Orphanin FQ/nociceptin blocks cocaine-induced behavioral sensitization in rats

Department of Psychiatry and Biobehavioral Sciences, Neuropsychiatric Institute, University of California, Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024, USA.
Psychopharmacology (Impact Factor: 3.88). 12/2002; 164(2):168-76. DOI: 10.1007/s00213-002-1192-1
Source: PubMed


Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand of the opioid receptor-like (ORL-1) receptor, shows similarities to dynorphin A (1-17) in structure and functions. Dynorphin and other kappa opioid receptor agonists have been shown to block cocaine sensitization.
The present study was designed to examine the ability of OFQ/N to block cocaine-induced behavioral sensitization.
Rats were habituated to testing chambers for 1 h, injected with artificial cerebrospinal fluid (aCSF) or OFQ/N (15 nmol) followed by saline or cocaine (20 mg/kg) and locomotor activity was measured for a further 1 h. Rats were treated similarly for the next 2 days except the dose of OFQ/N was doubled on each subsequent day. Rats were then challenged with cocaine (7.5 mg/kg) in the absence of OFQ/N on day 8. The specificity of OFQ/N's action was examined in the presence of J-113397 (30 nmol), an ORL-1 receptor antagonist. The ability of OFQ/N to block the context-independent component of cocaine sensitization was also tested wherein rats were treated in their home cages on days 1-3. Finally, the effect of intra-VTA OFQ/N administration on cocaine sensitization was examined.
Sensitization did not develop in rats repeatedly treated with OFQ/N, via either route of administration, prior to cocaine administration on days 1-3. The inhibitory effect of OFQ/N was not dependent on context and was blocked by pretreatment with J-113397.
Our results indicate that OFQ/N blocks cocaine-induced behavioral sensitization through activation of the ORL-1 receptor and that the VTA may be one of the substrates for this action of OFQ/N.


Available from: Kabirullah Lutfy, Mar 19, 2014
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    • "However, these results suggest that the endogenous OFQ/N/NOP receptor system may be involved in cocaine-induced locomotor sensitization. Considering that exogenous OFQ/N also blocks and even reverses cocaine sensitization (Bebawy et al., 2010; Lutfy et al., 2002 "
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    ABSTRACT: We have previously shown that orphanin FQ (also known as nociceptin; OFQ/N) attenuates the motor stimulatory effect of cocaine and blocks locomotor sensitization induced by cocaine. Furthermore, we have shown that cocaine treatment altered the level of endogenous OFQ/N, raising the possibility that endogenous OFQ/N and its receptor (NOP) may be crucial in these actions of cocaine. Accordingly, in the present study, we sought to determine the role of NOP receptors in psychomotor stimulation and locomotor sensitization induced by cocaine or amphetamine. Mice lacking the NOP receptor and their wild-type littermates were habituated to motor activity chambers for 1h, injected with cocaine (0, 15 or 30mg/kg) or amphetamine (0, 1 or 3mg/kg), and motor activity was recorded for 1h. For sensitization induced by these drugs, mice were treated with saline or the highest dose of each drug once daily for three consecutive days and tested on day 8. On this day, mice were habituated to the chambers for 1h, then received a challenge dose of cocaine (15mg/kg) or amphetamine (1mg/kg), and motor activity was recorded for 1h. Cocaine and amphetamine each induced hyperlocomotion but the extent of this response was not different between NOP receptor null mice and their controls. Sensitization developed to the motor stimulatory action of each drug, but the magnitude of cocaine-induced sensitization was only higher in null mice compared to their controls. Together, the present results suggest that the endogenous OFQ/N/NOP receptor system may modulate the development of cocaine-induced locomotor sensitization.
    European journal of pharmacology 03/2013; 707(1). DOI:10.1016/j.ejphar.2013.03.021 · 2.53 Impact Factor
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    • "The phenomenon of locomotor sensitization is referred to as a progressive and enduring increase in locomotor stimulation induced by repeated intermittent administration of morphine and other addictive drugs (Badiani et al., 2000; Kalivas et al., 1993; Lutfy et al., 2002; Marquez et al., 2006; Post and Rose, 1976; Shippenberg et al., 2009; Shippenberg and Heidbreder, 1995; Shuster et al., 1977; Steketee and Kalivas, 1991; Stewart and Badiani, 1993). This phenomenon is thought to mimic some aspects of addiction, e.g., compulsive drug-seeking behaviors and relapse [for review, see (Robinson and Berridge, 1993, 2000)]. "
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    ABSTRACT: Previous studies have shown that morphine-6-glucuronide (M6G), a metabolite of morphine, induces reward and psychomotor stimulation but the role of the mu opioid receptor in these actions of the drug is not fully characterized. Thus, using mice lacking exon-2 of the mu opioid receptor and their wild-type littermates/controls, we determined the role of this receptor in psychomotor stimulation, sensitization, and conditioned place preference (CPP) induced by M6G. For comparison, we also assessed the role of the mu opioid receptor in the rewarding action of morphine. For the measurement of locomotor activity and sensitization, mice were habituated to motor activity chambers for 1h, then injected with M6G (10mg/kg) and locomotor activity was recorded for an additional 1h. The same treatment was given for five days and mice were tested for sensitization a week later. For the CPP experiments, mice were tested for baseline place preference on day 1, then received single or repeated alternate-day saline/drug or drug/saline conditioning and tested for CPP the following day. Mice were also tested for CPP under a drugged state. M6G induced psychomotor stimulation, a response that was enhanced upon repeated administration of the drug, showing that locomotor sensitization developed to the motor stimulatory action of M6G. However, M6G induced a weaker CPP response compared to morphine. None of these actions of M6G was detected in mice lacking the mu opioid receptor. Together, the current results suggest that M6G induces psychomotor stimulation and a weaker rewarding action via the mu opioid receptor.
    European journal of pharmacology 02/2012; 682(1-3):86-91. DOI:10.1016/j.ejphar.2012.02.021 · 2.53 Impact Factor
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    • "A fourth receptor, nociceptin/orphanin FQ peptide receptor, also known as opioid receptor-like 1, and its endogenous ligand, orphanin FQ or nociceptin, have recently been described (Mollereau et al., 1994; Chen et al., 1994; Reinscheid et al., 1995). Nociceptin is structurally similar to dynorphin A (Reinscheid et al., 1998) and, similar to KOPr agonists, it reduces the rewarding properties of cocaine and other drugs of abuse (Lutfy et al., 2002; Márquez et al, 2008). "
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    ABSTRACT: A consistent finding in drug abuse research is that males and females show differences in their response to drugs of abuse. In women, increased plasma estradiol is associated with increased vulnerability to the psychostimulant and reinforcing effects of drugs of abuse. Our laboratory has focused on the role of estradiol in modulating the response to cocaine. We have seen that ovariectomy increases the locomotor response to a single cocaine injection, whereas estradiol exacerbates the locomotor response to repeated cocaine administration. Cocaine-induced sensitization of brain activity, as measured by fMRI, is also dependent on plasma estradiol. Moreover, we observed that although all ovariectomized rats show conditioned place preference to cocaine, it is more robust in ovariectomized rats with estradiol. Opioid receptors are enriched in brain regions associated with pleasure and reward. We find that in females, the effectiveness of kappa opioid agonists in decreasing the locomotor response to repeated cocaine varies with plasma estradiol. We also find that estradiol regulates the density of mu opioid receptors in brains areas associated with reward. These data hint that in females, estradiol modulates the behavioral effects of cocaine by regulating mu and kappa opioid signaling in mesocorticolimbic brain structures. Identifying the mechanisms that mediate differences in vulnerability to drugs of abuse may lead to effective therapeutic strategies for the treatment and prevention of addiction and relapse. We encourage health practitioners treating persons addicted to drugs to consider gender differences in response to particular pharmacotherapies, as well the sex steroid milieu of the patient.
    Hormones and Behavior 12/2009; 58(1):33-43. DOI:10.1016/j.yhbeh.2009.12.003 · 4.63 Impact Factor
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