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James E Zadina - One of the best experts on this subject based on the ideXlab platform.

  • Mu-opioid receptor is present in dendritic targets of Endomorphin-2 axon terminals in the nuclei of the solitary tract.
    Neuroscience, 2005
    Co-Authors: Marc Silverman, Sam M. Hermes, James E Zadina, Sue A. Aicher
    Abstract:

    Endomorphins represent a group of endogenous opioid peptides with high affinity for the mu-opioid receptor. In the brainstem, Endomorphin-2 is found in trigeminal dorsal horn and the nuclei of the solitary tract, suggesting its presence in both nociceptive and visceral primary afferents. If Endomorphin-2 were an endogenous ligand for the mu-opioid receptor, we would expect to find the receptor at cellular sites in close association with the peptide. We used dual-labeling immunocytochemistry combined with electron microscopy to examine interactions between Endomorphin-2-immunoreactive and mu-opioid receptor-immunoreactive profiles within the nuclei of the solitary tract in the rat. Endomorphin-2-immunoreactivity was found primarily in unmyelinated axons and axon terminals in nuclei of the solitary tract and the majority of these terminals contained dense core vesicles. Endomorphin-2-immunoreactive axon terminals often formed asymmetric synapses with dendritic spines lacking mu-opioid receptor-immunoreactivity, but mu-opioid receptor-immunoreactivity was found in many of the larger dendritic targets of Endomorphin-2-immunoreactive terminals. Thus, mu-opioid receptor-immunoreactivity was found in the postsynaptic targets of Endomorphin-2-immunoreactive axon terminals, consistent with the hypothesis that Endomorphin-2 is an endogenous ligand for this receptor within the nuclei of the solitary tract. A small number of Endomorphin-2-immunoreactive somata, dendrites, and axon terminals also contained mu-opioid receptor-immunoreactivity. Cells that contain both the opioid peptide and its receptor may be a substrate for potential autoregulation of nuclei of the solitary tract neurons by opioid ligands. Finally, using tract tracing and confocal microscopy, we found Endomorphin-2-immunoreactivity in a subset of vagal afferents. Together these findings support the hypothesis that Endomorphin-2 is a ligand for the mu-opioid receptor within nuclei of the solitary tract and that the peptide is at least partially derived from primary visceral afferents.

  • Differential antinociceptive effects induced by intrathecally administered Endomorphin-1 and Endomorphin-2 in the mouse
    European journal of pharmacology, 2001
    Co-Authors: Shinobu Sakurada, James E Zadina, Abba J Kastin, Tsutomu Fujimura, Kimie Murayama, Takafumi Hayashi, Masayuki Yuhki, Chikai Sakurada, Tohru Orito, Tsukasa Sakurada
    Abstract:

    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.

  • Saturable brain-to-blood transport of Endomorphins.
    Experimental brain research, 2001
    Co-Authors: Abba J Kastin, Melita B. Fasold, Rebecca Smith, Kristen A. Horner, James E Zadina
    Abstract:

    Opiate-modulating tetrapeptides such as tyrosine-melanocyte-stimulating hormone-release inhibiting factor-1 (Tyr-MIF-1; Tyr-Pro-Leu-Gly-NH2) and Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2) are saturably transported from brain to blood. We examined whether two recently described endogenous opiate tetrapeptides with similar structures, the mu-specific Endomorphins, also are transported across the blood-brain barrier (BBB). We found that the efflux rates of Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and Endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) were each self-inhibited by an excess of the respective Endomorphin, thereby defining saturable transport. Cross-inhibition of the transport of each Endomorphin by the other indicated shared transport. By contrast, no inhibition of the efflux of either Endomorphin resulted from coadministration of Tyr-MIF-1, indicating that peptide transport system-1 (PTS-1) was not involved. Tyr-W-MIF-1, which is partially transported by PTS-1, significantly (P

  • Differential antagonism of Endomorphin-1 and Endomorphin-2 spinal antinociception by naloxonazine and 3-methoxynaltrexone.
    Brain research, 2000
    Co-Authors: Shinobu Sakurada, James E Zadina, Akihiko Yonezawa, Tsutomu Fujimura, Kimie Murayama, Takafumi Hayashi, Masayuki Yuhki, Chikai Sakurada, Mitsuhiro Takeshita, Abba J Kastin
    Abstract:

    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.

  • Analgesic effects of Endomorphin-1 and Endomorphin-2 in the formalin test in mice.
    Life sciences, 2000
    Co-Authors: R. Denis Soignier, Abba J Kastin, Anthony L. Vaccarino, Angela M. Brennan, James E Zadina
    Abstract:

    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.

Leon F. Tseng - One of the best experts on this subject based on the ideXlab platform.

  • 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, 2002
    Co-Authors: Kuei-chun Hung, Hirokazu Mizoguchi, Tsukasa Sakurada, Shinobu Sakurada, Toru Okayama, Tsutomu Fujimura, Kimie Murayama, James M. Fujimoto, Leon F. Tseng
    Abstract:

    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.

  • spinal pretreatment with antisense oligodeoxynucleotides against exon 1 4 or 8 of μ opioid receptor clone leads to differential loss of spinal Endomorphin 1 and Endomorphin 2 induced antinociception in the mouse
    Journal of Pharmacology and Experimental Therapeutics, 2002
    Co-Authors: Hirokazu Mizoguchi, Kuei-chun Hung, James M. Fujimoto, Maia Terashvili, Randy J Leitermann, Leon F. Tseng
    Abstract:

    Intrathecal (i.t.) pretreatments with antisense oligodeoxynucleotides (AS ODNs) against exon-1, -4, or -8 of mu-opioid receptor clone (MOR-1) to knockdown different variants of MOR-1 on the antinociception induced by Endomorphin-1, enomorphin-2, or [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) given i.t. were investigated in male CD-1 mice. The antinociception was measured with the tail-flick test. AS ODNs against exon-1 (5 microg) given i.t. once daily for 3 days attenuated the antinociception induced by Endomorphin-1 and Endomorphin-2 with the dose-response curves shifted to the right by 4.5- and 5.3-fold, respectively. AS ODNs against exon-4 (5 microg) attenuated the antinociception induced by Endomorphin-1 and Endomorphin-2 with the dose-response curves shifted to the right by 2.4- and 5.3-fold, respectively. However, AS ODNs against exon-8 (5 microg) attenuated only the antinociception induced by Endomorphin-1, but not Endomorphin-2 with the dose-response curves shifted to the right by 3.9- and 1.3-fold, respectively. One more day of pretreatment with antisense probes failed to further reduce the antinociception. The antinociception induced by DAMGO was attenuated by i.t. pretreatment with AS ODNs directed against exon-1, and, to a lesser extent, by AS ODNs directed against exon-8. The mismatch AS ODNs against respective exon-1, -4, and -8 failed to exert significant effects. The selective actions of antisense probes directed against different exons of the MOR-1 in attenuating the antinociception induced by Endomorphin-1, Endomorphin-2, and DAMGO suggest that multiple splice variants of the MOR-1 exist and support the view that different subtypes of mu-opioid receptors are involved in antinociception induced by Endomorphin-1, Endomorphin-2, and DAMGO.

  • Acute antinociceptive tolerance and unidirectional cross-tolerance to Endomorphin-1 and Endomorphin-2 given intraventricularly in the rat.
    European journal of pharmacology, 2002
    Co-Authors: Kuei-chun Hung, Hirokazu Mizoguchi, Leon F. Tseng
    Abstract:

    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.

  • Acute antinociceptive tolerance and asymmetric cross-tolerance between Endomorphin-1 and Endomorphin-2 given intracerebroventricularly in the mouse.
    The Journal of pharmacology and experimental therapeutics, 2001
    Co-Authors: Kuei-chun Hung, Hirokazu Mizoguchi, James M. Fujimoto, Leon F. Tseng
    Abstract:

    Development of tolerance in mice pretreated intracerebroventricularly with μ-opioid receptor agonist Endomorphin-1, Endomorphin-2, or [d-Ala2, N -Me-Phe4,Gly-ol5]-enkephalin (DAMGO) was compared between Endomorphin-1- and Endomorphin-2-induced antinociception with the tail-flick test. A 2-h pretreatment with Endomorphin-1 (30 nmol) produced a 3-fold shift to the right in the dose-response curve for Endomorphin-1. Similarly, a 1-h pretreatment with Endomorphin-2 (70 nmol) caused a 3.9-fold shift to the right for Endomorphin-2. In cross-tolerance experiments, pretreatment with Endomorphin-2 (70 nmol) caused a 2.3-fold shift of the dose-response curve for Endomorphin-1, whereas pretreatment with Endomorphin-1 (30 nmol) caused no change of the Endomorphin-2 dose-response curve. Thus, mice acutely tolerant to Endomorphin-1 were not cross-tolerant to Endomorphin-2, although mice made tolerant to Endomorphin-2 were partially cross-tolerant to Endomorphin-1; an asymmetric cross-tolerance occurred. Pretreatment with DAMGO 3 h before intracerebroventricular injection of Endomorphin-1, Endomorphin-2, or DAMGO attenuated markedly the antinociception induced by Endomorphin-1 and DAMGO but not Endomorphin-2. It is proposed that two separate subtypes of μ-opioid receptors are involved in antinociceptive effects induced by Endomorphin-1 and Endomorphin-2. One subtype of opioid μ-receptors is stimulated by DAMGO, Endomorphin-1, and Endomorphin-2, and another subtype of μ-opioidreceptors is stimulated solely by Endomorphin-2.

  • Differential mechanisms mediating descending pain controls for antinociception induced by supraspinally administered Endomorphin-1 and Endomorphin-2 in the mouse.
    The Journal of pharmacology and experimental therapeutics, 2000
    Co-Authors: M Ohsawa, Hirokazu Mizoguchi, H Nagase, Minoru Narita, Mei Chu, Leon F. Tseng
    Abstract:

    We have previously demonstrated that both Endomorphin-1 and Endomorphin-2 produce their antinociception by the stimulation of μ-opioid receptors. However, the antinociception induced by Endomorphin-2 contains an additional component, which is mediated by the release of dynorphin A (1-17) acting on κ-opioid receptors. These studies were done to determine whether the antinociception induced by Endomorphin-1 and Endomorphin-2 given supraspinally was mediated by the activation of different descending pain control pathways in the mouse. Specific receptor antagonists or antisera against endogenous opioid peptides were injected intrathecally to block the receptors or bind the released endogenous opioid peptides, and Endomorphin-1 or Endomorphin-2 was then administered i.c.v. to activate the descending pain control systems to produce antinociception. The tail-flick response was used as antinociceptive test. The blockade of the α2-adrenoceptors and 5-hydroxytryptamine receptors in the spinal cord by i.t. injection of yohimbine and methysergide, respectively, inhibited the antinociception induced by i.c.v.-administered Endomorphin-1 and Endomorphin-2. However, the antinociception induced by Endomorphin-2 was inhibited by i.t. pretreatment with δ2-opioid receptor antagonist naltriben or κ-opioid receptor antagonist nor-binaltorphimine, but not by the μ-opioid receptor antagonistd-Phe-Cys-Tyr-d-Try-Orn-Thr-Pen-Thr-NH2or the δ1-opioid receptor antagonist 7-benzylidene naltrexamine. Intrathecal pretreatment with antiserum against Met-enkephalin attenuated the antinociception induced by i.c.v.-administered Endomorphin-2, but not Endomorphin-1. Furthermore, i.t. pretreatment with antiserum against dynorphin A (1-17) also inhibited the antinociception induced by i.c.v.-administered Endomorphin-2, but not Endomorphin-1. Intrathecal pretreatment with antiserum against Leu-enkephalin or β-endorphin did not inhibit i.c.v.-administered Endomorphin-1- or Endomorphin-2-induced antinociception. The results indicate that, like other opioid μ-receptor agonists, morphine, and [d-Ala2, N -Me-Phe4, Gly5-ol]-enkephalin, Endomorphin-1 and Endomorphin-2 given i.c.v. produce antinociception by activating spinipetal noradrenergic and serotonergic pathways for producing antinociception. However, the antinociception induced by Endomorphin-2 given i.c.v. also contains other components, which are mediated by the release of Met-enkephalin and dynorphin A (1-17) acting on opioid δ2- and κ-receptors, respectively, in the spinal cord.

Shinobu Sakurada - One of the best experts on this subject based on the ideXlab platform.

  • Involvement of multiple μ-opioid receptor subtypes on the presynaptic or postsynaptic inhibition of spinal pain transmission
    Peptides, 2014
    Co-Authors: Hirokazu Mizoguchi, Hirokazu Takagi, Chizuko Watanabe, Akihiko Yonezawa, Takumi Sato, Tsukasa Sakurada, Shinobu Sakurada
    Abstract:

    The involvement of the μ-opioid receptor subtypes on the presynaptic or postsynaptic inhibition of spinal pain transmission was characterized in ddY mice using Endomorphins. Intrathecal treatment with capsaicin, N-methyl-d-aspartate (NMDA) or substance P elicited characteristic nociceptive behaviors that consisted primarily of vigorous biting and/or licking with some scratching. Intrathecal co-administration of endogenous μ-opioid peptide Endomorphin-1 or Endomorphin-2 resulted in a potent antinociceptive effect against the nociceptive behaviors induced by capsaicin, NMDA or substance P, which was eliminated by i.t. co-administration of the μ-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP). The antinociceptive effect of Endomorphin-1 was significantly suppressed by i.t.-co-administration of the μ2-opioid receptor antagonist Tyr-D-Pro-Trp-Phe-NH2 (D-Pro2-Endomorphin-1) but not the μ1-opioid receptor antagonist Tyr-D-Pro-Phe-Phe-NH2 (D-Pro2-Endomorphin-2) on capsaicin- or NMDA-elicited nociceptive behaviors. In contrast, the antinociceptive effect of Endomorphin-2 was significantly suppressed by i.t.-co-administration of D-Pro2-Endomorphin-2 but not D-Pro2-Endomorphin-1 on capsaicin-, NMDA- or substance P-elicited nociceptive behaviors. Interestingly, regarding substance P-elicited nociceptive behaviors, the antinociceptive effect of Endomorphin-1 was significantly suppressed by i.t.-co-administration of another μ2-opioid receptor antagonist, Tyr-D-Pro-Trp-Gly-NH2 (D-Pro2-Tyr-W-MIF-1), but not D-Pro2-Endomorphin-1 or D-Pro2-Endomorphin-2. The present results suggest that the multiple μ-opioid receptor subtypes are involved in the presynaptic or postsynaptic inhibition of spinal pain transmission.

  • possible involvement of dynorphin a 1 17 release via μ1 opioid receptors in spinal antinociception by Endomorphin 2
    Journal of Pharmacology and Experimental Therapeutics, 2006
    Co-Authors: Hirokazu Mizoguchi, Tsukasa Sakurada, Tsutomu Fujimura, Takafumi Hayashi, Hiroyuki Watanabe, Wataru Sakurada, Toshiki Sawai, Shinobu Sakurada
    Abstract:

    The antinociception induced by i.t. or i.c.v. administration of Endomorphins is mediated via mu-opioid receptors. However, although Endomorphins do not have an appreciable affinity for kappa-opioid receptors, pretreatment with the kappa-opioid receptor antagonist norbinaltorphimine markedly reduces the antinociceptive response to i.c.v. or i.t. administered Endomorphin-2 but not Endomorphin-1. These results suggest that Endomorphin-2 initially stimulates mu-opioid receptors, which subsequently induce the release of dynorphins that act on kappa-opioid receptors to produce antinociception. The present study was performed in mice to determine whether the release of dynorphins by i.t. administered Endomorphin-2 is mediated through mu-opioid receptors to produce antinociception. Intrathecal pretreatment with an antiserum against dynorphin A-(1-17), but not against dynorphin B-(1-13) or alpha-neoendorphin, dose-dependently prevented the paw-withdrawal inhibition by Endomorphin-2. The pretreatments with these antisera did not affect the Endomorphin-1- or [D-Ala(2),MePhe(4),Gly(ol)(5)]enkephalin-induced paw-withdrawal inhibition. The attenuation of Endomorphin-2-induced antinociception by i.t. pretreatment with an antiserum against dynorphin A-(1-17) or s.c. pretreatment with norbinaltorphimine was blocked dose-dependently by s.c. pretreatment with the mu-opioid receptor antagonist beta-funaltrexamine or the mu(1)-opioid receptor antagonist naloxonazine at ultra-low doses that are ineffective against mu-opioid receptor agonists. These results suggest that the spinal antinociception induced by Endomorphin-2 is mediated through the stimulation of a distinct subtype of mu(1)-opioid receptor that induces the release of the endogenous kappa-opioid peptide dynorphin A-(1-17) in the spinal cord.

  • 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, 2002
    Co-Authors: Kuei-chun Hung, Hirokazu Mizoguchi, Tsukasa Sakurada, Shinobu Sakurada, Toru Okayama, Tsutomu Fujimura, Kimie Murayama, James M. Fujimoto, Leon F. Tseng
    Abstract:

    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.

  • Endomorphin analogues containing D‐Pro2 discriminate different μ‐opioid receptor mediated antinociception in mice
    British journal of pharmacology, 2002
    Co-Authors: Shinobu Sakurada, Tsutomu Fujimura, Kimie Murayama, Takafumi Hayashi, Masayuki Yuhki, Chikai Sakurada, Hiroyuki Watanabe, Tsukasa Sakurada
    Abstract:

    The antagonistic actions of D-Pro 2 -Endomorphins on inhibition of the paw withdrawal response by Endomorphins were studied in mice. D-Pro 2 -Endomorphin-1 and D-Pro 2 -Endomorphin-2, injected intrathecally (i.t.), had no significant eAect on the nociceptive thermal threshold alone. When D-Pro 2 Endomorphin-1 (0.05‐0.1 pmol) was injected simultaneously with i.t. Endomorphin-1 (5.0 nmol) or Endomorphin-2 (5.0 nmol), antinociception induced by endomoprhin-1 was reduced significantly, whereas Endomorphin-2-induced antinociception was not aAected by D-Pro 2 -Endomorphin-1. Antinociception induced by i.t. Endomorphin-2 (5.0 nmol) was reduced significantly by its analogue, D-Pro 2 -Endomorphin-2 (100 pmol), but not by D-Pro 2 -Endomorphin-1. D-Pro 2 -Endomorphin-1. DPro 2 -Endomorphin-1 also antagonized the antinociceptive eAect of i.t. DAMGO, a m-opioid receptor agonist, whereas D-Pro 2 -Endomorphin-2 failed to reduce the eAect of DAMGO. These results suggest that Endomorphin analogues containing D-Pro 2 are able to discriminate the antinociceptive actions of m1- and m2-opioid receptor agonists at the spinal cord level. British Journal of Pharmacology (2002) 137, 1143‐1146. doi:10.1038/sj.bjp.0705047

  • Differential antinociceptive effects induced by intrathecally administered Endomorphin-1 and Endomorphin-2 in the mouse
    European journal of pharmacology, 2001
    Co-Authors: Shinobu Sakurada, James E Zadina, Abba J Kastin, Tsutomu Fujimura, Kimie Murayama, Takafumi Hayashi, Masayuki Yuhki, Chikai Sakurada, Tohru Orito, Tsukasa Sakurada
    Abstract:

    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.

Hirokazu Mizoguchi - One of the best experts on this subject based on the ideXlab platform.

  • Involvement of multiple μ-opioid receptor subtypes on the presynaptic or postsynaptic inhibition of spinal pain transmission
    Peptides, 2014
    Co-Authors: Hirokazu Mizoguchi, Hirokazu Takagi, Chizuko Watanabe, Akihiko Yonezawa, Takumi Sato, Tsukasa Sakurada, Shinobu Sakurada
    Abstract:

    The involvement of the μ-opioid receptor subtypes on the presynaptic or postsynaptic inhibition of spinal pain transmission was characterized in ddY mice using Endomorphins. Intrathecal treatment with capsaicin, N-methyl-d-aspartate (NMDA) or substance P elicited characteristic nociceptive behaviors that consisted primarily of vigorous biting and/or licking with some scratching. Intrathecal co-administration of endogenous μ-opioid peptide Endomorphin-1 or Endomorphin-2 resulted in a potent antinociceptive effect against the nociceptive behaviors induced by capsaicin, NMDA or substance P, which was eliminated by i.t. co-administration of the μ-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP). The antinociceptive effect of Endomorphin-1 was significantly suppressed by i.t.-co-administration of the μ2-opioid receptor antagonist Tyr-D-Pro-Trp-Phe-NH2 (D-Pro2-Endomorphin-1) but not the μ1-opioid receptor antagonist Tyr-D-Pro-Phe-Phe-NH2 (D-Pro2-Endomorphin-2) on capsaicin- or NMDA-elicited nociceptive behaviors. In contrast, the antinociceptive effect of Endomorphin-2 was significantly suppressed by i.t.-co-administration of D-Pro2-Endomorphin-2 but not D-Pro2-Endomorphin-1 on capsaicin-, NMDA- or substance P-elicited nociceptive behaviors. Interestingly, regarding substance P-elicited nociceptive behaviors, the antinociceptive effect of Endomorphin-1 was significantly suppressed by i.t.-co-administration of another μ2-opioid receptor antagonist, Tyr-D-Pro-Trp-Gly-NH2 (D-Pro2-Tyr-W-MIF-1), but not D-Pro2-Endomorphin-1 or D-Pro2-Endomorphin-2. The present results suggest that the multiple μ-opioid receptor subtypes are involved in the presynaptic or postsynaptic inhibition of spinal pain transmission.

  • possible involvement of dynorphin a 1 17 release via μ1 opioid receptors in spinal antinociception by Endomorphin 2
    Journal of Pharmacology and Experimental Therapeutics, 2006
    Co-Authors: Hirokazu Mizoguchi, Tsukasa Sakurada, Tsutomu Fujimura, Takafumi Hayashi, Hiroyuki Watanabe, Wataru Sakurada, Toshiki Sawai, Shinobu Sakurada
    Abstract:

    The antinociception induced by i.t. or i.c.v. administration of Endomorphins is mediated via mu-opioid receptors. However, although Endomorphins do not have an appreciable affinity for kappa-opioid receptors, pretreatment with the kappa-opioid receptor antagonist norbinaltorphimine markedly reduces the antinociceptive response to i.c.v. or i.t. administered Endomorphin-2 but not Endomorphin-1. These results suggest that Endomorphin-2 initially stimulates mu-opioid receptors, which subsequently induce the release of dynorphins that act on kappa-opioid receptors to produce antinociception. The present study was performed in mice to determine whether the release of dynorphins by i.t. administered Endomorphin-2 is mediated through mu-opioid receptors to produce antinociception. Intrathecal pretreatment with an antiserum against dynorphin A-(1-17), but not against dynorphin B-(1-13) or alpha-neoendorphin, dose-dependently prevented the paw-withdrawal inhibition by Endomorphin-2. The pretreatments with these antisera did not affect the Endomorphin-1- or [D-Ala(2),MePhe(4),Gly(ol)(5)]enkephalin-induced paw-withdrawal inhibition. The attenuation of Endomorphin-2-induced antinociception by i.t. pretreatment with an antiserum against dynorphin A-(1-17) or s.c. pretreatment with norbinaltorphimine was blocked dose-dependently by s.c. pretreatment with the mu-opioid receptor antagonist beta-funaltrexamine or the mu(1)-opioid receptor antagonist naloxonazine at ultra-low doses that are ineffective against mu-opioid receptor agonists. These results suggest that the spinal antinociception induced by Endomorphin-2 is mediated through the stimulation of a distinct subtype of mu(1)-opioid receptor that induces the release of the endogenous kappa-opioid peptide dynorphin A-(1-17) in the spinal cord.

  • 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, 2002
    Co-Authors: Kuei-chun Hung, Hirokazu Mizoguchi, Tsukasa Sakurada, Shinobu Sakurada, Toru Okayama, Tsutomu Fujimura, Kimie Murayama, James M. Fujimoto, Leon F. Tseng
    Abstract:

    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.

  • spinal pretreatment with antisense oligodeoxynucleotides against exon 1 4 or 8 of μ opioid receptor clone leads to differential loss of spinal Endomorphin 1 and Endomorphin 2 induced antinociception in the mouse
    Journal of Pharmacology and Experimental Therapeutics, 2002
    Co-Authors: Hirokazu Mizoguchi, Kuei-chun Hung, James M. Fujimoto, Maia Terashvili, Randy J Leitermann, Leon F. Tseng
    Abstract:

    Intrathecal (i.t.) pretreatments with antisense oligodeoxynucleotides (AS ODNs) against exon-1, -4, or -8 of mu-opioid receptor clone (MOR-1) to knockdown different variants of MOR-1 on the antinociception induced by Endomorphin-1, enomorphin-2, or [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) given i.t. were investigated in male CD-1 mice. The antinociception was measured with the tail-flick test. AS ODNs against exon-1 (5 microg) given i.t. once daily for 3 days attenuated the antinociception induced by Endomorphin-1 and Endomorphin-2 with the dose-response curves shifted to the right by 4.5- and 5.3-fold, respectively. AS ODNs against exon-4 (5 microg) attenuated the antinociception induced by Endomorphin-1 and Endomorphin-2 with the dose-response curves shifted to the right by 2.4- and 5.3-fold, respectively. However, AS ODNs against exon-8 (5 microg) attenuated only the antinociception induced by Endomorphin-1, but not Endomorphin-2 with the dose-response curves shifted to the right by 3.9- and 1.3-fold, respectively. One more day of pretreatment with antisense probes failed to further reduce the antinociception. The antinociception induced by DAMGO was attenuated by i.t. pretreatment with AS ODNs directed against exon-1, and, to a lesser extent, by AS ODNs directed against exon-8. The mismatch AS ODNs against respective exon-1, -4, and -8 failed to exert significant effects. The selective actions of antisense probes directed against different exons of the MOR-1 in attenuating the antinociception induced by Endomorphin-1, Endomorphin-2, and DAMGO suggest that multiple splice variants of the MOR-1 exist and support the view that different subtypes of mu-opioid receptors are involved in antinociception induced by Endomorphin-1, Endomorphin-2, and DAMGO.

  • Acute antinociceptive tolerance and unidirectional cross-tolerance to Endomorphin-1 and Endomorphin-2 given intraventricularly in the rat.
    European journal of pharmacology, 2002
    Co-Authors: Kuei-chun Hung, Hirokazu Mizoguchi, Leon F. Tseng
    Abstract:

    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.

Hans Dieter Allescher - One of the best experts on this subject based on the ideXlab platform.

  • Endomorphins 1 and 2 reduce relaxant non-adrenergic, non-cholinergic neurotransmission in rat gastric fundus.
    Life sciences, 2002
    Co-Authors: Martin Storr, Evelyn Gaffal, Volker Schusdziarra, Hans Dieter Allescher
    Abstract:

    Abstract It is now well established that opioids modulate cholinergic excitatory neurotransmission in the gastrointestinal tract. The aim of the present study was to characterize a possible effect of Endomorphins on nonadrenergic, noncholinergic (NANC) relaxant neurotransmission in the rat gastric fundus in vitro. The drugs used in the experiments were the endogenous μ-opioid receptors (MORs) Endomorphin 1 and 2 and the μ-opioid receptor antagonist CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2). CTAP left the basal tonus and the spontaneous activity of the preparation unchanged. Electrical field stimulation (EFS) under NANC conditions at frequencies ranging from 0.5 to 16 Hz caused a frequency-dependent relaxant response on the 5-hydoxytryptamine (5-HT) (10 −7 M) precontracted smooth-muscle strip. Both Endomorphin 1 and Endomorphin 2 significantly reduced this relaxation in a concentration-dependent manner. Endomorphin 1 proved to be more potent in reducing the relaxant responses. The Endomorphin effects were significantly reversed by the MOR antagonist CTAP. CTAP itself did not influence the EFS-induced relaxation. In summary, these data provide evidence that the endogenous MOR agonists Endomorphin 1 and 2 can reduce nonadrenergic, noncholinergic neurotransmission in the rat gastric fundus smooth muscle via a pathway involving MORs. The physiological relevance of these findings remains to be established, since the data presented suggest that the Endomorphins act as neuromodulators within NANC relaxant neurotransmission.

  • effects of Endomorphin 1 and 2 on μ opioid receptors in myenteric neurons and in the peristaltic reflex in rat small intestine
    Clinical and Experimental Pharmacology and Physiology, 2002
    Co-Authors: Martin Storr, Andreas Hahn, Evelyn Gaffal, Dieter Saur, Hans Dieter Allescher
    Abstract:

    SUMMARY 1. The aim of the present investigations was to characterize the effect of Endomorphins on the function of rat small intestine smooth muscle and on the electrically induced ascending and descending reflex pathway of rat small intestine in vitro. 2. Endomorphin-1 and -2 left the basal tonus and the pharmacologically stimulated smooth muscle unchanged. In contrast, electrically induced twitch contractions were significantly reduced by Endomorphin-1 and -2 and this reduction was reversed by the μ-opioid receptor antagonist Cys-Tyr-Orn-Pen-amide (CTOP), suggesting a specific μ-opioid receptor-mediated effect on neural tissue. 3. In the reflex model, Endomorphin-1 caused a significant inhibition (IC50 2.3 × 10–8 mol/L) of the ascending contraction (10–8 mol/L: –28.3 ± 5.8%; 10–7 mol/L: –94.7 ± 0.2.8%; both P < 0.05; n = 7). Descending relaxation increased at a concentration of 10–8 mol/L Endomorphin-1 (+61.6 ± 24.5%; 10–7 mol/L: +237.0 ± 65.4%; both P < 0.05; n = 6). 4. Endomorphin-1 caused a further significant increase in the latency of the ascending contraction (10–8 mol/L: +44.7 ± 20.5%; 10–7mol/L: +93.5 ± 16.1%; both P < 0.05; n = 7), whereas the latency of the descending relaxation was unaltered (n = 7). Similar results were observed for Endomorphin-2. 5. All effects could be reversed by a wash-out afterwards and were blocked by pre-incubation with CTOP (10–6 mol/L). 6. Reverse transcription–polymerase chain reaction demonstrated mRNA expression of μ-opioid receptors in the rat ileum longitudinal muscle/myenteric plexus preparation, as well as in the oesophagus and stomach. 7. Endomorphin-1 and -2 reduce the cholinergic-induced contractile response of the rat ileal smooth muscle preparation via a presynaptic mechanism. 8. By a specific and reversible interaction with μ-opioid receptors, the ascending excitatory and descending inhibitory reflex responses were attenuated or facilitated, respectively. 9. In conclusion, the Endomorphins may be the physiological endogenous μ-opioid receptor agonists in the rat small intestine.

  • Effects Of Endomorphin‐1 And ‐2 On μ‐Opioid Receptors In Myenteric Neurons And In The Peristaltic Reflex In Rat Small Intestine
    Clinical and experimental pharmacology & physiology, 2002
    Co-Authors: Martin Storr, Andreas Hahn, Evelyn Gaffal, Dieter Saur, Hans Dieter Allescher
    Abstract:

    SUMMARY 1. The aim of the present investigations was to characterize the effect of Endomorphins on the function of rat small intestine smooth muscle and on the electrically induced ascending and descending reflex pathway of rat small intestine in vitro. 2. Endomorphin-1 and -2 left the basal tonus and the pharmacologically stimulated smooth muscle unchanged. In contrast, electrically induced twitch contractions were significantly reduced by Endomorphin-1 and -2 and this reduction was reversed by the μ-opioid receptor antagonist Cys-Tyr-Orn-Pen-amide (CTOP), suggesting a specific μ-opioid receptor-mediated effect on neural tissue. 3. In the reflex model, Endomorphin-1 caused a significant inhibition (IC50 2.3 × 10–8 mol/L) of the ascending contraction (10–8 mol/L: –28.3 ± 5.8%; 10–7 mol/L: –94.7 ± 0.2.8%; both P