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Fentanyl and Spiradoline Interactions in a Place-Conditioning Black-White Shuttle-Box

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      Abstract

      Rats were trained for multiple sessions in a place-conditioning shuttle-box to explore motivational interactions of mu and kappa opioid agonists, specifically fentanyl reward and spiradoline aversion. In Phase 1, groups of rats received various doses of mu or kappa agonists, or placebo, testing for preference or aversion. Group A always received saline SC before 15-minute sessions. Group B received fentanyl SC (0.003, 0.006, 0.012 mg/kg), Group C received low and medium doses of agonists SC, and Group D received spiradoline (0.3, 0.6, 1.2 mg/kg) SC during Training Sessions 1-4, rats being restricted to the drug-associated compartment. Rats received saline when restricted to the placebo-associate compartment and on test days with access to both shuttle-box compartments. In Phase 2 of the study, Training Session 5, Combinations of mu and kappa agonists were substituted in Groups B, C, and D. Dose-related preference to fentanyl and aversion to spiradoline occurred during Test Sessions 1-4. During Test Session 5, fentanyl preference in Group B was suppressed by spiradoline, rats in Group C had a saline-like response to combined agonists, and spiradoline aversion in Group D was attenuated by fentanyl. These findings suggest that combined doses of mu and kappa agonists, while additive for antinociception, offset the rewarding and punishing effects of each other.

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      Most cited references 44

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      Review. Neurobiological mechanisms for opponent motivational processes in addiction.

      The conceptualization of drug addiction as a compulsive disorder with excessive drug intake and loss of control over intake requires motivational mechanisms. Opponent process as a motivational theory for the negative reinforcement of drug dependence has long required a neurobiological explanation. Key neurochemical elements involved in reward and stress within basal forebrain structures involving the ventral striatum and extended amygdala are hypothesized to be dysregulated in addiction to convey the opponent motivational processes that drive dependence. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission such as dopamine and opioid peptides in the ventral striatum, but also recruitment of brain stress systems such as corticotropin-releasing factor (CRF), noradrenaline and dynorphin in the extended amygdala. Acute withdrawal from all major drugs of abuse produces increases in reward thresholds, anxiety-like responses and extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence and to contribute to stress-induced relapse. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for the long hypothesized opponent motivational processes responsible for the negative reinforcement driving addiction.
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        Visceral pain: a review of experimental studies.

         T Ness,  G F Gebhart (1990)
        This paper reviews clinical and basic science research reports and is directed toward an understanding of visceral pain, with emphasis on studies related to spinal processing. Four main types of visceral stimuli have been employed in experimental studies of visceral nociception: (1) electrical, (2) mechanical, (3) ischemic, and (4) chemical. Studies of visceral pain are discussed in relation to the use and 'adequacy' of these stimuli and the responses produced (e.g., behavioral, pseudoaffective, neuronal, etc.). We propose a definition of an adequate noxious visceral stimulus and speculate on spinal mechanisms of visceral pain.
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          Neuroanatomical sites mediating the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats.

          An unbiased conditioned place preference paradigm was used to examine the neuroanatomical substrates mediating the reinforcing and aversive effects of mu and kappa opioid agonists. Unilateral microinjection of the selective mu agonist DAMGO into the ventral tegmental area (VTA), the origin of the mesolimbic and mesocortical dopamine (DA) systems, resulted in dose-dependent preferences for the drug-associated place. Intracranial injections of DAMGO into terminal projection sites of VTA DA neurons, the nucleus accumbens and the medial prefrontal cortex, however, as well as into the lateral hypothalamus, were without effect. In contrast, microinjections of the kappa agonist U50,488H and the dynorphin derivative E-2078 into the VTA produced place aversions. Place aversions were also observed after microinjections of U50,488H and E-2078 into the nucleus accumbens, medial prefrontal cortex and lateral hypothalamus. However, microinjections of mu and kappa agonists into either the origin of the mesostriatal DA system, the substantia nigra or into its major terminal field, the nucleus caudatus-putamen, was without effect. Autoradiographic studies revealed that the substances remained within a restricted area around the injection site, confirming that the effects observed were mediated therein. Thus, these data suggest an important role for the A10 neurons in the VTA in the regulation of both mu and kappa opioid-induced motivational states. The rewarding effects are associated with the activation of mu receptors in the VTA, whereas aversive effects are associated with the activation of kappa receptors in the VTA and its limbic-cortical terminal regions.
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            Author and article information

            Affiliations
            [1 ] Department of Pharmacology/Toxicology, Michigan State University, East Lansing, MI 48824, USA; E-Mail: rech@ 123456msu.edu (R.H.R.)
            [2 ] Department of Environmental Quality, State of Michigan, Lansing, MI 48909, USA; E-Mail: briggss4@ 123456michigan.gov (S.L.B.)
            [3 ] Department of Biomedical Sciences, College of Osteopathic Medicine, University of New England, 11 Hills Beach Road, Biddeford, ME 04005, USA
            Author notes
            [* ]Author to whom correspondence should be addresses: E-Mail: dmokler@ 123456une.edu ; Tel.: +1-207-602-2210; Fax: +1-207-60205931.
            Journal
            Pharmaceuticals (Basel)
            Pharmaceuticals (Basel)
            Pharmaceuticals
            MDPI
            1424-8247
            January 2011
            24 December 2010
            : 4
            : 1
            : 101-116
            4052544
            10.3390/ph401101
            pharmaceuticals-04-00101
            © 2010 by the authors; licensee MDPI, Basel, Switzerland.

            This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

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