Orphanin FQ/nociceptin inhibits morphine withdrawal

doi:10.1016/S0024-3205(99)00648-7

Life Sciences

Volume 66, Issue 8, 14 January 2000, Pages PL119-PL123

https://doi.org/10.1016/S0024-3205(99)00648-7 Get rights and content

Abstract

The influence of orphanin FQ/nociceptin (OFQ/N) on the morphine-withdrawal symptom was investigated. Withdrawal syndrome was induced in the morphine-dependent rats by an intraperitoneal (ip) injection of 2 mg/kg naloxone hydrochloride — an opioid receptors antagonist. Wet-dog shakes were used as a measure of the abstinence syndrome. Intraventricular injections of OFQ/N (5–20 μg/animal) caused significant inhibition of the withdrawal signs at doses between 15–20 μg, in the morphine-dependent rats. OFQ/N alone did not change behavior of the morphine-dependent animals. The obtained results indicate that OFQ/N can inhibit the morphine withdrawal symptoms induced by naloxone.

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Cited by (28)

NOP agonist action of cebranopadol counteracts its liability to promote physical dependence
2019, Peptides
Citation Excerpt :
These results suggest a lower potential of cebranopadol to produce physical dependence than morphine. Based on literature evidence showing that N/OFQ and NOP agonists reduce the rewarding effects of classical opioids [4,16–19], and that N/OFQ inhibits the expression of naloxone‐precipitated withdrawal after morphine treatment in rats [20], the authors of the study speculated that the lower potential of cebranopadol to produce opioid like physical dependence may derive from the ability of the drug to stimulate the NOP receptor [15]. The aim of the present study is to experimentally investigate this hypothesis by testing cebranopadol in the naloxone-precipitated withdrawal jumping test in wild type mice (NOP(+/+)) and in mice knockout for the NOP receptor gene (NOP(-/-)).
Cebranopadol is a mixed NOP/opioid receptor agonist currently under development as innovative analgesic. In this study the liability of cebranopadol to produce opioid-type physical dependence has been evaluated in comparison with morphine in wild type mice and in mice knockout for the NOP receptor gene (NOP(-/-)). Mice were treated twice a day for 5 days with increasing doses of cebranopadol or morphine (cumulative doses 10.2 and 255 mg/kg, respectively) and the number of jumping in response to naloxone 10 mg/kg were measured after 2 h from the last injection. In wild type mice naloxone evoked a similar withdrawal jumping behavior in animal pretreated with morphine or cebranopadol. In NOP(-/-) mice morphine treatment produced the same signs of withdrawal as in NOP(+/+) animals, while cebranopadol treatment elicited a stronger withdrawal syndrome in NOP(-/-) than of NOP(+/+) mice. These results demonstrated that the activation of the NOP receptor reduces the liability of cebranopadol to produce opioid-like physical dependence. Thus, the simultaneous activation of NOP and opioid receptors can be an effective pharmacological strategy to counteract physical dependence to opioid drugs.
Nociceptin receptor activation does not alter acquisition, expression, extinction and reinstatement of conditioned cocaine preference in mice
2016, Brain Research
Citation Excerpt :
For example, when injected intracranially, nociceptin reduces drug-induced dopamine release and c-fos activation in the nucleus accumbens, key mechanisms involved in reward and motivation (Ciccocioppo et al., 2000; Di Giannuario and Pieretti, 2000; Lutfy et al., 2001). In behavioral studies, intracranial administration of nociceptin attenuates addiction-related responses to opioids (Murphy et al., 1999; Ciccocioppo et al., 2000), psychostimulants (Lutfy et al., 2002; Kotlinska et al., 2003; Zhao et al., 2003; Bebawy et al., 2010) and ethanol (Ciccocioppo et al., 1999; Martin-Fardon et al., 2000), and withdrawal symptoms induced by morphine (Kotlinska et al., 2000) and ethanol (Economidou et al., 2011; Aujla et al., 2013). More recently, using small molecule compounds, preclinical studies have revealed that NOP agonists attenuate addiction-related behaviors similarly to nociceptin (Shoblock et al., 2005; Economidou et al., 2006; Kuzmin et al., 2007; Toll et al., 2009), although some discordant result has been reported in cocaine studies (Kotlinska et al., 2002).
Growing evidence indicates that targeting nociceptin receptor (NOP) signaling may have therapeutic efficacy in treating alcohol and opioid addiction. However, little is known about the therapeutic value of selective NOP agonists for the treatment of cocaine dependence. Recently, we identified a highly selective, brain-penetrant NOP small molecule agonist (SR-8993), and using this compound, we previously showed that nociceptin receptor activation attenuated consolidation of fear-related memories. Here, we sought to determine whether SR-8993 also affects the rewarding properties of cocaine. Using a conditioned place preference (CPP) procedure, we show that SR-8993 (3 or 10 mg/kg) failed to disrupt acquisition or expression of cocaine CPP (7.5 or 15 mg/kg) in C57BL/6 mice. Additionally, SR-8993 did not affect rate of extinction or reinstatement (yohimbine- and cocaine-induced) of cocaine CPP. These studies indicate that selective activation of NOP may not be sufficient in reducing behavioral responses to cocaine.
Heterodimerization of ORL1 and opioid receptors and its consequences for N-type calcium channel regulation
2010, Journal of Biological Chemistry
Citation Excerpt :
Finally, it is worth noting that ORL1 receptors are expressed widely across the brain (43, 44), with receptor activity having been linked to physiological adaptations such as the regulation of food intake (45, 46), anxiety (47), and withdrawal symptoms (48, 49), providing yet further potential for physiological effects of ORL1/opioid receptor heterodimers and their formation of signaling complexes with N-type calcium channels.
We have investigated the heterodimerization of ORL1 receptors and classical members of the opioid receptor family. All three classes of opioid receptors could be co-immunoprecipitated with ORL1 receptors from both transfected tsA-201 cell lysate and rat dorsal root ganglia lysate, suggesting that these receptors can form heterodimers. Consistent with this hypothesis, in cells expressing either one of the opioid receptors together with ORL1, prolonged ORL1 receptor activation via nociceptin application resulted in internalization of the opioid receptors. Conversely, μ-, δ-, and κ-opioid receptor activation with the appropriate ligands triggered the internalization of ORL1. The μ-opioid receptor/ORL1 receptor heterodimers were shown to associate with N-type calcium channels, with activation of μ-opioid receptors triggering N-type channel internalization, but only in the presence of ORL1. Furthermore, the formation of opioid receptor/ORL1 receptor heterodimers attenuated the ORL1 receptor-mediated inhibition of N-type channels, in part because of constitutive opioid receptor activity. Collectively, our data support the existence of heterodimers between ORL1 and classical opioid receptors, with profound implications for effectors such as N-type calcium channels.
Role of nociceptin/orphanin FQ and the pseudopeptide [Phe<sup>1</sup>Ψ(CH<inf>2</inf>NH)Gly<sup>2</sup>]-nociceptin(1-13) -NH<inf>2</inf> and their interaction with classic opioids in the modulation of thermonociception in the land snail Helix aspersa
2008, European Journal of Pharmacology
The role in nociception of nociceptin/orphanin FQ (N/OFQ) and its receptor, the opioid receptor-like 1 (NOP), remains unclear because this peptide has been implicated in both suppression and enhancement of nociception. The present work characterises the effects of N/OFQ and the NOP receptor antagonist, the pseudopeptide [Phe¹Ψ(CH₂NH)Gly²]-nociceptin(1–13)-NH₂ (Phe¹Ψ), on thermonociception in the snail Helix aspersa using the hot plate assay. Additionally, the possible interaction of each of these compounds with morphine or dynorphin A_1–17 and naloxone was studied. Compounds were administered into the hemocoel cavity of H. aspersa and the latency to the aversive withdrawal behaviour recorded. Dose–response and time course curves were done. N/OFQ and naloxone produced a similar dose-dependent pronociceptive effect; however, N/OFQ reached its peak effect earlier and was 30 times more potent than naloxone. [Phe¹Ψ(CH₂NH)Gly²]-nociceptin(1–13)-NH₂ and the opioid agonists, morphine and dynorphin A_1–17 produced antinociception with a similar efficacy, but [Phe¹Ψ(CH₂NH)Gly²]-nociceptin(1–13)-NH₂ reached its peak effect more rapidly and lasted longer than that of dynorphin A_1–17 and morphine. [Phe¹Ψ(CH₂NH)Gly²]-nociceptin(1–13)-NH₂ was 50 times less potent than dynorphin A_1–17, but 30 times more potent than morphine. N/OFQ significantly reduced morphine and dynorphin A_1–17-induced antinociception. Combined administration of low doses of [Phe¹Ψ(CH₂NH)Gly²]-nociceptin(1–13)-NH₂ and morphine or dynorphin A_1–17 produced a potent antinociceptive effect. Sub-effective doses of naloxone and N/OFQ also synergised to produce pronociception. Data suggest that these two opioid classes regulate nociception through parallel systems. The H. aspersa model appears as a valuable experimental preparation to continue the study of these opioid receptor systems.
Influence of nociceptin(1-17) fragments and its tyrosine-substituted derivative on morphine-withdrawal signs in rats
2004, Neuropeptides
Our previous studies demonstrated that endogenous ligand of nociceptin (NOP) receptor, nociceptin(1-17) (also known as orphanin FQ), inhibits morphine-withdrawal syndrome measured as wet dog shakes in rats [Life Sci. 66 (2000) PL119]. This peptide is metabolized in the spinal cord, both in vitro and in vivo, to shorter fragments, including nociceptin(1-11) and nociceptin(1-6). These fragments, formed after cleavage by endogenous peptidase, are behaviorally active and modulate nociception in a bi-phasic process [Peptides 20 (1999) 239]. As these peptides induced transient naloxone-reversible analgesia in behavioral tests [Peptides 20 (1999) 239], in the present study we tested the influence of nociceptin(1-11) (10 and 20 μg) and nociceptin(1-6) (10, 20 and 40 μg) on the morphine-withdrawal syndrome in rats. Furthermore, the modified fragment of nociceptin(1-6) with an opioid-message domain achieved by replacement of Phe¹ with Tyr was tested. Morphine-withdrawal syndrome was precipitated by the i.p. injection of naloxone hydrochloride (2 mg/kg), 72 h after implantation of morphine pellets. The wet-dog shakes were chosen for statistical analyses of the abstinence signs. The results show that nociceptin(1-11) and (1-6) attenuate this morphine-withdrawal symptom. The replacement of Phe¹ with Tyr in nociceptin(1-6) fragment did not potentiate the influence of nociceptin(1-6) on wet dog shakes precipitated by naloxone in morphine-dependent rats.
Dexamethasone exposure during the neonatal period alters ORL1 mRNA expression in the hypothalamic paraventricular nucleus and hippocampus of the adult rat
2003, Developmental Brain Research
Dexamethasone is commonly used to limit the severity of chronic lung disease in premature infants with severe respiratory distress syndrome. Recent literature has demonstrated an association between dexamethasone exposure in critically ill premature neonates and later development of cerebral palsy. However, the majority of children exposed to dexamethasone in the neonatal period do not develop cerebral palsy or global developmental delay, and other more subtle effects of early life glucocorticoid exposure may go unnoticed. Presently, little is known regarding possible effects of early dexamethasone exposure on development of neuropeptide systems that are sensitive to glucocorticoid modulation. One such system is the pain-related opioid system that interacts with the stress-related limbic–hypothalamic pituitary adrenal (LHPA) axis. In the present study, a neonatal rat model was used to expose newborn rats to dexamethasone. Using a within-litter design, on postnatal days P3 through P6, pups were either handled, or they received a daily intramuscular injection of saline or dexamethasone. Adult animals were sacrificed on day of life P120, their brains were removed and quick-frozen. Using in situ hybridization histochemistry, mRNA expression of the opioid receptor-like (ORL1) receptor was measured in the paraventricular nucleus of the hypothalamus (PVN) and the hippocampal formation. In dexamethasone-treated adult male rats, ORL1 mRNA expression was increased in the PVN and dentate gyrus, but decreased in area CA1, when compared to handled and vehicle controls. These results suggest that prolonged glucocorticoid receptor (GR) occupation in the neonatal period leads to permanent alterations in ORL1 expression in the LHPA stress axis of the adult rat.

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Pharmacology letter Accelerated communicationOrphanin FQ/nociceptin inhibits morphine withdrawal

Abstract

Neuroscience

Eur. J. Pharmacol.

Trends Neurosci.

Neuroscience

FEBS Lett.

FEBS Lett.

Peptides

Brain Res.

Therapie

Pharmacology letter Accelerated communication
Orphanin FQ/nociceptin inhibits morphine withdrawal