Association of aminopeptidase N and endopeptidase 24.15 inhibitors potentiate behavioral effects mediated by nociceptin/orphanin FQ in mice

Noble, Florence; Roques, Bernárd P.

doi:10.1016/s0014-5793(96)01476-7

Cited by 54 publications

(36 citation statements)

References 24 publications

(33 reference statements)

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“…2) In contrast, mice injected with 0.1 and 0.3 nmol showed a decrease in locomotor activity and muscular tone (especially in the hindpaws), ataxia, and loss of the righting reflex; however, a normal tail-pinch reflex was maintained. These behavioral effects of [Arg 14 ,Lys 15 ]NC were very similar to those evoked by high doses (i.e., 10 nmol) of NC, as reported by several investigators (Reinscheid et al, 1995;Devine et al, 1996;Noble and Roques, 1997;Calo' et al, 1998b [Arg 14 ,Lys 15 ]Nociceptin, a Potent OP 4 Receptor Agonist pared with saline. This effect was statistically significant for 0.1 and 0.3 nmol (p Ͻ 0.05 according to ANOVA followed by the Dunnett test).…”

Section: Insupporting

confidence: 86%

[Arg¹⁴,Lys¹⁵]Nociceptin, a Highly Potent Agonist of the Nociceptin/Orphanin FQ Receptor: in Vitro and in Vivo Studies

Rizzi¹,

Rizzi²,

Bigoni³

et al. 2002

J Pharmacol Exp Ther

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Nociceptin (NC)/orphanin FQ is the endogenous ligand of a seven-transmembrane domain G protein-coupled receptor, referred to as OP 4 . NC and the OP 4 receptor are structurally related to opioid peptides and receptors; however, NC does not interact with classical opioid receptors, and the OP 4 receptor does not bind any selective opioid receptor ligand (for recent reviews, see Calo' et al., 2000c;Meunier, 2000). It has been demonstrated that NC modulates several biological functions, including pain threshold, morphine analgesia, food intake, anxiety, locomotor activity, memory processes, and cardiovascular, renal, respiratory, and gastrointestinal functions (Calo' et al., 2000c;Meunier, 2000). Further investigations of physiological and pathological roles of the NC/OP 4 system require new molecules that potently activate (agonists) or block (antagonists) the OP 4 receptor. Identification of such new molecules (at least of peptide nature) should be facilitated by the knowledge of the amino acid residues of the NC sequence that are critical for receptor occupation and activation. Over the last 5 years, several structure-activity relationship studies have been performed on NC (Dooley and

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Section: Insupporting

confidence: 86%

[Arg¹⁴,Lys¹⁵]Nociceptin, a Highly Potent Agonist of the Nociceptin/Orphanin FQ Receptor: in Vitro and in Vivo Studies

Rizzi¹,

Rizzi²,

Bigoni³

et al. 2002

J Pharmacol Exp Ther

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“…NEP 24.11 appears to be less important in the brain, where aminopeptidase N and endopeptidase 24.15 have been indicated as the main enzymes responsible for NC degradation. 14,15 We found that the fragment NC(1-9)NH 2 , which does not alter MBP, tends to induce tachycardia, an effect opposite to that evoked by NC. Further studies are necessary to determine whether this action is due to interaction of NC(1-9)NH 2 with unrelated receptors or to other unforeseen properties of the fragment.…”

Section: Discussionmentioning

confidence: 71%

Cardiovascular Effects of Nociceptin in Unanesthetized Mice

Madeddu

Salis

Milia³

et al. 1999

Hypertension

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Abstract-We evaluated the systemic hemodynamic effects induced by nociceptin (NC) and NC-related peptides, including the NC receptor antagonist [Phe 1 (CH 2 -NH)Gly 2 ]NC(1-13)NH 2 ([F/G]NC(1-13)NH 2 ) in unanesthetized normotensive Swiss Morini mice. Bolus intravenous injection of NC decreased mean blood pressure and heart rate. The hypotensive response to 10 nmol/kg NC lasted Ͻ10 minutes, whereas a more prolonged hypotension was evoked by 100 nmol/kg (from 114Ϯ3 to 97Ϯ2 mm Hg at 10 minutes, PϽ0.01). The latter dose reduced heart rate from 542Ϯ43 to 479Ϯ31 beats/min (PϽ0.05) and increased aortic blood flow by 41Ϯ5% (PϽ0.05). Hypotension and bradycardia were also evoked by NC(1-17)NH 2 and NC(1-13)NH 2 fragments, whereas NC(1-13)OH and NC(1-9)NH 2 were ineffective. Thiorphan, an inhibitor of neutral endopeptidase 24.11, enhanced the hypotension induced by NC(1-13)NH 2 and revealed the ability of NC(1-13)OH to decrease mean blood pressure. [F/G]NC(1-13)NH 2 , a recently synthesized antagonist of the NC receptor, did not alter basal mean blood pressure or heart rate, but it prevented the hypotension, bradycardia, and increase in aortic blood flow evoked by NC. In contrast, [F/G]NC(1-13)NH 2 did not alter the hypotension induced by bradykinin or endomorphin-1 (a -receptor agonist), and the bradycardia induced by leu-enkephalin (a ␦-receptor agonist) or U504885 (a synthetic -receptor agonist). In conclusion, NC and some of its fragments cause hypotension and bradycardia and increase aortic blood flow in mice, with the NC(1-13) sequence being critical for these biological effects. Our results also demonstrate that the compound [F/G]NC(1-13)NH 2 is a potent and selective antagonist of the NC receptor in vivo. (Hypertension. 1999;33:914-919.)

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“…Its location on the cell surface mandates that its functional activity is dictated by substrates that are available in the immediate intercellular space. CD13/APN has been implicated in the catabolism of neuroactive peptides, [32][33][34] amino acid scavenging and degradation of regulatory peptides, 35,36 cell adhesion alterations, 37 tumor invasion and metastasis, 38,39 as well as antigen processing and presentation. 40,41 Because the switch from the quiescent to angiogenic endothelial phenotype involves an alteration in the relative levels of angiogenic inhibitors and activators, 1 it is intriguing to postulate a role for CD13/APN in the processing of small regulatory molecules required to initiate, maintain, or suppress the angiogenic program in tumor vessel endothelium.…”

Section: Discussionmentioning

confidence: 99%

CD13/APN is activated by angiogenic signals and is essential for capillary tube formation

Bhagwat

Lahdenranta

Giordano

et al. 2001

Blood

283

277

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In the hematopoietic compartment, the CD13/APN metalloprotease is one of the earliest markers of cells committed to the myeloid lineage where it is expressed exclusively on the surface of myeloid progenitors and their differentiated progeny. CD13/APN is also found in nonhematopoietic tissues, and its novel expression on the endothelial cells of angiogenic, but not normal, vasculature was recently IntroductionAngiogenesis refers to the formation of new blood vessels from the existing vasculature and occurs at extremely low levels in the adult organism. One notable exception to this paradigm occurs in tumors that have undergone the "angiogenic switch" from a benign to a metastatic phenotype, in which new vessels are actively assembled and directly responsible for the sustained growth and dissemination of the tumor. 1 It is clear that the modulation of blood vessel growth is a remarkably effective means to limit or control tumor growth and spread, and therefore, the search for unique targets modulating angiogenesis is of significant importance.Recent studies designed to identify unique peptides that home specifically to solid tumors in murine breast carcinoma models revealed that the NGR motif binds strictly to the endothelium of angiogenic blood vessels. 2 Further investigation identified the CD13/APN cell-surface antigen as the principal receptor for this peptide motif and demonstrated that this protein is expressed exclusively on the endothelial cells of angiogenic but not normal vasculature, 3 thereby explaining the tumorspecific destination of the NGR peptide. CD13/APN was originally described in studies seeking to identify lineage-specific markers that would facilitate the classification of human leukemias. 4 In this regard, the appearance of CD13 coincides with commitment to the myeloid lineage and is exclusively expressed on the normal and leukemic progeny of myeloid cells within the hematopoietic compartment. The subsequent molecular cloning of the gene encoding this cell surface glycoprotein identified it as the membrane-bound metalloprotease, aminopeptidase N (APN, EC 3.4.11.2), thus extending its known range of expression beyond the hematopoietic system to include fibroblasts and epithelial cells in the liver, intestine, brain, and lung. 5 CD13/APN cleaves amino terminal residues from short peptides, and consequently, its specific function in individual tissues (primarily the activation or inactivation of small bioactive molecules) is mandated by available substrates (reviewed in Shipp and Look 6 ). Insights into the function of this unique vascular marker in angiogenesis were gained through experiments in which treatment of animals with CD13/APN functional inhibitors significantly arrested retinal neovascularization, chorioallantoic membrane angiogenesis, and xenograft tumor growth, indicating that CD13/ APN plays an important role in the progression of tumor vasculogenesis and identifying it as a critical regulator of angiogenesis. 3 Therefore, understanding the mechanisms regulating the expression o...

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Association of aminopeptidase N and endopeptidase 24.15 inhibitors potentiate behavioral effects mediated by nociceptin/orphanin FQ in mice

Cited by 54 publications

References 24 publications

[Arg¹⁴,Lys¹⁵]Nociceptin, a Highly Potent Agonist of the Nociceptin/Orphanin FQ Receptor: in Vitro and in Vivo Studies

[Arg¹⁴,Lys¹⁵]Nociceptin, a Highly Potent Agonist of the Nociceptin/Orphanin FQ Receptor: in Vitro and in Vivo Studies

Cardiovascular Effects of Nociceptin in Unanesthetized Mice

CD13/APN is activated by angiogenic signals and is essential for capillary tube formation

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Association of aminopeptidase N and endopeptidase 24.15 inhibitors potentiate behavioral effects mediated by nociceptin/orphanin FQ in mice

Cited by 54 publications

References 24 publications

[Arg14,Lys15]Nociceptin, a Highly Potent Agonist of the Nociceptin/Orphanin FQ Receptor: in Vitro and in Vivo Studies

[Arg14,Lys15]Nociceptin, a Highly Potent Agonist of the Nociceptin/Orphanin FQ Receptor: in Vitro and in Vivo Studies

Cardiovascular Effects of Nociceptin in Unanesthetized Mice

CD13/APN is activated by angiogenic signals and is essential for capillary tube formation

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Product

Resources

About

[Arg¹⁴,Lys¹⁵]Nociceptin, a Highly Potent Agonist of the Nociceptin/Orphanin FQ Receptor: in Vitro and in Vivo Studies

[Arg¹⁴,Lys¹⁵]Nociceptin, a Highly Potent Agonist of the Nociceptin/Orphanin FQ Receptor: in Vitro and in Vivo Studies