Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Nociceptin”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed2000

[Nphe(1)]-Nociceptin (1-13)-NH(2), a nociceptin receptor antagonist, reverses nociceptin-induced spatial memory impairments in the Morris water maze task in rats.

1. The present study was undertaken to investigate the effects of the novel nociceptin receptor antagonist, [Nphe(1)]-Nociceptin (1-13)-NH(2) (bilateral intrahippocampal injection, 50 nmole rat(-1)) on purported nociceptin-induced (bilateral intrahippocampal injection, 5 nmole rat(-1)) deficits in spatial learning in the rat Morris water maze task. In addition, experiments were performed in an 'open field' to investigate possible peptide-induced changes in exploratory behaviour. 2. Nociceptin significantly impaired the ability of the animal to locate the hidden platform throughout training (P<0.001 versus control group). 3. Pretreatment with [Nphe(1)]-Nociceptin (1-13)-NH(2) significantly blocked nociceptin-induced impairment of spatial learning (P<0.001 versus nociceptin group). 4. A probe trial revealed that vehicle-treated animals spent more time in the quadrant that had previously contained the hidden platform, whereas nociceptin-treated animals did not spend more time in any one quadrant. 5. Learning impairments were not attributable to non-specific deficits in motor performance or change in exploratory behaviour. 6. Taken together, our results reveal that [Nphe(1)]-Nociceptin (1-13)-NH(2) represents an effective and useful in vivo antagonist at the nociceptin receptors involved in learning and memory.

Animals↗
PubMed2000

Antagonistic effects of [Nphe1]nociceptin(1-13)NH2 on nociceptin receptor mediated inhibition of cAMP formation in Chinese hamster ovary cells stably expressing the recombinant human nociceptin receptor.

Nociceptin/orphanin FQ (NC) is the endogenous ligand for the nociceptin receptor (NCR) which is negatively coupled to adenylyl cyclase to inhibit the formation of cAMP. In this study we describe the inhibitory action of the novel NC analogue, [Nphe1]nociceptin(1-13)NH2 on cAMP formation in Chinese hamster ovary cells expressing the human NCR. NC, NC(1-13)NH2, the pseudopeptides [Phe1psi(CH2-NH)Gly2]NC(1-17)NH2 and [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2, the hexapeptide, acetyl-Arg-Tyr-Tyr-Arg-Trp-Lys-NH2 and buprenorphine all produced a concentration dependent inhibition of forskolin stimulated cAMP formation. This inhibition was competitively reversed by [Nphe1]NC(1-13)NH2 with essentially identical pA2 values (6.12-6.48). [Nphe1]NC(1-13)NH2 showed per se a negligible residual agonist activity (alpha < 0.15).

Animals↗
PubMed1999

Nociceptin, Phe(1)psi-nociceptin(1 - 13), nocistatin and prepronociceptin(154 - 181) effects on calcium channel currents and a potassium current in rat locus coeruleus in vitro.

1. The actions of the neuropeptide nociceptin, the putative nociceptin receptor antagonist [Phe1psi(CH(2)-NH)Gly(2)]-nociceptin-(1 - 13)NH(2) (Phe(1)psi-nociceptin(1 - 13)) and the putative nociceptin precursor products nocistatin (rat prepronociceptin(125 - 132)) and rat prepronociceptin(154 - 181) were examined on membrane properties of rat locus coeruleus (LC) neurons using whole cell patch clamp techniques. 2. Nociceptin inhibited I(Ba) in all LC neurons, (pD(2) of 8.9, maximum inhibition 50%). The inhibition of I(Ba) by nociceptin was associated with slowing of the activation of I(Ba) and could be significantly reversed by a strong depolarizing prepulse. Phe(1)psi-nociceptin(1 - 13) also inhibited I(Ba) in LC neurons (notional pD(2) of 7.6, maximum inhibition 18%). Application of Phe(1)psi-nociceptin(1 - 13) (1 microM) significantly occluded the subsequent effects of a co-application of nociceptin (3 nM) on I(Ba). 3. As previously reported for nociceptin, Phe(1)psi-nociceptin(1 - 13) caused an outward current in LC neurons voltage clamped at -60 mV (pD(2) of 7.1, maximum current 50% of that of methionine enkephalin, 10 microM). The Phe(1)psi-nociceptin(1 - 13) induced current reversed polarity at -112 mV and exhibited pronounced inward rectification. Phe(1)psi-nociceptin(1 - 13) (1 microM) reversibly inhibited the current caused by nociceptin (300 nM) by 30%. 4. Neither nocistatin nor rat prepronociceptin(154 - 181) inhibited I(Ba) in LC neurons, or prevented the subsequent inhibition by nociceptin. Neither nocistatin or prepronociceptin(154 - 181) affected the membrane properties of LC neurons. 5. This study demonstrates that nociceptin modulates somatic I(Ba) in rat LC neurons. The putative ORL1 antagonist Phe(1)psi-nociceptin(1 - 13) exhibited partial agonist activity at inhibiting I(Ba) and opening K(+) channels in LC. Other putative nociceptin precursor products were without effect on LC cells.

Animals↗
PubMed1998

Analysis of Vasodepressor Responses to Nociceptin and Nociceptin Analogs in the Systemic Vascular Bed of the Anesthetized Rabbit In Vivo.

Background: The heptadecapeptide nociceptin, also known as Orphanin FQ, is a recently discovered endogenous ligand for the opioid-like G-protein-coupled receptor ORL(1). Methods and Results: In the present study, responses to nociceptin, [Tyr(1)]-nociceptin, nociceptin-(2-17), nociceptin-(1-11), and nociceptin-(1-7) were compared in the systemic vascular bed of the rabbit. Nociceptin and [Tyr(1)]-nociceptin induced dose related decreases in systemic arterial pressure (SAP) when injected in doses of 1-30 nmol/kg intravenous (IV); in terms of relative vasodepressor activity, [Tyr(1)]-nociceptin and nocicpetin were similar in potency. However, nocicpetin-(2-17), nocicpetin-(1-11), and nociceptin-(1-7) had no effect on SAP when injected in doses up to 30 nmol/kg IV. The decreases in SAP in response to nociceptin and [Tyr(1)]-nociceptin were not altered by the opioid receptor antagonist naloxone at a time when depressor responses to methionine-enkephalin were reduced significantly. Conclusions: The results of the present study show that vasodepressor responses to nociceptin and [Tyr(1)]-nocicpetin are mediated by the activation of a naloxene-insensitive opioid receptor and are not dependent on the presence of Phe at the N-terminus of the nociceptin sequence. Moreover, the present results show that nociceptin-(2-17), nociceptin-(1-11), and nociceptin-(1-7) do not alter SAP in the rabbit, indicating that peptide chain length is important for the expression of vasodepressor activity.

Journal Article↗
PubMed1999

In vitro agonist effects of nociceptin and [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) in the mouse and rat colon and the mouse vas deferens.

Nociceptin is an endogenous ligand of the opioid receptor-like (ORL1) receptor, a G-protein coupled receptor with sequence similarities to the opioid receptors. ORL1 receptors are present at both central and peripheral sites in several mammalian species but their functions are as yet poorly understood. The main aim of this investigation was to study the effects of nociceptin and the putative ORL1 receptor antagonist [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) in two peripheral tissues, the isolated proximal colon of the mouse and the distal colon of the rat. Nociceptin, [D-Ala(2), MePhe(4), Gly-ol(5)]enkephalin (DAMGO; mu-opioid receptor selective) and [D-Pen(2), D-Pen(5)]enkephalin (DPDPE; delta-opioid receptor selective) caused concentration-dependent contractions of mouse and rat isolated colon preparations (nociceptin EC(50)=1.20 and 0.28 nM in the mouse and rat, respectively). Des[Phe(1)]nociceptin (250 nM) had no contractile effect. Naloxone (300 nM) antagonised the effects of DAMGO and DPDPE but had no effect in either preparation on contractions seen in response to nociceptin. [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) also caused contractions in the colonic preparations (EC(50)=6.0 and 3.1 nM in the mouse and rat, respectively); there was no evidence of any antagonist activity. Tetrodotoxin (1 microM) abolished the contractile effects of nociceptin in the mouse colon but had no effect in the rat. In the vas deferens preparation isolated from DBA/2 mice, nociceptin caused concentration-dependent inhibitions of electrically-evoked contractions which were antagonised by [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) (apparent pK(B)=6. 31). However, [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) (0.3-10 microM) also possessed agonist activity in this preparation, as it inhibited the electrically-evoked contractions in a concentration-dependent manner. These observations do not support the proposal that [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) has agonist activity at central ORL1 receptors but is an antagonist in the periphery and that these differences in efficacy point to differences in the receptors. Rather, these data along with those of others suggest that [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) is a partial agonist and that differences in receptor reserve can account for the varied pharmacological actions of this pseudopeptide at central and peripheral sites.

Animals↗
PubMed2000

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

1.. Nociceptin (orphanin FQ) is a novel neuropeptide capable of inducing a variety of biological actions via activation of a specific G-protein coupled receptor. However, the lack of a selective nociceptin receptor antagonist has hampered our understanding of nociceptin actions and the role of this peptide in pathophysiological states. As part of a broader programme of research, geared to the identification and characterization of nociceptin receptor ligands, we report that the novel peptide [Nphe(1)]nociceptin(1-13)NH(2) acts as the first truly selective and competitive nociceptin receptor antagonist and is devoid of any residual agonist activity. 2. [Nphe(1)]nociceptin(1-13)NH(2) binds selectively to recombinant nociceptin receptors expressed in Chinese hamster ovary (CHO) cells (pK(i) 8.4) and competitively antagonizes the inhibitory effects of nociceptin (i) on cyclic AMP accumulation in CHO cells (pA(2) 6.0) and (ii) on electrically evoked contractions in isolated tissues of the mouse, rat and guinea-pig with pA(2) values ranging from 6.0 to 6.4. 3. [Nphe(1)]nociceptin(1-13)NH(2) is also active in vivo, where it prevents the pronociceptive and antimorphine actions of intracerebroventricularly applied nociceptin, measured in the mouse tail withdrawal assay. Moreover, [Nphe(1)]nociceptin(1-13)NH(2) produces per se a dose dependent, naloxone resistant antinociceptive action and, at relatively low doses, potentiates morphine-induced analgesia. 4. Collectively our data indicate that [Nphe(1)]nociceptin(1-13)NH(2), acting as a nociceptin receptor antagonist, may be the prototype of a new class of analgesics.

Analgesics, Opioid↗
PubMedDate not supplied

[Tyr1]-nociceptin and nociceptin have similar naloxone-insensitive erectile activity in the cat.

The heptadecapeptide nociceptin, also known as Orphanin FQ, is a newly discovered endogenous ligand for the opioid-like G-protein-coupled receptor ORL1. The present study was undertaken to investigate responses to intracavernosal injections of the nociceptin analog [Tyr1]-nociceptin and to investigate the effects of naloxone on erectile responses in anesthetized cats to [Tyr1]-nociceptin and to nociceptin. Intracavernosal injections of [Tyr1]-nociceptin and of nociceptin in doses of 0.3-30 nmol elicited dose-related increases in cavernosal pressure, which, at the highest dose studied, were comparable to increases induced by the triple-drug standard (papaverine, phentolamine, and prostaglandin E1), a preparation used in the treatment of erectile dysfunction. Responses to [Tyr1]-nociceptin were rapid in onset and had a time course similar to responses to nociceptin. Metenkephalin increased cavernosal pressure, whereas injections of nociceptin-(2-17), dynorphin A, and beta-endorphin did not alter cavernosal pressure. Erectile responses to nociceptin and to [Tyr1]-nociceptin were not altered after administration of the opioid receptor antagonist naloxone at a time when erectile responses to metenkephalin were attenuated. These data show that [Tyr1]-nociceptin and nociceptin have similar naloxone-insensitive erectile activity in the cat.

Amino Acid Sequence↗
PubMed2000

Evidence that N-terminal fragments of nociceptin modulate nociceptin-induced scratching, biting and licking in mice.

The intrathecal (i.t.) injection of 3.0 fmol nociceptin (orphanin FQ) elicited scratching, biting and licking responses in mice. N-terminal fragments of nociceptin, nociceptin (1-7), nociceptin (1-9) and nociceptin (1-13), induced no characteristic behavioral response. When these N-terminal fragments of nociceptin were injected simultaneously with nociceptin, the behavioral response induced by nociceptin was reduced dose-dependently. Nociceptin (1-13) was much more potent than nociceptin (1-7) and nociceptin (1-9) and antagonized nociceptin-induced response at equimolar doses. No significant effects of the N-terminal fragments were observed against the scratching, biting and licking response elicited by i.t. administration of substance P or N-methyl-D-aspartate. These results suggest that N-terminal fragments formed endogenously in the spinal cord may have an antagonistic effect on nociceptin-induced behavioral responses.

Animals↗
PubMed1998

[Phe1psi(CH2-NH)Gly2]-nociceptin-(1-13)NH2, a proposed antagonist of the nociceptin receptor, is a potent and stable agonist in the rat spinal cord.

[Phe1psi(CH2-NH)Gly2]-nociceptin-(1-13)NH2 is an nociceptin analogue which has been shown to be a selective antagonist of the nociceptin receptor in peripheral tissues. We now report that intrathecal [Phe1psi(CH2-NH)Gly2]-nociceptin-(1-13)NH2 produced a dose-dependent depression of the nociceptive flexor reflex in rats, an effect that is similar to nociceptin. The duration of depression produced by [Phe1psi(CH2-NH)Gly2]-nociceptin-(1-13)NH2 was significantly more prolonged than by nociceptin. The reflex depressive effect of nociceptin was not blocked by [Phe1psi(CH2-NH)Gly2]-nociceptin-(1-13)NH2. The results indicated that the proposed nociceptin receptor antagonist [Phe1psi(CH2-NH)Gly2]-nociceptin-(1-13)NH2 is a potent agonist in rat spinal cord and more resistant to enzymatic degradation compared to nociceptin.

Animals↗
PubMed1999

Effect of nociceptin and [Phe1psi (CH2-NH) Gly2]-nociceptin-(1-13)-NH2 on tonic activity of rat hypothalamic neurons.

The effect of nociceptin, an endogenous ligand for a unique member of the cloned opioid receptor family ORL1-receptor, on tonic activity of neurons in the preoptic area/anterior hypothalamus (PO/AH) has been examined in rat brain slices using extracellular recordings. Nociceptin (1, 10 and 100 nM) decreased dose-dependently tonic activity of PO/AH neurons. This effect was not significantly different from the effect of [Phe1psi (CH2-NH) Gly2]-nociceptin-(1-13)-NH2 (1, 10 and 100 nM), recently proposed as a selective antagonist of the nociceptin receptor. Thus, [Phe1psi (CH2-NH) Gly2]-nociceptin-(1-13)-NH2 appears to be an agonist rather than an antagonist of nociceptin (ORL1) receptor in rat PO/AH neurons. However, there was neither antagonism nor additive synergism when nociceptin and [Phe1psi (CH2-NH) Gly2]-nociceptin-(1-13)-NH2 were applied simultaneously at equimolar concentrations. The effect of nociceptin on tonic activity of rat PO/AH neurons was not blocked by selective mu-, kappa- and delta-opioid receptor antagonists (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), nor-binaltorphimine and naltrindol, respectively) at 10 times higher concentrations than nociceptin. These data suggest that the effect of nociceptin on tonic activity of PO/AH neurons is not due to an action on mu-, kappa-, or delta-opioid receptors but results from a specific effect on the ORL1-receptor.

Animals↗
PubMed1999

Nociceptin (1 - 7) antagonizes nociceptin-induced hyperalgesia in mice.

Nociceptin and its N-terminal fragment, nociceptin (1 7), were administered intrathecally (i.t.) into conscious mice. Nociceptin (3.0 fmol) produced a significant reduction in the nociceptive thermal threshold (hyperalgesia) measured as the tail-flick and paw-withdrawal responses. Nociceptin (1-7), injected i.t., at 150-1200 fmol had no significant effect. However, when nociceptin (1-7) (150 1200 fmol) was injected simultaneously with nociceptin (3.0 fmol), nociceptin-induced hyperalgesia was significantly reduced. Analgesia induced by a high dose (1200 pmol) of nociceptin was not antagonized by co-administration of nociceptin (1-7) (1200 fmol). These results suggest that N-terminal fragments of nociceptin formed endogenously could modulate the hyperalgesic action of nociceptin in the spinal cord.

Amino Acid Sequence↗
PubMed1997

Recognition and activation of the opioid receptor-like ORL 1 receptor by nociceptin, nociceptin analogs and opioids.

Nociceptin, also known as orphanin FQ, was recently identified as the naturally occurring agonist of orphan opioid receptor-like ORL1 receptor (Meunier et al., 1995, Nature 377, 532; Reinscheid et al., 1995, Science 270, 792). Nociceptin is a heptadecapeptide which, although it resembles dynorphin A, the endogenous agonist of the kappa-opioid receptor, displays very low potency in competing with binding of [3H]diprenorphine to or inhibiting adenylate cyclase via mu-, delta- and kappa-opioid receptors. Tritium-labeled nociceptin ([3H]nociceptin) was used here to establish a pharmacological profile in vitro of the ORL 1 receptor. In membranes from recombinant Chinese hamster ovary (CHO) cells expressing the ORL 1 receptor, equilibrium binding of [3H]nociceptin is highly specific, saturable (Bmax in the range 1.3-1.8 pmol/mg protein) and of high affinity (Kd approximately equal to 0.1 nM). It is selectively decreased in the presence of Na+ ions and/or of the GTP analog 5'-guanylylimido-diphosphate, an allosteric regulation that is analogous to that of opiate binding to opioid receptors. A few opiates, namely lofentanil, a 4-anilinopiperidine derivative and etorphine, a 6,14-endo-ethenotetrahydrothebaine derivative, were found to be quite potent not only in competing with binding of [3H]nociceptin at the ORL 1 receptor but also in inhibiting forskolin-induced accumulation of cyclic AMP in intact recombinant CHO cells. In a preliminary attempt to delineate active parts of the neuropeptide, nociceptin analogs were also tested, including N- and C-terminal truncation products. Our results suggest that the highly basic, internal core of nociceptin might be essential in conferring on the peptide both affinity for and activity at the ORL 1 receptor. In this respect, the message and address division of dynorphin A, nociceptin's closest structural analog, do not seem to apply to nociceptin.

Adenylyl Cyclase Inhibitors↗
PubMed1999

[Nphe(1)]nociceptin-(1-13)-NH(2) antagonizes nociceptin effects in the mouse colon.

Nociceptin, nociceptin-(1-13)-NH(2), Ac-RYYRWK-NH(2), [Phe(1)psi(CH(2)&z.sbnd;NH)Gly(2)]nociceptin-(1-13)-NH(2), the new nociceptin analog [Nphe(1)]nociceptin-(1-13)-NH(2), and endomorphin-1 have been tested in the isolated mouse colon. All peptides, except [Nphe(1)]nociceptin-(1-13)-NH(2), caused concentration-dependent, tetrodotoxin-sensitive contractions showing similar maximal effects. Naloxone (1 microM) blocked the effect of endomorphin-1 but not that of the other peptides. [Nphe(1)]nociceptin-(1-13)-NH(2) (10 microM) was inactive against endomorphin-1, but antagonized the contractile effects of nociceptin receptor ligands showing similar pA(2) values (approximately 6.0). The present findings indicate that [Nphe(1)]nociceptin-(1-13)-NH(2) is a low-potency, selective nociceptin receptor antagonist, devoid of residual agonist activity.

Animals↗
PubMed1997

[Tyr1]-nociceptin, a novel nociceptin analog, decreases systemic arterial pressure by a naloxone-insensitive mechanism in the rat.

The heptadecapeptide nociceptin, also known as Orphanin FQ, is a newly discovered endogenous ligand for the opioid-like G-protein-coupled receptor ORL1. In the present study, responses to a novel nociceptin analog, [Tyr1]-nociceptin, were investigated in the systemic vascular bed of the rat. [Tyr1]-nociceptin induced dose-related decrease in systemic arterial pressure when injected in doses of 1-30 nmol/kg i.v. In terms of relative vasodepressor activity, [Tyr1]-nociceptin was comparable in potency to nociceptin. The decreases in systemic arterial pressure in response to [Tyr1]-nociceptin were not altered by the opioid receptor antagonist naloxone in a dose that reduced responses to Met-enkephalin. The results of the present study show that vasodepressor responses to [Tyr1]-nociceptin are not mediated by the activation of a naloxone-sensitive opioid receptor and are not dependent on the presence of Phe at the N-terminus of the nociceptin sequence.

Amino Acid Sequence↗
PubMed2000

[Nphe(1)]nociceptin-(1-13)NH(2) selectively antagonizes nociceptin effects in the rabbit isolated ileum.

When suspended in vitro in isolated organ baths, segments of the rabbit ileum show a fairly strong and stable spontaneous activity, which derives from the continuous release of acetylcholine and the activation of muscarinic receptors, since the activity is completely eliminated by atropine. Dynorphin A (pEC(50): 8.6+/-0.07), neuropeptide Y and its congener human pancreatic polypeptide (pEC(50): 9.40+/-0.10), and nociceptin (pEC(50): 8.08+/-0.12) dose-dependently inhibit the spontaneous activity through the activation of receptors, which are specifically antagonised respectively by naloxone (pA(2): 7.17+/-0.12), 2-(naphtalen-1-ylamino)-3-phenylpropionitrile (JCF 104; pA(2): 5. 80+/-0.10), and [Nphe(1)]nociceptin-(1-13)NH(2) (pA(2): 6.17+/-0.19). This last compound, a selective nociceptin-receptor (OP(4)) antagonist, inhibits the effect of nociceptin in a competitive manner, as demonstrated by Schild analysis. [Nphe(1)]nociceptin-(1-13)NH(2) also antagonizes the effects of other OP(4) receptor ligands such as the full agonist, nociceptin-(1-13)-NH(2), and the partial agonists, [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin-(1-13)-NH(2) (intrinsic activity (alpha(E))=0.5) and Ac-RYYWK-NH(2) (alpha(E)=0.5), with pA(2) values ranged from 5.8 to 6.2. These results indicate that the functional site mediating the inhibitory effect of nociceptin in the rabbit ileum, is pharmacologically identical to the OP(4) sites of other species (mouse, rat, guinea pig, man), since the potencies (pA(2) values) of the pure and competitive antagonist [Nphe(1)]nociceptin-(1-13)NH(2) is very similar to the values obtained in the other species. Moreover, the rabbit ileum is one of the few isolated organs that allow classifying compounds, which interact with OP(4) receptors as full agonists, partial agonists, or pure antagonists.

Animals↗
PubMed1998

[Phe1psi(CH2-NH)Gly2]nociceptin-(1-13)-NH2 is an agonist of the nociceptin (ORL1) receptor.

[Phe1psi(CH2-NH)Gly2]nociceptin-(1-13)-NH2, a pseudopeptide analog of nociceptin, has been shown to be a selective 'antagonist' of the nociceptin receptor in the isolated guinea pig ileum and mouse vas deferens preparations (Guerrini et al., 1998. Br. J. Pharmacol. 123, 163-165). However, in recombinant chinese hamster ovary cells expressing the human nociceptin receptor, we find that the pseudopeptide is a potent (IC50 = 7.5 nM) and fully efficacious inhibitor of forskolin-induced accumulation of cAMP, thus behaving as a pure 'agonist' rather than an antagonist of the receptor. The contrary behaviour of the pseudopeptide in smooth muscle and transformed cells may suggest that different nociceptin receptor types are being addressed in the two systems.

Animals↗
PubMed1997

Address and message sequences for the nociceptin receptor: a structure-activity study of nociceptin-(1-13)-peptide amide.

Nociceptin (NC) and some of its fragments as well as nociceptin-(1-13)-peptide amide [NC- (1-13)-NH2] and a series of its analogues were prepared and tested in the mouse vas deferens in an attempt to identify the sequences involved in the activation (message) and in the binding (address) of nociceptin to its receptor. The NC receptor that inhibits the electrically evoked twitches of the mouse vas deferens was demonstrated to be distinct from the delta opioid receptor, since naloxone and Dmt-Tic-OH (a selective delta opioid receptor antagonist) block the delta opioid receptor but have no effect on the nociceptin receptor. Results from structure-activity experiments suggest that (a) the entire sequence of NC may not be required for full biological activities, since NC(1-13)-NH2 is as active as NC; (b) fragments of NC have however to be amidated as in NC(1-13)-NH2 in order to be protected from degradation by proteases; (c) cationic residues (as Arg8,12, Lys9,13) appear to play a functional role, since their replacement with Ala in the sequence of NC(1-13)-NH2 leads to inactivity; (d) the N-terminal tetrapeptide Phe-Gly-Gly-Phe is essential for activity: its full length and flexibility appear to be required for NC receptor activation and/or occupation; (e) Phe4 and not Phe1 appears to be the residue involved in receptor activation, since the replacement of Phe1 with Leu has no effect, while that of Phe4 leads to inactivity. Results summarized in this paper indicate that the structural requirements of NC for occupation and activation of its receptor are different from that of opioids, particularly delta agonists.

Amino Acid Sequence↗
PubMed1999

Comparison of the effects of [Phe1psi(CH2-NH)Gly2]nociceptin(1-13)NH2 in rat brain, rat vas deferens and CHO cells expressing recombinant human nociceptin receptors.

Nociceptin(NC) is the endogenous ligand for the opioid receptor like-1 receptor (NC-receptor). [Phe1(psi)(CH2-NH)Gly2]Nociceptin(1-13)NH2 ([F/G]NC(1-13)NH2) has been reported to antagonize NC actions in peripheral guinea-pig and mouse tissues. In this study, we investigated the effects of a range of NC C-terminal truncated fragments and [F/G]NC(1-13)NH2 on NC receptor binding, glutamate release from rat cerebrocortical slices (rCX), inhibition of cyclic AMP accumulation in CHO cells expressing the NC receptor (CHO(NCR)) and electrically evoked contractions of the rat vas deferens (rVD). In radioligand binding assays, a range of ligands inhibited [125I]-Tyr14-NC binding in membranes from rCX and CHO(NCR) cells. As the peptide was truncated there was a general decline in pKi. [F/G]NC(1-13)NH2 was as potent as NC(1-13)NH2. The order of potency for NC fragments to inhibit cyclic AMP accumulation in whole CHO(NCR) cells was NCNH2> or =NC=NC(1-13)NH2>NC(1-12)NH2> >NC(1-11)NH2. [F/G]NC(1-13)NH2 was a full agonist with a pEC50 value of 8.65. NCNH2 and [F/G]NC(1-13)NH2 both inhibited K+ evoked glutamate release from rCX with pEC50 and maximum inhibition of 8.16, 48.5+/-4.9% and 7.39, 58.9+/-6.8% respectively. In rVD NC inhibited electrically evoked contractions with a pEC50 of 6.63. Although [F/G]NC(1-13)NH2, displayed a small (instrinsic activity alpha = 0.19) but consistent residual agonist activity, it acted as a competitive antagonist (pA2 6.76) in the rVD. The differences between [F/G]NC(1-13)NH2 action on central and peripheral NC signalling could be explained if [F/G]NC(1-13)NH2 was a partial agonist with high strength of coupling in the CNS and low in the periphery. An alternative explanation could be the existence of central and peripheral receptor isoforms.

Animals↗