Possible Pharmacotherapy of the Opioid κ Receptor Agonist for Drug Dependence

Hasebe, Ko; Kawai, Koji; Suzuki, Tomohiko; Kawamura, Kuniaki; Tanaka, Toshiaki; Narita, Minoru; Nagase, Hiroshi; Suzuki, Tsutomu

doi:10.1196/annals.1316.050

Cited by 54 publications

(42 citation statements)

References 31 publications

(52 reference statements)

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“…Accordingly, both pharmacological and genetic studies have provided evidence that the rewarding effects of cannabinoids are mediated by the activation of m-opioid receptors, whereas the stimulation of k-opioid receptors (KORs) by opioid peptides derived from pro-dynorphin seem to mediate their aversive effects (Ghozland et al, 2002;Zimmer et al, 2001). Moreover, several studies suggest that the k/dynorphin system opposes drug-rewarding effects, giving support to the idea that KORs could act as a possible pharmacotherapy for drug dependence (for a review, see Hasebe et al, 2004). Thus, KORs inhibit the rewarding effects of several drugs of abuse, such as morphine or cocaine, and also attenuate the elevation of dopamine turnover induced by morphine in the limbic forebrain (Narita et al, 1993;Schenk et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Involvement of κ/Dynorphin System in WIN 55,212-2 Self-Administration in Mice

Mendizábal

Zimmer

Maldonado

2005

Neuropsychopharmacol

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Self-administration procedures have not yet provided evidence that freely moving mice can reliably acquire and maintain an operant behavior to self-administer cannabinoid agonists. The aim of the present work was to establish a model of cannabinoid operant intravenous self-administration in freely moving mice given the relevance of this species for the use of genetically modified animals. In addition, the possible involvement of the k/dynorphin system in cannabinoid self-administration was evaluated by using pro-dynorphin knockout mice. Outbred CD1 wild-type mice as well as pro-dynorphin knockout and wild-type mice were trained to self-administer the cannabinoid receptor agonist WIN 55,212-2 under an FR1 schedule of reinforcement. Two cannabinoid training doses (6.25 and 12.5 mg/ kg/infusion) were used in the acquisition studies in outbred mice. Animals acquired a reliable operant responding to self-administer WIN 55,212-2 (12.5 mg/kg/infusion), but required as many as 15 sessions to attain this behavior. Interestingly, when a previous injection of WIN 55,212-2 (0.1 mg/kg, i.p.) was administered in the home-cage 24 h before the first session, mice acquired operant responding for cannabinoid self-administration by the fourth session. When the k-opioid agonist antagonist nor-binaltorphimine (5 mg/kg s.c.) was administered 4 h before the first session, the time required to acquire a reliable cannabinoid self-administration was also significantly reduced. Finally, a shift to the left in the dose-intake curve to self-administer WIN 55,212-2 was observed in pro-dynorphin knockout mice when compared to wild-type mice. These results indicate that the activation of the k/dynorphin opioid system after WIN 55,212-2 administration could counteract cannabinoid rewarding effects.

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Section: Introductionmentioning

confidence: 99%

Involvement of κ/Dynorphin System in WIN 55,212-2 Self-Administration in Mice

Mendizábal

Zimmer

Maldonado

2005

Neuropsychopharmacol

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“…b-Arrestins 1 and 2 are associated with ND D Sun et al roles in the opioid receptor and MAPK signaling transduction processes [24][25][26]46 and the extensive evidence that opioid receptors and MAPK cascades are involved in drug addiction, [18][19][20][21][22][27][28][29][30] ARRB1 and ARRB2 were considered plausible candidates for ND.…”

Section: Discussionmentioning

confidence: 99%

“…Considerable evidence has shown the opioid receptors play a central role in the development of drug abuse via the disinhibition of ventral tegmental area (VTA) dopaminergic neurons. [18][19][20][21] Previous reports indicated that the reinforcing properties of nicotine are strongly diminished in mice lacking the m-opioid receptor, 22 and acute nicotine administration increased the expression of m-opioid receptors in the VTA. 23 b-arrestins have been proven to be important regulators of signal transduction mediated by opioid receptors through promotion of receptor desensitization and internalization.…”

Section: Introductionmentioning

confidence: 99%

β-Arrestins 1 and 2 are associated with nicotine dependence in European American smokers

Sun

Payne

et al. 2007

Mol Psychiatry

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On the basis of our previous identified linkage regions for nicotine dependence (ND), we selected seven and four single nucleotide polymorphisms (SNPs) in the b-arrestins 1 (ARRB1) and 2 (ARRB2), respectively, to determine the associations of the two genes with ND in a total of 2037 subjects from 602 nuclear families of European American (EA) and African American (AA) origin. ND was assessed by Smoking Quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerströ m Test for ND (FTND) score. Individual SNP analysis indicated that SNPs rs472112 within ARRB1 and rs4790694 within ARRB2 in the EA sample was significantly associated with HSI and FTND score, and the association of rs4790694 for ARRB2 remained significant after correction for multiple testing. Haplotype analysis revealed that haplotype C-G-C-G-G-T within ARRB1 at a frequency of 20%, formed by SNPs rs528833, rs1320709, rs480174, rs5786130, rs611908 and rs472112, was positively associated with HSI and FTND in EAs. We also found a haplotype within ARRB2, C-C-A-T at a frequency of 10.7%, formed by SNPs rs3786047, rs4522461, rs1045280 and rs4790694, that showed a significant positive association with HSI and FTND in the EA sample. No significant associations for either individual SNPs or major haplotype of both ARRB1 and ARRB2 were found in the AA sample. Further, the strength of these associations increased after removing the SQ component from HSI and FTND scores in both the EA and AA samples, suggesting that ARRB1 and ARRB2 play an important role in biological processes involved in the regulation of smoking urgency (that is time to smoke first cigarette). In summary, our results provide the first evidence of a significant association for ARRB1 and ARRB2 variants with ND in an EA sample. Molecular Psychiatry (2008) 13, 398-406; doi:10.1038/sj.mp.4002036; published online 19 June 2007Keywords: haplotype; SNP; ARRB1; ARRB2; association analysis; nicotine dependence Introduction Tobacco use is a leading preventable cause of death in the United States, with one in every five deaths attributable to smoking. 1 Nicotine is believed to be the primary addictive component of cigarette smoke. Nicotine dependence (ND) is a complex quantitative trait that is influenced by both genetic and environmental factors. 2 A number of linkage and association studies have identified susceptibility genes for ND; 3,4 however, few association studies of candidate genes and/or linkage analyses for susceptibility loci have been replicated in independent samples. 3,5 Previously, we identified several chromosomal regions that are likely to harbor susceptibility loci for ND in the Framingham Heart Study (FSH) and Mid-South Tobacco Family (MSTF) samples, including one region on chromosome 11q13 and one on chromosome 17p13, 3,[6][7][8] where the two genes of interest, b-arrestins 1 and 2 (ARRB1 and ARRB2), are located, 9,10 respectively. b-arrestins are key negative regulators and scaffolds for G-protein-coupled receptor (GPCR) signaling, one of the most fundamental cellular signal ...

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“…However, in humans it has been shown that activation of kappa opioid receptors acutely may cause dysphoria and psychotomimesis (Pfeiffer et al, 1986) and this limits the clinical usefulness of these drugs. Research to develop kappa-opioid receptor agonists that do not have the dysphoric properties is ongoing (Hasebe et al, 2004;Park et al, 2006). A better understanding of the systems involved in mediating the long-term effects of kappa-opioid receptor agonists on cocainestimulated locomotor activity will aid in the development of compounds that may be able to bypass the dysphoric properties associated with the currently available kappa receptor agonists while preserving the ability to block the effects of cocaine.…”

Section: Introductionmentioning

confidence: 99%

Depletion of serotonin decreases the effects of the kappa-opioid receptor agonist U-69593 on cocaine-stimulated activity

Захарова

Collins

Åberg

et al. 2008

European Journal of Pharmacology

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Treatment with a kappa-opioid receptor agonist for five days decreases locomotor activity and reduces activity in response to a cocaine challenge three days later. In addition, chronic cocaine increases kappa-opioid receptor density, striatal dynorphin, and dynorphin gene expression in the striatum. The upregulation of kappa-opioid receptors after cocaine treatment occurs predominantly in brain regions that are highly innervated by serotonin. To determine if serotonin plays a role in the effects of kappa-opioid receptor agonists on cocaine-stimulated activity, parachloroamphetamine (PCA), which depleted serotonin by 53%-66%, or saline, was given prior to a five-day treatment with U-69593 or vehicle. Three days later each rat received a single injection of cocaine and locomotor activity was measured. Treatment with PCA had no effect on the ability of U-69593 alone to decrease locomotor activity. Thus, the behavioral effects of U-69593 alone were not dependent upon serotonin. In rats pretreated with saline, U-69593 treatment significantly blocked the locomotoractivating effects of cocaine. Following PCA pretreatment, however, there were no significant differences in locomotor activity in rats challenged with an injection of cocaine after treatment with U-69593 or vehicle. Thus, serotonin depletion prevented the long-lasting blockade of the locomotoractivating effects of cocaine subsequent to repeated administration of U-69593 but did not alter the effects of cocaine in rats that were treated with vehicle. Thus, the effects of PCA on U-69593 are not due to non-specific alterations in cocaine-induced locomotor activity. These findings suggest that serotonin plays an important role in mediating the effects of kappa-opioid receptor agonists on the behavioral response to cocaine.

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Possible Pharmacotherapy of the Opioid κ Receptor Agonist for Drug Dependence

Cited by 54 publications

References 31 publications

Involvement of κ/Dynorphin System in WIN 55,212-2 Self-Administration in Mice

Involvement of κ/Dynorphin System in WIN 55,212-2 Self-Administration in Mice

β-Arrestins 1 and 2 are associated with nicotine dependence in European American smokers

Depletion of serotonin decreases the effects of the kappa-opioid receptor agonist U-69593 on cocaine-stimulated activity

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