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At least 19 recordsLinked to original sources
PubMed1999

[Behavioral pharmacological characterization of mice lacking the nociceptin receptor].

Nociceptin and nociceptin receptor, which show structural similarities to opioid peptides and opioid receptors, respectively, have been recently found to constitute a novel neuromodulatory system. In the central nervous system, however, the physiological role of modulation via the nociceptin receptor is still unclear. Here, we report the behavioral pharmacological characterization of mice lacking the nociceptin receptor. Nociceptin produced hyperalgesia and hypolocomotion, whereas the nociceptin receptor-knockout mice showed no significant abnormalities in nociceptive thresholds (tail-flick, hot-plate, electric, and acetic acid-induced writhing tests) and locomotion. In the learning and memory tests, nociceptin induced impairment of learning and memory in wild-type mice. Nociceptin receptor-knockout mice possessed greater learning ability and had better memory than wild-type mice. These results suggest that the nociceptin system plays a role in regulation of nociception or locomotion and seems to play negative roles in learning and memory. Next, we compared nociceptive responses induced by various opioids between the nociceptin receptor-knockout and wild-type mice. As previously reported, morphine (mu-opioid receptor agonist), U-50,488 H (kappa 1-opioid receptor agonist), and naloxone benzoylhydrazone (NalBzoH; kappa 3-opioid receptor agonist) induced antinociceptive effects in wild-type mice. Surprisingly, knockout mice lacked the antinociceptive effect induced by NalBzoH, but not by morphine and U-50,488H. Further, NalBzoH completely inhibited nociceptin-induced hyperalgesia and hypolocomotion in wild-type mice. Experiments on the cultured cells transfected with the nociceptin receptor cDNA showed that NalBzoH competed in [3H]-nociceptin binding and attenuated the nociceptin-induced inhibition of cyclic AMP accumulation induced by forskolin. These results clearly suggest that NalBzoH acts as a potent antagonist for the nociceptin receptor. Our studies suggest that the nociceptive system and/or learning and memory processes could be modulated by ligands to the nociceptin receptor, and further that the antagonists are worth testing for the alleviation of pain and memory disorders.

Animals↗
PubMed1999

Pharmacological properties of TRK-820 on cloned mu-, delta- and kappa-opioid receptors and nociceptin receptor.

We analyzed the pharmacological properties of 17-cyclopropylmethyl-3,14beta-dihydroxy-4,5alpha-epoxy-6b eta-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride (TRK-820) using Chinese hamster ovary (CHO) cells expressing cloned rat mu-, delta- and kappa-opioid receptors and human nociceptin receptor. TRK-820 showed high affinity for the kappa-opioid receptor, with a Ki value of 3.5 +/- 0.9 nM. In CHO cells expressing kappa-opioid receptors, TRK-820 inhibited forskolin-stimulated cAMP accumulation, and the maximal inhibitory effect was equivalent to that of (+)-(5alpha,7alpha,8beta)-N-methyl-N-[7-(1-pyrrolidiny l)-1-oxaspiro-(4,5)dec-8-yl]benzeneacetamide (U69,593), a full agonist of kappa-opioid receptor. In CHO cells expressing mu-opioid receptors, TRK-820 inhibited cAMP accumulation, but the maximal inhibitory effect was significantly smaller than that of [D-Ala2, N-MePhe4, Gly-ol5]enkephalin (DAMGO), a full agonist of mu-opioid receptor. In CHO cells expressing delta-opioid receptor, the inhibitory effect of TRK-820 on cAMP accumulation was very weak. Using site-directed mutagenesis, the high affinity of TRK-820 for the kappa-opioid receptor was revealed to require Glu297. TRK-820 bound to the nociceptin receptor with a Ki value of 380 +/- 50 nM. TRK-820 by itself had no effect on cAMP accumulation in CHO cells expressing nociceptin receptors, but significantly antagonized the nociceptin (10 nM)-mediated inhibition of cAMP accumulation at high concentrations. These results indicate that TRK-820 acts as a full agonist for the kappa-opioid receptor, a partial agonist for the mu-opioid receptor and a low-affinity antagonist for the nociceptin receptor.

Animals↗
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↗
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↗
PubMed2002

Characterisation of the non-peptide nociceptin receptor agonist, Ro64-6198 in Chinese hamster ovary cells expressing recombinant human nociceptin receptors.

Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the opioid receptor-like receptor or nociceptin receptor (NOP). We have compared a novel non-peptide NOP agonist Ro64-6198 with N/OFQ in a series of GTPgamma35S binding and inhibition of forskolin stimulated cAMP formation assays. GTPgamma35S binding assays were performed in membranes prepared from Chinese hamster ovary cells expressing the recombinant human NOP (CHOhNOP). cAMP inhibition studies were performed in whole CHOhNOP cells. Both Ro64-6198 and N/OFQ stimulated GTPgamma35S binding with pEC50 values(95%CL) of 7.61(0.18) and 8.58(0.21) respectively. Both Ro64-6198 and N/OFQ inhibited cAMP formation with pEC50 values of 8.45(0.9) and 9.28(028) respectively. In each assay Ro64-6198 and N/OFQ were full agonists. Ro64-6198 stimulation of GTPgamma35S binding and inhibition of cAMP formation was competitively antagonised by the NOP antagonists [Nphe1]NC(1 - 13)NH2 (10microM), J-113397 (100nM) and III-BTD (1microM) with pKB values of 7.04(0.34) and 6.29(0.10), 8.65(0.34) and 7.90(0.30) and 7.59(0.22) and 7.60(0.22) respectively. Despite the slightly reduced potency of Ro64-6198 compared with N/OFQ, by virtue of high selectivity and relative metabolic stability this molecule will be of considerable use in studies of the actions of the NOP.

Animals↗
PubMed1998

Facilitation of long-term potentiation and memory in mice lacking nociceptin receptors.

The peptide nociceptin (also named orphanin FQ) acts in the brain to produce various pharmacological effects, including hyperalgesia and hypolocomotion. The nociceptin receptor uses guanine-nucleotide-binding proteins to mediate the inhibition of adenylyl cyclase, the activation of potassium channels and inhibition of calcium channels. It has been shown using knock-out mice that the nociceptin receptor is not required for regulation of nociceptive responses or locomotion activity, but modulates the auditory function. Here we show that mice lacking the nociceptin receptor possess greater learning ability and have better memory than control mice. Histological analysis revealed the expression of both the nociceptin precursor and the nociceptin receptor in the hippocampus, thought to take part in aspects of learning and memory. Moreover, the receptor-deficient mice showed larger long-term potentiation in the hippocampal CA1 region than control mice, without apparent changes in presynaptic or postsynaptic electrophysiological properties. These results show that the loss of the nociceptin receptor results in a gain-of-function mutation in both the memory process and the long-term potentiation mechanism in CA1, perhaps as a result of altered intracellular signal transduction systems in neurons.

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↗
PubMed2006

Agonist-regulated endocytosis and desensitization of the human nociceptin receptor.

A series of nociceptin receptor ligands has been investigated in relationship to their capability to promote receptor endocytosis, desensitization (evaluated as inhibition of forskolin-stimulated cAMP production) and compensatory upregulation of adenylyl cyclase activity in CHO-K1 cells expressing the cloned human nociceptin receptor. Nociceptin (NC), [Arg14, Lys15]NC-NH2 and NNC 63-0532 (0.01 nM-10 microM) induce a concentration-dependent endocytosis and recycling of the nociceptin receptor. This mechanism contributes to maintain receptor signaling as it counteracts desensitization development and enhances a compensatory upregulation of adenyl cyclase activity. In contrast, the partial agonists [Phe1,Psi(CH2NH)Gly2]NC(1-13)-NH2, Ac-RYYRIK-NH2 and Ac-RYYRWK-NH2 (up to 100 microM) fail to induce receptor endocytosis and cause a pronounced receptor desensitization that is not influenced by monensin, a blocker of recycling of the internalized receptors.

Analgesics, Opioid↗
PubMed2001

Morphine tolerance and dependence in the nociceptin receptor knockout mice.

Here we report the involvement of nociceptin receptor in tolerance to morphine-induced antinociception and in morphine dependence. There was no different nociceptive perception and antinociceptive effects of morphine between wild-type and the nociceptin receptor knockout mice. Tolerance to morphine (10 mg/kg)-induced antinociception was developed in both wild-type and the nociceptin receptor knockout mice after administration of morphine (10 mg/kg) twice a day for 5 days. When naloxone (5 mg/kg) was administered to mice treated with morphine repeatedly on the 6th day, morphine withdrawal syndrome was observed in both wild-type and the nociceptin receptor knockout mice, which were accompanied by the elevation of cyclic AMP levels. While naloxone benzoylhydrazone (1 mg/kg), a putative antagonist for nociceptin receptor/naloxone benzoylhydrazone-sensitive sites, also induced the morphine withdrawal signs in both wild-type and the nociceptin receptor knockout mice, the jumping signs in the nociceptin receptor knockout mice were less severe than those in wild-type mice. Treatment with naloxone benzoylhydrazone in morphine-dependent wild-type mice caused a significant increase in cyclic AMP levels in the thalamus while it had no effect in the nociceptin receptor knockout mice. The analysis of opioid mu-receptor binding showed no difference between wild-type and the nociceptin receptor knockout mice. These results suggest that the nociceptin receptor/naloxone benzoylhydrazone-sensitive sites contribute to the induction of morphine withdrawal syndrome in part. Furthermore, it is demonstrated that morphine withdrawal syndrome excepting jumping can be induced by naloxone benzoylhydrazone without any changes in the cyclic AMP levels in the thalamus.

Analgesics, Opioid↗
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↗
PubMed1998

Activation of phospholipase A2 by the nociceptin receptor expressed in Chinese hamster ovary cells.

To gain insight into the molecular mechanism for nociceptin function, functional coupling of the nociceptin receptor expressed in Chinese hamster ovary (CHO) cells with phospholipase A2 (PLA2) was examined. In the presence of A23187, a calcium ionophore, activation of the nociceptin receptor induced time- and dose-dependent release of arachidonate, which was abolished by pretreatment of the cells with pertussis toxin (PTX). Immunoblot analysis using anti-Ca2+-dependent cytosolic PLA2 (cPLA2) monoclonal antibody demonstrates that activation of the nociceptin receptor induces a time- and dose-dependent electrophoretic mobility shift of cPLA2, suggesting that phosphorylation of cPLA2 is induced by the nociceptin receptor. Pretreatment of the cells with PD98059, a specific mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1 inhibitor, or staurosporine, a potent inhibitor of serine/threonine protein kinases and tyrosine protein kinases, partially inhibited the nociceptin-induced cPLA2 phosphorylation and arachidonate release. These results indicate that the nociceptin receptor expressed in CHO cells couples with cPLA2 through the action of PTX-sensitive G proteins and suggest that cPLA2 is activated by phosphorylation induced by the nociceptin receptor via mechanisms partially dependent on p44 and p42 mitogen-activated protein kinases.

Animals↗
PubMed2004

Methamphetamine sensitization in nociceptin receptor knockout mice: locomotor and c-fos expression.

The role of endogenous nociceptin in the development and expression of sensitization to repeated methamphetamine administration in a novel environment was studied in nociceptin receptor knockout mice. No differences in acute or sensitized locomotor responses were found in nociceptin receptor knockout mice. However, analysis of c-fos expression revealed significant interactions between chronic methamphetamine treatment and genotype in the nucleus accumbens and lateral septum. This was due to increased c-fos expression in chronically methamphetamine-treated nociceptin receptor knockout mice contrasted with reduced c-fos expression in chronically vehicle-treated nociceptin receptor knockout mice. Two further regions (nucleus accumbens core and ventromedial caudate putamen) showed significant interactions between genotype, chronic, and acute methamphetamine treatment due to accentuated c-fos expression in nociceptin receptor knockout mice sensitized and challenged with methamphetamine. These findings suggest endogenous nociceptin modulates the response of the central nervous system to repeated psychostimulant administration, although this is little reflected in locomotion.

Animals↗
PubMed2000

Pharmacological activation of nociceptin receptors in the nucleus tractus solitarius inhibits baroreceptor reflex in pentobarbital-anesthetized rats.

Nociceptin receptors are densely distributed in the nucleus tractus solitarius pre- and postsynaptically. This study tested whether nociceptin receptors in this brain area are involved in the modulation of baroreceptor reflex. In pentobarbital-anesthetized rats, pharmacological activation of nociceptin receptors with bilateral microinjection of a synthetic peptide agonist, nociceptin, into the nucleus tractus solitarius attenuated baroreflex sensitivity as demonstrated by a marked reduction in baroreflex bradycardia induced by a single dose of intravenous phenylephrine. The inhibitory effect of nociceptin was dose dependent (0.04, 0.2 and 1nmol) and was blocked by pretreatment with microinjection of 1nmol nocistatin, a peptide that can functionally reverse the action of nociceptin. In contrast, injection of an opioid receptor antagonist, naloxone (5nmol), did not modify the inhibition of baroreflex sensitivity induced by nociceptin. Neither nocistatin nor naloxone injected into the nucleus alone had any detectable effect on baseline blood pressure and heart rate and baroreflex bradycardia. These data indicate that the newly discovered nociceptin receptors in the central nervous system possess an inhibitory influence on baroreflex transmission at the level of the nucleus tractus solitarius.

Analgesics, Opioid↗
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↗
PubMed2005

Enhanced hippocampal acetylcholine release in nociceptin-receptor knockout mice.

Nociceptin (NOC), an endogenous ligand of the opioid receptor-like 1 receptor, is thought to be involved in learning and memory processes. Since acetylcholine (ACh) is involved in hippocampal function, and the hippocampus plays a critical role on the learning and memory function, hippocampal ACh release in NOC-receptor knockout mice was examined using an in vivo microdialysis method. The release of hippocampal ACh was largely increased in the knockout mice. Furthermore, in the knockout mice, an enhanced hippocampal theta rhythm, which is known to be linked to hippocampal memory function, was also observed. Immunohistochemically, in septum, co-existence of NOC receptor with cholinergic, but not with GABAergic neurons, was verified. The findings demonstrate that the NOC receptor is involved in hippocampal cholinergic function.

Acetylcholine↗
PubMed2000

Nociceptin receptor activation produces nitric oxide-mediated systemic hypotension.

The purpose of the present study was to investigate the effects of L-N5-(1-iminoethyl)ornithine hydrochloride (L-NIO), an inhibitor of nitric oxide (NO) formation, and [Phe1-psi(CH2NH)-Gly2]Nociceptin(1-13)-NH2 (Phe-NOC), a nociceptin receptor antagonist, on the systemic vasodepressor response to nociceptin in the anesthetized rat. The systemic vasodepressor response to bolus intravenous (i.v.) injections of nociceptin was significantly reduced by L-NIO and Phe-NOC. The present data suggest activation of nociceptin receptors dilates the systemic vascular bed through a NO-dependent pathway. These data also demonstrate Phe-NOC is an efficacious and selective nociceptin receptor antagonist in vivo.

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↗