Non-opioid actions of opioid peptides

Wollemann, M; Benyhe, Sándor

doi:10.1016/j.lfs.2003.12.005

Cited by 71 publications

(47 citation statements)

References 76 publications

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“…The present study clearly shows that this EM-2-and EM-1-induced accumbal dopamine efflux H Okutsu et al also holds for effects of EM-2 in the central nervous system. Indeed, endomorphins have been found to bind to nonopioid binding sites in tissues lacking mu receptors, such as rat cerebellum or brain of homozygous transgenic MOR À/À mice (review: Wollemann and Benyhe, 2004). Remarkably, there are more agents that are known to act as opioid receptor agonists, but nevertheless produce effects that are not at all mediated via these receptors.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…1), P60 activates MRGX1 in a dose-dependent manner, with affinity estimated within the nanomolar range, slightly lower than that of the positive control used (BAM22) (18). In addition, further experimental results indicate that P60 and BAM22 differ in their activation of opioidrelated receptors (19). Although BAM22 activates the latter, P60 is specific to MRGXs (activating MRGX1 and weakly activating MRGX2), and it did not activate any of the known opioid receptors (D1, M1, L1, and K1) that were included in the screen.…”

Section: Generation Of In Silico Predicted Human Gpcr-activatingmentioning

confidence: 97%

Discovery and Validation of Novel Peptide Agonists for G-protein-coupled Receptors

Shemesh

Toporik

Levine

et al. 2008

Journal of Biological Chemistry

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G-protein-coupled receptors (GPCRs) represent an important group of targets for pharmaceutical therapeutics. The completion of the human genome revealed a large number of putative GPCRs. However, the identification of their natural ligands, and especially peptides, suffers from low discovery rates, thus impeding development of therapeutics based on these potential drug targets. We describe the discovery of novel GPCR ligands encrypted in the human proteome. Hundreds of potential peptide ligands were predicted by machine learning algorithms. In vitro screening of selected 33 peptides on a set of 152 GPCRs, including a group of designated orphan receptors, was conducted by intracellular calcium measurements and cAMP assays. The screening revealed eight novel peptides as potential agonists that specifically activated six different receptors in a dose-dependent manner. Most of the peptides showed distinct stimulatory patterns targeted at designated and orphan GPCRs. Further analysis demonstrated a significant in vivo effect for one of the peptides in a mouse inflammation model.

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“…The finding that EM-2-induced effects are not always mediated via opioid receptors is consistent with an earlier study reporting that the inhibitory action of EM-2 on tachykinergic contractions of isolated guinea pig bronchus was not sensitive to selective antagonists of μ-, κ-, or δ-opioid receptors or to non-specific opioid receptor antagonists such as naloxone (28). The endomorphins bind non-opioid binding sites in tissues lacking μ-opioid receptors, such as rat cerebellum or in the brain of transgenic mice lacking μ-opioid receptors (for review, see 29). Table 1 shows the putative involvement of δ-and μ-opioid receptors in increased DA efflux in the nucleus accumbens of rats after intra-accumbal infusion of δ-or μ-opioid receptor agonists.…”

Section: μ-Opioid Receptor Agonistsmentioning

confidence: 99%

Mechanisms underlying δ- and μ-opioid receptor agonist-induced increases in extracellular dopamine level in the nucleus accumbens of freely moving rats

2017

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Abstract:The nucleus accumbens is a terminal area of the mesolimbic dopaminergic system that arises in the ventral tegmental area. Opioids are thought to enhance dopaminergic activity in the nucleus accumbens by activating δ-and μ-opioid receptors in the ventral tegmental area. However, δ-and μ-opioid receptor agonists increase extracellular levels of accumbal dopamine when infused directly into the nucleus accumbens of rats. Therefore, the roles of δ-and μ-opioid receptors in regulation of accumbal dopaminergic neural activity have been analyzed by using δ-and μ-opioid receptor ligands. This review describes the mechanisms underlying the stimulatory effects on accumbal dopamine efflux, which are induced by local administration of δ-and μ-opioid receptor agonists into the nucleus accumbens of freely moving rats. The focus of this article is neurochemical studies that use in vivo microdialysis techniques. Taken together, the in vivo neurochemical evidence from these studies indicates that δ-and μ-opioid receptor agonists increase accumbal dopamine efflux by activating naloxone-sensitive opioid receptors, and by mechanisms independent of naloxone-sensitive opioid receptors, in the nucleus accumbens.

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Non-opioid actions of opioid peptides

Cited by 71 publications

References 76 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

Discovery and Validation of Novel Peptide Agonists for G-protein-coupled Receptors

Mechanisms underlying δ- and μ-opioid receptor agonist-induced increases in extracellular dopamine level in the nucleus accumbens of freely moving rats

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