Studies on the antinociceptive effect of [Nphe1]nociceptin(1–13)NH2 in mice

doi:10.1016/S0304-3940(01)02352-7

Neuroscience Letters

Volume 316, Issue 1, 4 December 2001, Pages 25-28

https://doi.org/10.1016/S0304-3940(01)02352-7 Get rights and content

Abstract

Nociceptin/orphanin FQ (NC) and its receptor (OP₄) have been implicated in the regulation of various functions including nociception. [Nphe¹]NC(1–13)NH₂ (Nphe) is a selective OP₄ antagonist which prevents the pronociceptive effects of supraspinal NC and causes per se a naloxone-insensitive antinociceptive effect. In the present study, we tested Nphe in wild type (WT) and OP₄ receptor knock out mice and found that a clear antinociceptive effect of the antagonist was evident only in WT mice. Moreover, we evaluated, over 5 days of treatment, the antinociceptive effects of Nphe in comparison with those of DAMGO and found that tolerance develops to the effects of the opioid receptor agonist but not to Nphe. These data demonstrate that the antinociceptive action of Nphe is due to the block of OP₄ receptors and that no tolerance develops to this kind of antinociception.

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Acknowledgements

We would like to thank G. Marzola (Pharmacology, University of Ferrara, Italy) for technical assistance and Dr D.G. Lambert (Anaesthesiology, University of Leicester, UK) for helpful discussion and proof-reading of the manuscript. This work was supported by founds from the University of Ferrara (60% grant to G.C.) and from the Italian Ministry of the University (Cofin 1999 grant to D.R.).

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Cited by (28)

In vitro functional characterization of novel nociceptin/orphanin FQ receptor agonists in recombinant and native preparations
2016, European Journal of Pharmacology
Citation Excerpt :
To investigate the receptor involved in the action of AT compounds in this preparation, knockout studies were performed. In line with previous studies (Di Giannuario et al., 2001) the action of N/OFQ was no longer evident in NOP(−/−) tissues while that elicited by the mu-selective agonist endomorphin-1 was unaffected or even increased. The effect of 1 µm Ro 65-6570 was only slightly and nonsignificantly reduced in NOP(−/−) tissue while that elicited by 0.1 µm of AT compounds was virtually abolished.
Nociceptin/Orphanin FQ (N/OFQ) regulates several biological functions via selective activation of the N/OFQ receptor (NOP). In this study novel nonpeptide NOP ligands were characterized in vitro in receptor binding and [³⁵S]GTPγS stimulated binding in membranes of cells expressing human NOP and classical opioid receptors, calcium mobilization assay in cells coexpressing the receptors and chimeric G proteins, bioluminescence resonance energy transfer (BRET) based assay for studying NOP receptor interaction with G protein and arrestin, the electrically stimulated mouse vas deferens and the mouse colon bioassays. The action of the AT compounds were compared with standard NOP agonists (N/OFQ and Ro 65–6570) and the NOP selective antagonist SB-612111. AT compounds displayed high NOP affinity and behaved as NOP agonists in all the functional assays consistently showing the following rank order of potency AT-127≥AT-090≥AT-035>AT-004= AT-001. AT compounds behaved as NOP full agonists in the calcium mobilization and mouse colon assays and as partial agonists in the [³⁵S]GTPγS and BRET assays. Interestingly AT-090 and AT-127, contrary to standard nonpeptide agonists that display G protein biased agonism, behaved as an unbiased agonists. AT-090 and AT-127 displayed higher NOP selectivity than Ro 65-6570 at native mouse receptors. AT-090 and AT-127 might be useful pharmacological tools for investigating the therapeutic potential of NOP partial agonists.
Endogenous nociceptin/orphanin FQ signalling produces opposite spinal antinociceptive and supraspinal pronociceptive effects in the mouse formalin test: Pharmacological and genetic evidences
2006, Pain
Nociceptin/orphanin FQ (N/OFQ) has been demonstrated to modulate nociceptive transmission via selective activation of N/OFQ peptide (NOP) receptors. Despite huge research efforts, the role(s) of the endogenous N/OFQ–NOP receptor system in pain processing remains incompletely understood. In the present study, we investigated the role of endogenous N/OFQ in the processing of tonic nociceptive input. To address this issue the effects of NOP-selective antagonists [Nphe¹,Arg¹⁴,Lys¹⁵]N/OFQ-NH₂ (UFP-101) and J-113397 on nociceptive behaviour, and the nociceptive phenotype of NOP receptor-deficient mice were tested in the mouse formalin test. Twenty microliters of 1.5% formalin solution was injected subcutaneously into the right hind paw causing a characteristic pattern of nociceptive behaviours (licking, biting and lifting of the injected paw). In control mice, the injection of formalin resulted in a classical biphasic nociceptive response with the first phase lasting from 0 to 10 min and the second phase from 15 to 45 min. UFP-101 at 10 nmol/mouse (but not at 1 nmol/mouse) produced antinociceptive action when injected intracerebroventricularly and a pronociceptive action when given intrathecally. Systemic administration of J-113397 (10 mg/kg, intravenously) and the genetic ablation of the NOP receptor gene both produced a significant increase of mouse nociceptive behaviour. Collectively, these results demonstrate that endogenous N/OFQ–NOP receptor signalling is activated during the mouse formalin test producing spinal antinociceptive and supraspinal pronociceptive effects. The overall effect of blocking NOP receptor signalling, by either systemic pharmacological antagonism or genetic ablation, indicates that the spinal antinociceptive action prevails over supraspinal pronociceptive effects.
In vitro and in vivo pharmacological characterization of the nociceptin/orphanin FQ receptor ligand Ac-RYYRIK-ol
2006, European Journal of Pharmacology
It was recently reported that the hexapeptide Ac-RYYRIK-ol binds with high affinity nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors and competitively antagonizes N/OFQ actions in the mouse vas deferens assay. Here we further describe the in vitro and in vivo pharmacological features of this NOP receptor ligand. In mouse brain homogenate the degradation half life of Ac-RYYRIK-ol (2.48 min) was significantly higher than that of the parent compound Ac-RYYRIK-NH₂ (1.20 min). In the electrically stimulated mouse vas deferens, Ac-RYYRIK-ol (10–1000 nM) competitively antagonized the inhibitory effect of N/OFQ (pA₂ = 8.46), while in the isolated mouse colon the hexapeptide mimicked N/OFQ contractile effects thus behaving as a NOP receptor agonist (pEC₅₀ = 9.09). This latter effect was no longer evident in colon tissues taken from mice knock out for the NOP receptor gene (NOP^−/−). In vivo in mice, similarly to N/OFQ, Ac-RYYRIK-ol (dose range 0.001–1 nmol) produced: i) pronociceptive effects after intracerebroventricular (i.c.v.) administration and antinociceptive actions when given intrathecally (i.t.) in the tail withdrawal assay; ii) inhibition of locomotor activity and iii) stimulation of food intake after supraspinal administration. Finally, in the forced swimming test, Ac-RYYRIK-ol was inactive per se, but reversed the antidepressant-like effects elicited by the NOP receptor selective antagonist UFP-101 ([Nphe¹,Arg¹⁴,Lys¹⁵]N/OFQ-NH₂). Thus, in all these in vivo assays Ac-RYYRIK-ol mimicked the actions of N/OFQ showing however higher potency.
In conclusion, Ac-RYYRIK-ol displayed a complex pharmacological profile which is likely due to the low efficacy agonist nature of this novel ligand of the NOP receptor. The high potency, selectivity of action, and in vivo effectiveness make Ac-RYYRIK-ol a useful pharmacological tool for future studies in the field of N/OFQ and its NOP receptor.
Novel potent agonist [(pF)Phe4,Aib7,Aib11,Arg14,Lys15]N/OFQ-NH<inf>2</inf> and antagonist [Nphe1,(pF)Phe4,Aib7,Aib11,Arg14,Lys15]N/OFQ-NH<inf>2</inf> of nociceptin/orphanin FQ receptor
2006, Regulatory Peptides
Two novel ligands for the nociceptin/orphanin FQ (N/OFQ) receptor (NOP), [(pF)Phe⁴,Aib⁷, Aib¹¹,Arg¹⁴,Lys¹⁵]N/OFQ-NH₂ (peptide-1) and [Nphe¹,(pF)Phe⁴,Aib⁷,Aib¹¹,Arg¹⁴,Lys¹⁵]N/OFQ-NH₂ (peptide-2), have been generated by combining different modifications of N/OFQ sequence. In the present study, we investigated the actions of two analogues and compared them with those of N/OFQ in four assays. Peptide-1 mimicked N/OFQ effects in mouse vas deferens and mouse colon and showed similar maximal effects but higher potency relative to N/OFQ. The effects of peptide-1 were sensitive to NOP receptor selective antagonist ([Nphe¹]N/OFQ(1-13)-NH₂) but not to naloxone in vitro. Peptide-1 (25 pmol, i.c.v.) mimicked the pronociceptive action of N/OFQ (2.5 nmol, i.c.v.) in mouse tail withdrawal assay, displaying higher potency and longer lasting effects. In anesthetized rats, peptide-1 (1 nmol/kg, i.v.) produced a marked decrease in mean arterial pressure, which was comparable to that evoked by i.v. N/OFQ (100 nmol/kg). Peptide-2 did not produce any effect per se but antagonized N/OFQ actions in mouse vas deferens and mouse colon assays. Peptide-2 is active in vivo where it prevented the pronociceptive effect induced by 2.5 nmol N/OFQ i.c.v. in the mouse tail withdrawal assay. Furthermore, peptide-2 at 5 nmol produced alone a robust and long lasting antinociceptive effect. Moreover, peptide-2 (10 and 40 nmol/kg i.v.) didn't produce any effect per se but antagonized hypotensive actions produced by i.v. administration of N/OFQ. Collectively, these findings demonstrate that [(pF)Phe⁴,Aib⁷,Aib¹¹, Arg¹⁴,Lys¹⁵]N/OFQ-NH₂ behaves as a highly potent NOP receptor agonist which produces long lasting effects in vivo and [Nphe¹,(pF)Phe⁴,Aib⁷,Aib¹¹,Arg¹⁴,Lys¹⁵]N/OFQ-NH₂ acts as a pure and competitive antagonist of the NOP receptor.
Nociceptin/orphanin FQ: Pain, stress and neural circuits
2005, Life Sciences
First isolated some 10 years ago as the endogenous ligand for the “orphan opioid receptor” (ORL-1, now designated NOP), nociceptin/orphanin FQ (N/OFQ) has proved to be a potent inhibitory neuropeptide found across the neuraxis. Because of the homologies between opioids and N/OFQ, functional studies of this peptide have focused most heavily on pain and analgesia. This behavioral literature has been marked by a lack of consistency across laboratories, but much of the data can be explained by considering the potent inhibitory actions of N/OFQ in well-defined modulatory circuits. Presently, the most closely studied such circuit is the rostral ventromedial medulla (RVM), where administration of N/OFQ can block opioid analgesia (by inhibiting opioid-activated pain-inhibiting neurons), but under other conditions produces apparent hypoalgesia (by inhibiting pain-facilitating neurons). The net behavioral effect of N/OFQ in the RVM thus depends on whether experimental conditions are such that the pain-facilitating or pain-inhibiting neurons are active at the time the peptide is given.
An important recent finding is that N/OFQ antagonists have antinociceptive properties when given supraspinally. Although the likelihood of interactions between stress and analgesia systems must be considered in interpreting these data, they suggest that N/OFQ antagonists have potential as clinically useful analgesic drugs.
Tonic inhibition by orphanin FQ/nociceptin of noradrenaline neurotransmission in the amygdala
2004, European Journal of Pharmacology
The present microdialysis study investigated whether nociceptin/orphanin FQ exerts a tonic inhibition of the release of noradrenaline in the basolateral nucleus of the amygdala in awake rats. The non-peptide competitive nociceptin/orphanin FQ (N/OFQ) peptide receptor antagonist J-113397 (20 mg/kg i.p.) induced an increase in the release of noradrenaline to about 150–200%. The increase was strongly suppressed by local infusion of an endogenous N/OFQ peptide receptor agonist, nociceptin/orphanin FQ (1 μM) via retrograde microdialysis, into the basolateral nucleus of the amygdala. Local infusion of nociceptin/orphanin FQ (1 μM) itself reduced noradrenaline release in the basolateral nucleus of the amygdala to about 70% of basal levels. These results indicate that a large part of basal release of noradrenaline in the basolateral nucleus of the amygdala is under tonic inhibitory control by endogenous nociceptin/orphanin FQ through the N/OFQ peptide receptors localized within the basolateral nucleus of the amygdala.

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Studies on the antinociceptive effect of [Nphe1]nociceptin(1–13)NH2 in mice

Abstract

Section snippets

Acknowledgements

Peptides

G-proteins, and antiopiates, Peptides

Life Sci.

Eur. J. Pharmacol.

Characterization of [Nphe(1)]nociceptin(1–13)NH(2), a new selective nociceptin receptor antagonist

Br. J. Pharmacol.

Studies on the antinociceptive effect of [Nphe¹]nociceptin(1–13)NH₂ in mice