murayama, James E. Zadina, Abba J. Kastin, Takafumi Hayashi, Masayuki Yuhki, Chikai Sakurada, Tohru Orito, Tsukasa SakuradaAbstract:Abstract Two highly selective μ-opioid receptor agonists, Endomorphin-1 and Endomorphin-2, have been identified and postulated to be endogenous ligands for μ-opioid receptors. Intrathecal (i.t.) administration of Endomorphin-1 and Endomorphin-2 at doses from 0.039 to 5 nmol dose-dependently produced antinociception with the paw-withdrawal test. The paw-withdrawal inhibition rapidly reached its peak at 1 min, rapidly declined and returned to the pre-injection levels in 20 min. The inhibition of the paw-withdrawal responses to Endomorphin-1 and Endomorphin-2 at a dose of 5 nmol observed at 1 and 5 min after injection was blocked by pretreatment with a non-selective opioid receptor antagonist naloxone (1 mg/kg, s.c.). The antinociceptive effect of Endomorphin-2 was more sensitive to the μ 1 -opioid receptor antagonist, naloxonazine than that of Endomorphin-1. The Endomorphin-2-induced paw-withdrawal inhibition at both 1 and 5 min after injection was blocked by pretreatment with κ-opioid receptor antagonist nor-binaltorphimine (10 mg/kg, s.c.) or the δ 2 -opioid receptor antagonist naltriben (0.6 mg/kg, s.c.) but not the δ 1 -opioid receptor antagonist 7-benzylidine naltrexone (BNTX) (0.6 mg/kg s.c.). In contrast, the paw-withdrawal inhibition induced by Endomorphin-1 observed at both 1 and 5 min after injection was not blocked by naloxonazine (35 mg/kg, s.c.), nor-binaltorphimine (10 mg/kg, s.c.), naltriben (0.6 mg/kg, s.c.) or BNTX (0.6 mg/kg s.c.). The Endomorphin-2-induced paw-withdrawal inhibition was blocked by the pretreatment with an antiserum against dynorphin A-(1-17) or [Met 5 ]enkephalin, but not by antiserum against dynorphin B-(1-13). Pretreatment with these antisera did not affect the Endomorphin-1-induced paw-withdrawal inhibition. Our results indicate that Endomorphin-2 given i.t. produces its antinociceptive effects via the stimulation of μ 1 -opioid receptors (naloxonazine-sensitive site) in the spinal cord. The antinociception induced by endomophin-2 contains additional components, which are mediated by the release of dynorphin A-(1-17) and [Met 5 ]enkephalin which subsequently act on κ-opioid receptors and δ 2 -opioid receptors to produce antinociception.
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Differential antagonism of Endomorphin-1 and Endomorphin-2 spinal antinociception by naloxonazine and 3-methoxynaltrexone.
Brain research, 2000Co-Authors: Shinobu Sakurada, Tsutomu Fujimura, Kimie Murayama, James E. Zadina, Takafumi Hayashi, Masayuki Yuhki, Akihiko Yonezawa, Chikai Sakurada, Mitsuhiro Takeshita, Abba J. KastinAbstract:Abstract To determine the role of spinal mu-opioid receptor subtypes in antinociception induced by intrathecal (i.t.) injection of Endomorphin-1 and -2, we assessed the effects of β-funaltrexamine (a selective mu-opioid receptor antagonist) naloxonazine (a selective antagonist at the mu 1 -opioid receptor) and a novel receptor antagonist (3-methoxynaltrexone) using the paw-withdrawal test. Antinociception of i.t. Endomorphins and [ d -Ala 2 , MePhe 4 , Gly(ol) 5 ]enkephalin (DAMGO) was completely reversed by pretreatment with β-funaltrexamine (40 mg/kg s.c.). Pretreatment with a variety of doses of i.t. or s.c. naloxonazine 24 h before testing antagonized the antinociception of Endomorphin-1, -2 and DAMGO. Judging from the ID 50 values of naloxonazine, the antinociceptive effect of Endomorphin-2 was more sensitive to naloxonazine than that of Endomorphin-1 or DAMGO. The selective morphine-6β-glucuronide antagonist, 3-methoxynaltrexone, which blocked Endomorphin-2-induced antinociception at each dose (0.25 mg/kg s.c. or 2.5 ng i.t.) that was inactive against DAMGO, did not affect Endomorphin-1-induced antinociception but shifted the dose–response curve of Endomorphin-2 3-fold to the right. These findings may be interpreted as indicative of the existence of a novel mu-opioid receptor subtype in spinal sites, where antinociception of morphine-6β-glucuronide and Endomorphin-2 are antagonized by 3-methoxynaltrexone. The present results suggest that Endomorphin-1 and Endomorphin-2 may produce antinociception through different subtypes of mu-opioid receptor.
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Analgesic effects of Endomorphin-1 and Endomorphin-2 in the formalin test in mice.
Life sciences, 2000Co-Authors: R. Denis Soignier, Abba J. Kastin, Anthony L. Vaccarino, Angela M. Brennan, James E. ZadinaAbstract:Two recently isolated peptides, Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and Endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), are highly selective micro-opioid receptor agonists with analgesic actions in the tail-flick test. To further assess the analgesic properties of these peptides, the effects of Endomorphin-1, Endomorphin-2, and morphine were examined in the formalin test. Male Swiss Webster mice were injected i.c.v. with Endomorphin-1, Endomorphin-2, or morphine (0, 1, 3, 10 microg) 5 min before injection of 20 microl of 5% formalin s.c. into the plantar surface of one hind-paw. The mice were observed for 60 min after formalin injection. Endomorphin-1 and Endomorphin-2 produced dose-dependent analgesia that was shorter in duration than for morphine. Increased locomotion was observed after morphine, but not after Endomorphin-1 or Endomorphin-2. These findings extend previous results and suggest that Endomorphins may have therapeutic potential for the treatment of acute pain.
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Dissociation of analgesic and rewarding effects of Endomorphin-1 in rats
Peptides, 2000Co-Authors: Aimee M Wilson, James E. Zadina, Abba J. Kastin, R. Denis Soignier, William L. Nores, Richard D. Olson, Gayle A. OlsonAbstract:Abstract The μ-receptor is the primary mediator of the effects of morphine and the endogenous opiates, Endomorphin-1 and Endomorphin-2. Here we demonstrate a dissociation of the analgesic and rewarding effects of Endomorphin-1 in rats. Tail-flick results revealed that Endomorphin-1 produced significant analgesic effects within 10-min after injection. However, it failed to show reward properties in the standard 45- min conditioned place preference (CPP) paradigm or in an abbreviated 10-min pairing which paralleled the time frame of the tail-flick findings. Morphine induced both analgesia and reward. Endomorphin-1 therefore is the first mu opiate shown to produce potent analgesia in the absence of reward behavior, and thus may have significant clinical potential.
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Differential involvement of μ-opioid receptor subtypes in Endomorphin-1- and -2-induced antinociception
European journal of pharmacology, 1999Co-Authors: Shinobu Sakurada, Tsutomu Fujimura, Kimie Murayama, James E. Zadina, Abba J. Kastin, Sou Katsuyama, Masayuki Yuki, Hiroshi Ueda, Tsukasa SakuradaAbstract:We investigated the role of μ-opioid receptor subtypes in both Endomorphin-1 and Endomorphin-2 induced antinociception in mice using supraspinally mediated behavior. With tail pressure as a mechanical noxious stimulus, both intracerebroventricularly (i.c.v.) and intrathecally (i.t.) injected-Endomorphins produced potent and significant antinociceptive activity. Antinociception induced by i.t. and i.c.v. injection of Endomorphin-1 was not reversed by pretreatment with a selective μ1-opioid receptor antagonist, naloxonazine (35 mg/kg, s.c.). By contrast, antinociception induced by i.t. and i.c.v. Endomorphin-2 was significantly decreased by μ1-opioid receptor antagonist. Antinociception of both i.t. and i.c.v. Endomorphin-1 and -2 was completely reversed by pretreatment with β-funaltrexamine (40 mg/kg, s.c.). The results indicate that Endomorphins may produce antinociception through the distinct μ1 and μ2 subtypes of μ-opioid receptor.
Hunter C. Champion - One of the best experts on this subject based on the ideXlab platform.
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Endomorphin 1 and 2, the endogenous μ-opioid agonists, produce biphasic changes in systemic arterial pressure in the cat
Life Sciences, 1998Co-Authors: Hunter C. Champion, James E. Zadina, Abba J. Kastin, T J Bivalacqua, D G Lambert, S M Mcwilliams, Philip J. KadowitzAbstract:The endogenous peptides Endomorphin 1 and 2 are newly isolated, potent, selective mu-opioid receptor agonists. In the present study, responses to the Endomorphin peptides were investigated in the systemic vascular bed of the cat. Endomorphin 1 and 2 induced dose-related biphasic changes in systemic arterial pressure when injected in doses of 1-30 nmol/kg i.v. The biphasic responses to Endomorphin 1 and 2 were characterized by an initial increase followed by a decrease in systemic arterial pressure. In terms of relative vasodepressor activity, Endomorphin 1 and 2 were similar in potency and approximately 10-fold less potent than the ORL1 ligand nociceptin (orphanin FQ) in decreasing systemic arterial pressure. The biphasic arterial pressure changes in response to Endomorphin 1 and 2 were inhibited by the opioid receptor antagonist naloxone in a dose of 2 mg/kg i.v. These results demonstrate that Endomorphin 1 and 2 produce significant, naloxone-sensitive changes in systemic arterial pressure that are characterized by an initial increase followed by a secondary decrease in arterial pressure in the cat.
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Endomorphin 1 and 2 Have Vasodepressor Activity in the Anesthetized Mouse
Peptides, 1998Co-Authors: Hunter C. Champion, James E. Zadina, Abba J. Kastin, Philip J. KadowitzAbstract:The endogenous peptides Endomorphin 1 and 2 are newly discovered, potent, selective μ-opioid receptor agonists. In the present study, we investigated responses to the Endomorphin peptides in the systemic vascular bed of the anesthetized mouse. Endomorphin 1 and 2 induced dose-related decreases in mean arterial pressure when injected in doses of 3–100 nmol/kg IV. Mean arterial pressure decreased 14 ± 4, 23 ± 4, and 42 ± 5 mm Hg at the 10, 30, and 100 nmol/kg doses, respectively, of Endomorphin 1 (n = 5–7; p < 0.05), and similar changes were observed in response to Endomorphin 2. Interms of relative vasodepressor activity, Endomorphin 1 and 2 were about equipotent and about threefold more potent than the μ-opioid selective agonist PL017 in decreasing mean arterial pressure; all three peptides decreased heart rate. The time-course of the vasodepressor responses to Endomorphin 1 and 2 were similar in rate of onset and decay. Vasodepressor responses to Endomorphin 1 and 2 and PL017 but not to nociceptin were inhibited by the opioid receptor antagonist naloxone in a dose of 2 mg/kg IV. When compared in the mouse and rat, the relative decreases in systemic arterial pressure in response to IV injections of Endomorphin 1 and 2 did not differ greatly. However, the duration of the vasodepressor response was significantly longer in the rat. These results demonstrate that Endomorphin 1 and 2 have significant, naloxone-sensitive, vasodepressor activity in the mouse.
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Endomorphin 1 and 2, endogenous μ-opioid agonists, decrease systemic arterial pressure in the rat
Life sciences, 1998Co-Authors: Marc A. Czapla, Hunter C. Champion, James E. Zadina, Abba J. Kastin, Laszlo Hackler, Philip J. KadowitzAbstract:The endogenous opioid peptides, Endomorphin 1 and 2, are newly isolated, potent, and selective mu-opioid receptor agonists. In the present study, responses to Endomorphin 1 and 2 were investigated in the systemic vascular bed of the rat. Endomorphin 1 and 2 induced dose-related decreases in systemic arterial pressure when injected in doses of 1-30 nmol/kg i.v. In terms of relative vasodepressor activity, Endomorphin 1 and 2 were approximately equipotent with each other and with the ORL1 ligand, nociceptin (orphanin FQ), and were about 10-fold more potent than met-enkephalin in decreasing systemic arterial pressure. Vasodepressor responses to Endomorphin 1 and 2 and met-enkephalin, but not to nociceptin, were inhibited by the opioid receptor antagonist, naloxone. These results demonstrate that Endomorphin 1 and 2 produce significant naloxone-sensitive decreases in systemic arterial pressure.
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Endomorphin 1 and 2, the endogenous mu-opioid agonists, produce biphasic changes in systemic arterial pressure in the cat.
Life sciences, 1998Co-Authors: Hunter C. Champion, James E. Zadina, Abba J. Kastin, T J Bivalacqua, D G Lambert, S M Mcwilliams, Philip J. KadowitzAbstract:The endogenous peptides Endomorphin 1 and 2 are newly isolated, potent, selective mu-opioid receptor agonists. In the present study, responses to the Endomorphin peptides were investigated in the systemic vascular bed of the cat. Endomorphin 1 and 2 induced dose-related biphasic changes in systemic arterial pressure when injected in doses of 1-30 nmol/kg i.v. The biphasic responses to Endomorphin 1 and 2 were characterized by an initial increase followed by a decrease in systemic arterial pressure. In terms of relative vasodepressor activity, Endomorphin 1 and 2 were similar in potency and approximately 10-fold less potent than the ORL1 ligand nociceptin (orphanin FQ) in decreasing systemic arterial pressure. The biphasic arterial pressure changes in response to Endomorphin 1 and 2 were inhibited by the opioid receptor antagonist naloxone in a dose of 2 mg/kg i.v. These results demonstrate that Endomorphin 1 and 2 produce significant, naloxone-sensitive changes in systemic arterial pressure that are characterized by an initial increase followed by a secondary decrease in arterial pressure in the cat.
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Nitric oxide release mediates vasodilator responses to Endomorphin 1 but not nociceptin/OFQ in the hindquarters vascular bed of the rat
Peptides, 1998Co-Authors: Hunter C. Champion, James E. Zadina, Abba J. Kastin, T J Bivalacqua, D. E. Friedman, P. J. KadowitzAbstract:We have recently shown that Endomorphin 1, an endogenous ligand for the mu-opioid receptor, and nociceptin (Orphanin FQ; OFQ), an endogenous ligand for the ORL1 receptor, have substantial vasodilator activity in the hindquarters vascular bed of the rat. In the present study, the role of nitric oxide, vasodilator prostaglandins, and the opening of K+ ATP channels in mediating vasodilator responses to Endomorphin 1, PL017, and DAMGO was investigated in the regional vascular bed in the rat. Under constant-flow conditions, injections of the mu-selective agonists Endomorphin 1, PL017 ([N-MePhe3,D-Pro4]-morphiceptin), and DAMGO, and the ORL1 receptor agonist nociceptin/ OFQ produced dose-dependent decreases in hindquarters perfusion pressure. Vasodilator responses to Endomorphin 1, PL017, and DAMGO, and the endothelium-dependent vasodilators acetylcholine and adrenomedullin were attenuated by the nitric oxide synthase inhibitor L-NAME (50 mg/kg IV) at a time when vasodilator responses to nociceptin/OFQ were not altered. Vasodilator responses to isoproterenol and prostaglandin E1, agents known to increase cAMP levels, and the nitric oxide donor DEA/NO were not altered by the nitric oxide synthase inhibitor. Responses to Endomorphin 1, PL017, DAMGO, and nociceptin/OFQ were not altered by sodium meclofenamate at a time when vasodilator responses to arachidonic acid were reduced significantly or after administration of U-37883A at a time when vasodilator responses to levcromakalim were reduced significantly. The results of these studies indicate that responses to Endomorphin 1, PL017, and DAMGO are mediated in large part by the release of nitric oxide, while responses to nociceptin/OFQ are mediated by an L-NAME-insensitive mechanism. Moreover, these results demonstrate that responses to these peptides are not mediated by the release of vasodilator prostaglandins or the opening of K+ATP channels the hindquarters vascular bed.
Leon F. Tseng - One of the best experts on this subject based on the ideXlab platform.
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Opposite conditioned place preference responses to Endomorphin-1 and Endomorphin-2 in the mouse.
Neuroscience letters, 2004Co-Authors: Ryan S Macdougall, Andrew D. Clithero, Randy J. Leitermann, Maia Terashvili, Leon F. TsengAbstract:Abstract An unbiased conditioned place preference paradigm was used to evaluate the reward effect of selective endogenous μ-opioid ligands, Endomorphin-1 and Endomorphin-2, in male CD-1 mice. Pre- and post-conditioning free-movement were measured on day 1 and day 5, respectively. Conditioning sessions were conducted twice daily from day 2 through day 4 consisting of the alternate injection of conditioning drug or vehicle. Intracerebroventricular (i.c.v.) injection of Endomorphin-1 (0.3–10 μg) induced place preference in a dose-dependent manner; whereas, Endomorphin-2 (1–10 μg) dose-dependently induced place aversion. Both Endomorphin-1-induced place preference and Endomorphin-2-induced place aversion were blocked by pretreatment i.c.v. with μ-opioid receptor antagonist, β-funaltrexamine. Selective δ-opioid receptor antagonist, naltrindole, co-administered i.c.v. with Endomorphin-1 or Endomorphin-2 did not affect reward effect. However, Endomorphin-2-induced place aversion, but not Endomorphin-1-induced place preference, was blocked by the i.c.v.-administered selective κ-opioid receptor antagonist, WIN 44,441-3. It is concluded that Endomorphin-1 produces conditioned place preference, which is mediated by the stimulation of μ-, but not δ- or κ-opioid receptors, while Endomorphin-2 produces conditioned place aversion, which is mediated by the stimulation of μ- and κ-, but not δ-opioid receptors.
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d-Pro2-Endomorphin-1 andd-Pro2-Endomorphin-2, Respectively, Attenuate the Antinociception Induced by Endomorphin-1 and Endomorphin-2 Given Intrathecally in the Mouse
The Journal of pharmacology and experimental therapeutics, 2002Co-Authors: Kuei-chun Hung, Hirokazu Mizoguchi, Shinobu Sakurada, Toru Okayama, Tsutomu Fujimura, Kimie Murayama, Tsukasa Sakurada, James M. Fujimoto, Leon F. TsengAbstract:First, the antinociception with the tail-flick test ofd-Pro2-Endomorphin-1 andd-Pro2-Endomorphin-2 given i.t. was compared with that produced by Endomorphin-1 and -2 in male CD-1 mice. High doses of d-Pro2-Endomorphin-1 (0.2–0.4 pmol) and d-Pro2-Endomorphin-2 (300–800 pmol) given i.t. produced antinociception with low intrinsic activity [about 25% maximum possible effect (MPE)] compared with that of Endomorphin-1 (16.4 nmol) and Endomorphin-2 (35 nmol) (>90% MPE). Second, coadministration of a low dose ofd-Pro2-Endomorphin-1 (0.1 pmol), which given alone did not affect the tail-flick latencies, markedly attenuated the antinociception induced by Endomorphin-1 (16.4 nmol) but not by Endomorphin-2 (35 nmol). Similarly, coadministration of a low dose ofd-Pro2-Endomorphin-2 (200 pmol), which given alone did not affect the tail-flick latencies, significantly attenuated the antinociception induced by Endomorphin-2 (35 nmol) and, to a much lesser extent, Endomorphin-1 (16.4 nmol). It is concluded thatd-Pro2-Endomorphin-1 andd-Pro2-Endomorphin-2 at high doses were partial opioid receptor agonists to produce antinociception, and at low doses were opioid receptor antagonists to block selectively the antinociception induced by Endomorphin-1 and Endomorphin-2, respectively. Furthermore, our results are consistent with the view that the antinociception induced by Endomorphin-1 and Endomorphin-2 is mediated by the stimulation of different subtypes of μ-opioid receptors.
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Acute antinociceptive tolerance and unidirectional cross-tolerance to Endomorphin-1 and Endomorphin-2 given intraventricularly in the rat.
European journal of pharmacology, 2002Co-Authors: Kuei-chun Hung, Hirokazu Mizoguchi, Leon F. TsengAbstract:The effect of the pretreatment with Endomorphin-1 or Endomorphin-2 given into anterior 4th ventricle (i.vt.) on the antinociception with the tail-flick test induced by subsequent intraventricular (i.vt.) injection of Endomorphin-1 or Endomorphin-2 were studied in rats. The i.vt. pretreatment with 30 nmol of Endomorphin-1 or 60 nmol of Endomorphin-2 developed an antinociceptive tolerance to the subsequently challenging dose of i.vt.-administered Endomorphin-1 or Endomorphin-2, respectively, with different time courses. The Endomorphin-1-induced antinociceptive tolerance reached a maximal level at 2 h, recovered slowly in 24 h after the pretreatment with Endomorphin-1, whereas Endomorphin-2-induced antinociceptive tolerance developed in 1 h and recovered in 4 h. Rats made tolerant to Endomorphin-1 by i.vt. pretreatment with Endomorphin-1 exhibited nearly no cross-tolerance to Endomorphin-2 to produce antinociception. On the other hand, rats made tolerant to Endomorphin-2 exhibited a complete cross-tolerance to Endomorphin-1 to produce antinociception. We propose that different degrees of receptor endocytosis for receptor inactivation after stimulation of mu-opioid receptors by Endomorphin-1 and Endomorphin-2 and/or two separate subtypes of mu-opioid receptors are involved in the antinociception induced by Endomorphin-1 and Endomorphin-2.
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Release of [Met5]enkephalin from the spinal cord by intraventricularly administered Endomorphin-2, but not Endomorphin-1 in the anesthetized rat
Neuroscience letters, 2001Co-Authors: M Ohsawa, Hirokazu Mizoguchi, H Nagase, Minoru Narita, Maho Shiraki, Michiko Narita, Koji Kawai, Eugene Y. Cheng, Leon F. TsengAbstract:Abstract Effects of intraventricular injection of Endomorphin-1, Endomorphin-2 and β-endorphin on the release of immunoreactive [Met 5 ]enkephalin from the spinal cord were studied in pentobarbital anesthetized rats. Intraventricular injection of Endomorphin-2, but not Endomorphin-1, caused an increased release of immunoreactive [Met 5 ]enkephalin in the spinal perfusates. β-Endorphin given intraventricularly also increased the release of immunoreactive [Met 5 ]enkephalin in an amount 15-fold higher than that produced by Endomorphin-2. The increase of the release of immunoreactive [Met 5 ]enkephalin induced by Endomorphin-2 was blocked by μ-opioid receptor antagonist CTOP. Our result suggests that Endomorphin-2 stimulates another subtype of μ-opioid receptor different from that acted by Endomorphin-1 at the supraspinal site and subsequently increases the release of [Met 5 ]enkephalin from the spinal cord.
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Lack of the involvement of μ1-opioid receptor subtype on motivational effects induced by the endogenous μ-opioid receptor ligands Endomorphin-1 and -2 in the mouse
Neuroscience letters, 2001Co-Authors: Minoru Narita, Hirokazu Mizoguchi, Leon F. Tseng, H Nagase, Satoru Ozaki, Masumi Ioka, Tsutomu SuzukiAbstract:Abstract The present study was designed to investigate the role of μ-opioid receptor subtypes in the motivational effect of endogenous μ-opioid receptor ligands, Endomorphin-1 and -2. In C57BL/6J mice, Endomorphin-1 produced a significant place preference, whereas Endomorphin-2 exhibited a significant place aversion. These effects were abolished by a μ 1 /μ 2 -opioid receptor antagonist β-funaltrexamine. Under these conditions, both Endomorphin-1 and -2 produced their motivational effects in μ 1 -opioid receptor-deficient CXBK mice, indicating the μ 2 -opioid receptor involvement. Furthermore, in the lower midbrain including ventral tegmental area, both Endomorphin-1 and -2 equally produced dose-related increases in guanosine-5′- o -(3-[ 35 S] thio) triphosphate bindings in C57BL/6J and CXBK mice. These findings indicate that Endomorphin-1 and -2 may produce distinct motivational effects via respective μ 2 -opioid receptor isoforms in the mouse. Furthermore, Endomorphin-1 and -2 produced the μ 1 -resistant G-protein activation in the mouse lower midbtrain.
Philip J. Kadowitz - One of the best experts on this subject based on the ideXlab platform.
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Endomorphin 1 and 2, the endogenous μ-opioid agonists, produce biphasic changes in systemic arterial pressure in the cat
Life Sciences, 1998Co-Authors: Hunter C. Champion, James E. Zadina, Abba J. Kastin, T J Bivalacqua, D G Lambert, S M Mcwilliams, Philip J. KadowitzAbstract:The endogenous peptides Endomorphin 1 and 2 are newly isolated, potent, selective mu-opioid receptor agonists. In the present study, responses to the Endomorphin peptides were investigated in the systemic vascular bed of the cat. Endomorphin 1 and 2 induced dose-related biphasic changes in systemic arterial pressure when injected in doses of 1-30 nmol/kg i.v. The biphasic responses to Endomorphin 1 and 2 were characterized by an initial increase followed by a decrease in systemic arterial pressure. In terms of relative vasodepressor activity, Endomorphin 1 and 2 were similar in potency and approximately 10-fold less potent than the ORL1 ligand nociceptin (orphanin FQ) in decreasing systemic arterial pressure. The biphasic arterial pressure changes in response to Endomorphin 1 and 2 were inhibited by the opioid receptor antagonist naloxone in a dose of 2 mg/kg i.v. These results demonstrate that Endomorphin 1 and 2 produce significant, naloxone-sensitive changes in systemic arterial pressure that are characterized by an initial increase followed by a secondary decrease in arterial pressure in the cat.
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Endomorphin 1 and 2 Have Vasodepressor Activity in the Anesthetized Mouse
Peptides, 1998Co-Authors: Hunter C. Champion, James E. Zadina, Abba J. Kastin, Philip J. KadowitzAbstract:The endogenous peptides Endomorphin 1 and 2 are newly discovered, potent, selective μ-opioid receptor agonists. In the present study, we investigated responses to the Endomorphin peptides in the systemic vascular bed of the anesthetized mouse. Endomorphin 1 and 2 induced dose-related decreases in mean arterial pressure when injected in doses of 3–100 nmol/kg IV. Mean arterial pressure decreased 14 ± 4, 23 ± 4, and 42 ± 5 mm Hg at the 10, 30, and 100 nmol/kg doses, respectively, of Endomorphin 1 (n = 5–7; p < 0.05), and similar changes were observed in response to Endomorphin 2. Interms of relative vasodepressor activity, Endomorphin 1 and 2 were about equipotent and about threefold more potent than the μ-opioid selective agonist PL017 in decreasing mean arterial pressure; all three peptides decreased heart rate. The time-course of the vasodepressor responses to Endomorphin 1 and 2 were similar in rate of onset and decay. Vasodepressor responses to Endomorphin 1 and 2 and PL017 but not to nociceptin were inhibited by the opioid receptor antagonist naloxone in a dose of 2 mg/kg IV. When compared in the mouse and rat, the relative decreases in systemic arterial pressure in response to IV injections of Endomorphin 1 and 2 did not differ greatly. However, the duration of the vasodepressor response was significantly longer in the rat. These results demonstrate that Endomorphin 1 and 2 have significant, naloxone-sensitive, vasodepressor activity in the mouse.
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Endomorphin 1 and 2, endogenous μ-opioid agonists, decrease systemic arterial pressure in the rat
Life sciences, 1998Co-Authors: Marc A. Czapla, Hunter C. Champion, James E. Zadina, Abba J. Kastin, Laszlo Hackler, Philip J. KadowitzAbstract:The endogenous opioid peptides, Endomorphin 1 and 2, are newly isolated, potent, and selective mu-opioid receptor agonists. In the present study, responses to Endomorphin 1 and 2 were investigated in the systemic vascular bed of the rat. Endomorphin 1 and 2 induced dose-related decreases in systemic arterial pressure when injected in doses of 1-30 nmol/kg i.v. In terms of relative vasodepressor activity, Endomorphin 1 and 2 were approximately equipotent with each other and with the ORL1 ligand, nociceptin (orphanin FQ), and were about 10-fold more potent than met-enkephalin in decreasing systemic arterial pressure. Vasodepressor responses to Endomorphin 1 and 2 and met-enkephalin, but not to nociceptin, were inhibited by the opioid receptor antagonist, naloxone. These results demonstrate that Endomorphin 1 and 2 produce significant naloxone-sensitive decreases in systemic arterial pressure.
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Endomorphin 1 and 2, the endogenous mu-opioid agonists, produce biphasic changes in systemic arterial pressure in the cat.
Life sciences, 1998Co-Authors: Hunter C. Champion, James E. Zadina, Abba J. Kastin, T J Bivalacqua, D G Lambert, S M Mcwilliams, Philip J. KadowitzAbstract:The endogenous peptides Endomorphin 1 and 2 are newly isolated, potent, selective mu-opioid receptor agonists. In the present study, responses to the Endomorphin peptides were investigated in the systemic vascular bed of the cat. Endomorphin 1 and 2 induced dose-related biphasic changes in systemic arterial pressure when injected in doses of 1-30 nmol/kg i.v. The biphasic responses to Endomorphin 1 and 2 were characterized by an initial increase followed by a decrease in systemic arterial pressure. In terms of relative vasodepressor activity, Endomorphin 1 and 2 were similar in potency and approximately 10-fold less potent than the ORL1 ligand nociceptin (orphanin FQ) in decreasing systemic arterial pressure. The biphasic arterial pressure changes in response to Endomorphin 1 and 2 were inhibited by the opioid receptor antagonist naloxone in a dose of 2 mg/kg i.v. These results demonstrate that Endomorphin 1 and 2 produce significant, naloxone-sensitive changes in systemic arterial pressure that are characterized by an initial increase followed by a secondary decrease in arterial pressure in the cat.
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THE ENDOGENOUS μ-OPIOID AGONISTS, Endomorphin 1 AND 2, HAVE VASODILATOR ACTIVITY IN THE HINDQUARTERS VASCULAR BED OF THE RAT
Life sciences, 1997Co-Authors: Hunter C. Champion, James E. Zadina, Abba J. Kastin, Philip J. KadowitzAbstract:Abstract Endomorphin 1 and Endomorphin 2 are newly-discovered endogenous ligands for the μ-opioid receptor. In the present study, responses to intra-arterial injections of Endomorphin 1 and 2 were investigated in the hindquarters vascular bed of the rat. Under constant-flow conditions, Endomorphin 1 and 2 induced dose-dependent decreases in hindquarters perfusion pressure when injected in doses of 3–100 nmol into the hindquarters perfusion circuit. Vasodilator responses to Endomorphin 1 and 2 and met-enkephalin were attenuated by the opioid receptor antagonist naloxone (2 mg/kg i.v.) at a time when vasodilator responses to isoproterenol were not altered. In terms of relative vasodilator activity, Endomorphin 1 and 2 were similar to ATP, 100-fold less potent than isoproterneol, and 10,000-fold less potent than acetylcholine. These data demonstrate that Endomorphin 1 and 2 have significant naloxone-sensitive vasodilator activity in the hindquarters vascular bed of the rat. © 1997 Elsevier Science Inc.