Differential antagonism of endomorphin-1 and endomorphin-2 spinal antinociception by naloxonazine and 3-methoxynaltrexone

Sakurada, Shinobu; Hayashi, Takafumi; Yuhki, Masayuki; Fujimura, Tsutomu; Murayama, Kimie; Yonezawa, Akihiko; Sakurada, Chikai; Takeshita, Mitsuhiro; Zadina, James E.; Kastin, Abba J.; Sakurada, Tsukasa

doi:10.1016/s0006-8993(00)02770-0

Cited by 69 publications

(52 citation statements)

References 35 publications

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“…However, pharmacological intervention studies have also revealed that the mechanisms of the action of the two endomorphins are not completely identical. Thus, the antinociceptive effect of EM-2 is more sensitive to naloxonazine than that of EM-1 (Sakurada et al, 1999(Sakurada et al, , 2000(Sakurada et al, , 2001(Sakurada et al, , 2002. The studies of Sakurada and coworkers have suggested that EM-2 acts predominantly as a mu1-opioid receptor agonist and EM-1 as a mu2-opioid receptor agonist.…”

Section: Introductionmentioning

confidence: 99%

Endomorphin-2 and Endomorphin-1 Promote the Extracellular Amount of Accumbal Dopamine via Nonopioid and Mu-Opioid Receptors, Respectively

Okutsu

Watanabe

Takahashi

et al. 2005

Neuropsychopharmacol

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Activation of mu-opioid receptors in the nucleus accumbens (NAc) is known to increase accumbal dopamine efflux in rats. Endomorphin-2 (Tyr-Pro-Phe-Phe-NH 2 ; EM-2) and endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2 ; EM-1) are suggested to be the endogenous ligands for the mu-opioid receptor. As the ability of EM-2 and EM-1 to alter the accumbal extracellular dopamine level has not yet been studied in freely moving rats, the present study was performed, using a microdialysis technique that allows on-line monitoring of the extracellular dopamine with a temporal resolution of 5 min. A 25 min infusion of either EM-2 or EM-1 into the NAc (5, 25, and 50 nmol) produced a dose-dependent increase of the accumbal dopamine level. The EM-2 (50 nmol)-and EM-1 (25 and 50 nmol)-induced dopamine efflux were abolished by intra-accumbal perfusion of tetrodotoxin (2 mM). Intra-accumbal perfusion of the mu-opioid receptor antagonist CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH 2 ; 3 nmol) failed to affect the EM-2 (50 nmol)-induced dopamine release, whereas it significantly inhibited the EM-1 (25 and 50 nmol)-induced dopamine release. The EM-1 (50 nmol)-induced accumbal dopamine efflux was significantly reduced by the systemic administration of the putative mu1-opioid receptor antagonist naloxonazine (15 mg/kg, intraperitoneally (i.p.), given 24 h before starting the perfusion). Systemic administration of the aspecific opioid receptor antagonist naloxone (1 mg/kg, i.p., given 10 or 20 min before starting the perfusion) also failed to affect the EM-2 (50 nmol)-induced dopamine efflux, whereas it significantly inhibited the EM-1 (25 and 50 nmol)-induced dopamine efflux. The present study shows that the intra-accumbal infusion of EM-2 and EM-1 increases accumbal dopamine efflux by mechanisms that fully differ. It is concluded that the effects of EM-2 are not mediated via opioid receptors in contrast to the effects of EM-1 that are mediated via mu1-opioid receptors in the NAc.

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Section: Introductionmentioning

confidence: 99%

Endomorphin-2 and Endomorphin-1 Promote the Extracellular Amount of Accumbal Dopamine via Nonopioid and Mu-Opioid Receptors, Respectively

Okutsu

Watanabe

Takahashi

et al. 2005

Neuropsychopharmacol

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“…However, the antinociceptive effects produced by endomorphin-1 and endomorphin-2 are mediated by the stimulation of different subtypes of μ-opioid receptors (Tseng, 2002). This is evidenced by the finding that pretreatment with the μ-opioid receptor antagonist 3-methoxynaltrexone selectively inhibits the antinociception induced by endomorphin-2, but not endomorphin-1, whereas β-funaltrexamine inhibits both (Sakurada et al, 2000). Pretreatment with endomorphin-1 or endomorphin-2 given intrathecally or intracerebral periaquaductal gray attenuates the antinociception produced by morphine.…”

Section: The Hyperalgesia Induced By Endomorphin-2 Is Mediated By Thementioning

confidence: 98%

“…However, the antinociceptive effects produced by endomorphin-1 and endomorphin-2 are mediated by the stimulation of different subtypes of μ-opioid receptors. This view is evidenced by the finding that μ-opioid receptor antagonists, 3-methoxynaltrexone blocks the antinociception produced by endomorphin-2, but not endomorphin-1 (Sakurada et al, 2000). Intrathecal treatment with antisense oligodeoxynucleotides against specific exons of the μ-opioid receptor clone leads to a differential loss of antinociception produced by endomorphin-1 and endomorphin-2 (Wu et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Paradoxical hyperalgesia induced by μ-opioid receptor agonist endomorphin-2, but not endomorphin-1, microinjected into the centromedial amygdala of the rat

Terashvili¹,

Wu²,

Schwasinger³

et al. 2007

European Journal of Pharmacology

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The effects of endomorphin-2 or endomorphin-1 microinjected into the centromedial amygdala on the thermally induced tail-flick response were studied in male CD rats. Microinjection of endomorphin-2 (8.7-35.0 nmol) given into the centromedial amygdala time-and dosedependently decreased the tail-flick latencies. On the other hand, endomorphin-1 (8-32.6 nmol) given into the same site did not cause any change of the tail-flick latency. However, endomorphin-1 (32.6 nmol) or endomorphin-2 (35.0 nmol) given into the basolateral site of amygdala did not affect the tail-flick latency. Pretreatment with the antiserum against dynorphin A(1-17) (200 µg) significantly reversed the decrease of the tail-flick latency induced by endomorphin-2. The decrease of the tail-flick latency induced by endomorphin-2 was also blocked by the endomorphin-2 selective μ-opioid receptor antagonist 3-methoxynaltrexone (6.4 pmol) and by the Nmethyl-D-aspartate (NMDA) receptor antagonist MK-801 (30 nmol), but not by the κ-opioid receptor antagonist nor-binaltorphimine (6.6 nmol). It is concluded that endomorphin-2, but not endomorphin-1, given into the centromedial amygdala stimulates a 3-methoxynaltrexonesensitive μ-opioid receptor subtype to induce the release of dynorphin A(1-17), which then acts on the NMDA receptor, but not κ-opioid receptor for producing hyperalgesia. This conclusion is further supported by the additional findings that dynorphin A(1-17) (2.3 nmol) given into the centromedial amygdala also caused the decrease of the tail-flick latency, which was similarly blocked by the NMDA receptor antagonist MK-801 (30 nmol), but not κ-opioid receptor antagonist nor-binaltorphimine (6.6 nmol).

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“…Systemic pretreatment with the MOP1-R antagonist naloxonazine attenuates the antinociception induced by EM-2, but not EM-1 given i.t. or i.c.v., suggesting that antinociception induced by EM-2, but not EM-1 is mediated by the stimulation of naloxonazine sensitive MOP-Rs (24,25). Pretreatment with different antisense oligodeoxynucleotides (ODN) against a different G-protein subunit is also be able to differentiate antinociceptive effects induced by EM-1 and EM-2.…”

Section: Differential Antinociception Induced By Spinally-administerementioning

confidence: 99%

Recent Advances in the Search for the μ-Opioidergic System: The Antinociceptive Properties of Endomorphin-1 and Endomorphin-2 in the Mouse

Tseng

2002

Japanese Journal of Pharmacology

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ABSTRACT-Two highly selective m -opioid receptor agonists, endomorphin-1 (EM-1) and endomorphin-2 (EM-2), have been identified and postulated to be endogenous m -opioid receptor ligands. The present minireview describes the antinociceptive properties with the tail-flick test of these two ligands given intracerebroventricularly (i.c.v.) and intrathecally (i.t.) in ICR mice. EM-1 or EM-2 given i.c.v. or i.t. dose-dependently produce antinociception. These antinociceptive effects induced by EM-1 and EM-2 given i.c.v. or i.t. are selectively mediated by the stimulation of m-, but not d-or k-opioid receptors. Like other m-opioid agonists morphine and DAMGO ([D-Ala 2 ,NMePhe 4 ,Gly 5 -ol]enkephalin), EM-1 and EM-2 given i.c.v. activate descending pain controls by the releases of noradrenaline and 5-HT and subsequently act on a2-adrenoceptors and 5-HT receptors, respectively, in the spinal cord to produce antinociception. However, the antinociception induced by EM-2 given i.c.v. or i.t. also contain an additional component, which is mediated by the release of dynorphin A(1 -17) acting on k-opioid receptors at the supraspinal and spinal sites. In addition, the antinociception induced by EM-2 given i.c.v. contains another component, which is mediated by the release of Met-enkephalin acting on d2-opioid receptors in the spinal cord. It is proposed that there are two subtypes of m-opioid receptors,which are involved in EM-1-and EM-2-induced antinociception. One subtype of m-opioid receptors is stimulated by EM-1, EM-2 and other m -opioid agonists morphine and DAMGO; and another subtype of m-opioid is sorely stimulated by EM-2 and is involved in the releases of dynorphin A(1 -17) and Met-enkephalin for the production of antinociception.Keywords: Endomorphin-1, Endomorphin-2, Antinociception, m-Opioid receptor, Descending pain control systemSince the initial demonstration of m -opioid receptors (MOP-Rs) over 25 years ago, investigators have searched for their endogenous ligands. The search led to the discovery of enkephalins, endorphins and dynorphins in the 1970's, yet they have either low selectivity or efficacy at the MOP-Rs. The enkephalins are the endogenous ligands for d-opioid receptors (DOP-Rs) and dynorphin A(1 -17) is the endogenous ligand for k-opioid receptors (KOP-Rs). b -Endorphin has been proposed to be an endogenous ligand for the e -opioid receptor (1, 2). However, it also binds equally well to MOP-and DOP-Rs with high affinity. Thus, many investigators felt that these peptides were not the endogenous ligands for MOP-Rs because of their selectivity profiles.Recently, two new peptides, endomorphin-1 (EM-1) and endomorphin-2 (EM-2), have been isolated from mammalian brain and found to activate MOP-Rs with high affinity and selectivity, raising the possibility that they are two endogenous MOP-R ligands (3). In opioid receptor binding assays, both EM-1 and EM-2 compete with m 1 (MOP1)-and MOP2-R sites potently (4). Neither compound has appreciable affinities for DOP-Rs and KOP1-Rs. EMs were found in the brain an...

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Differential antagonism of endomorphin-1 and endomorphin-2 spinal antinociception by naloxonazine and 3-methoxynaltrexone

Cited by 69 publications

References 35 publications

Endomorphin-2 and Endomorphin-1 Promote the Extracellular Amount of Accumbal Dopamine via Nonopioid and Mu-Opioid Receptors, Respectively

Endomorphin-2 and Endomorphin-1 Promote the Extracellular Amount of Accumbal Dopamine via Nonopioid and Mu-Opioid Receptors, Respectively

Paradoxical hyperalgesia induced by μ-opioid receptor agonist endomorphin-2, but not endomorphin-1, microinjected into the centromedial amygdala of the rat

Recent Advances in the Search for the μ-Opioidergic System: The Antinociceptive Properties of Endomorphin-1 and Endomorphin-2 in the Mouse

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