Differential effects of morphine- and cocaine-induced nNOS immunoreactivity in the dentate gyrus of hippocampus of mice lacking μ-opioid receptors

doi:10.1016/j.neulet.2005.10.089

Neuroscience Letters

Volume 395, Issue 2, 6 March 2006, Pages 98-102

https://doi.org/10.1016/j.neulet.2005.10.089 Get rights and content

Abstract

This study investigated the expression of nNOS after repeated morphine or cocaine administration in order to determine if nNOS (neuronal nitric oxide synthase) is involved in the morphine- or cocaine-induced behavioral sensitization in μ-opioid receptor knockout (MOR^−/−) mice. Higher numbers of nNOS-positive cells were observed in the dentate gyrus of the hippocampus (DG) of the wild-type (MOR^+/+) mice repeatedly treated with either morphine or cocaine than in the saline treated MOR^+/+ mice (morphine, +122%; cocaine, +82%). Moreover, the MOR^−/− mice also showed significantly higher morphine- or cocaine-induced nNOS expression levels in the DG than in the saline treated MOR^+/+ mice (morphine, +234%; cocaine, +54%). The MOR^−/− mice showed a significantly higher morphine-induced nNOS expression level (+103%) or a lower cocaine-induced nNOS expression level (+38%) in the DG than in the morphine- or cocaine-treated MOR^+/+ mice. These results suggest that morphine and cocaine sensitization is differentially regulated by the μ-opioid receptors in MOR^−/− mice via the nNOS systems in the DG.

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Acknowledgements

This work was supported by Korea Research Foundation Grant (2003-041-E00327) and Brain Research Center of the 21st Century Frontier Research Program (M103KV010008 05K2201 00830).

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Our morphometric analysis revealed that the numerical densities of nNOS immunopositive neurons are significantly increased in the right temporal cortex and the left hypothalamic PVN of individuals who died from heroin abuse. In previous studies it was shown that repeated administration in mice of the heroin metabolite morphine leads to increased expression of nNOS in the dentate gyrus of the hippocampus (Yoo et al., 2006), the olfactory bulb and nuclei, medulla oblongata, locus coeruleus and cerebellum, but not in the hypothalamus (Cuéllar et al., 2000). Withdrawal of morphine further increased the number of nNOS expressing neurons in some brain areas (Cuéllar et al., 2000).
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In some reports, the locomotor response to cocaine was reduced in mu KO mice (Chefer et al., 2004; Yoo et al., 2006, 2003) as well as in βend KO mice (Marquez et al., 2008), while in many other mu KO studies, this cocaine effect was unchanged (Becker et al., 2002; Chefer et al., 2004; Contarino et al., 2002; Hall et al., 2004; Lesscher et al., 2005). Furthermore, sensitization to locomotor effects of cocaine was reduced (Yoo et al., 2006, 2003), maintained (Lesscher et al., 2005), or enhanced (Hummel et al., 2004), depending on the mouse genetic background (Hummel et al., 2004) and the pattern of drug exposure (administration regimen and timing of injections) (Allouche et al., 2013; Puig et al., 2012). In mu KO mice also, methamphetamine-induced locomotion, was decreased at one dose, maintained in lower and higher doses, and no behavioral sensitization was found (Shen et al., 2010), therefore altogether, evidence exists that mu receptor activity contributes to locomotor effects of cocaine, and the adaptive response to repeated exposure to the drug.
The endogenous opioid system is expressed throughout the brain reinforcement circuitry, and plays a major role in reward processing, mood control and the development of addiction. This neuromodulator system is composed of three receptors, mu, delta and kappa, interacting with a family of opioid peptides derived from POMC (β-endorphin), preproenkephalin (pEnk) and preprodynorphin (pDyn) precursors. Knockout mice targeting each gene of the opioid system have been created almost two decades ago. Extending classical pharmacology, these mutant mice represent unique tools to tease apart the specific role of each opioid receptor and peptide in vivo, and a powerful approach to understand how the opioid system modulates behavioral effects of drugs of abuse. The present review summarizes these studies, with a focus on major drugs of abuse including morphine/heroin, cannabinoids, psychostimulants, nicotine or alcohol. Genetic data, altogether, set the mu receptor as the primary target for morphine and heroin. In addition, this receptor is essential to mediate rewarding properties of non-opioid drugs of abuse, with a demonstrated implication of β-endorphin for cocaine and nicotine. Delta receptor activity reduces levels of anxiety and depressive-like behaviors, and facilitates morphine-context association. pEnk is involved in these processes and delta/pEnk signaling likely regulates alcohol intake. The kappa receptor mainly interacts with pDyn peptides to limit drug reward, and mediate dysphoric effects of cannabinoids and nicotine. Kappa/dynorphin activity also increases sensitivity to cocaine reward under stressful conditions. The opioid system remains a prime candidate to develop successful therapies in addicted individuals, and understanding opioid-mediated processes at systems level, through emerging genetic and imaging technologies, represents the next challenging goal and a promising avenue in addiction research.
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Results showed that chronic morphine not only up regulates procaspase 3, but also promotes the cleavage of procaspase 3 leading to the appearance of active caspase 3 (Fig. 2C). Chronic morphine exposure induces neuronal nitric oxide synthase (nNOS) level in brain (Yoo et al., 2006) as well as produce NO in non-neural cells (Bhat et al., 2004; Frenklakh et al., 2006; Ding et al., 2008). Since, increase levels of NO are potential neurotoxic agents, the possible role of NO in the loss of cell viability of astrocytes on morphine exposure was investigated.
Unlike neurons and various other non-neuronal cells, astrocytes have been reported to be resistant to morphine induced cytotoxicity. The present work demonstrates that primary cultures of astrocytes are also sensitive to morphine toxicity depending upon the thyroidal status of the culture medium. Chronic morphine treatment of astrocytes, cultured under thyroid hormone (TH)-deficient conditions, induced apoptotic cell death which was characterized by nuclear condensation, DNA fragmentation and activation of caspase-3 like enzymes. Cell death was accompanied with increase in nNOS level, nitration of cellular proteins and down regulation of pAKT level. Phosphorylation of ERK1/2 showed a biphasic response, an initial induction followed by sustained decline during chronic morphine treatment and the initial induction of pERK1/2 level appeared to be critical for apoptosis in the cells. Interestingly, supplementation with normal levels of TH to cells attenuated morphine-induced apoptosis as well as the biphasic response of pERK1/2 in the astrocytes. However, in the presence of glutathione synthetase inhibitor l-buthionine-S,R-sulfoximine, TH failed to protect astrocytes. Overall, the study demonstrates a possible signaling mechanism of morphine induced toxicity to cells and suggests that alteration of glutathione homeostasis by TH protect astrocytes from morphine by regulating NO and pERK1/2 pathways in the cells.
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Nitric oxide (NO) is generated from l-arginine by NO synthases, of which three forms have been identified: endothelial, inducible and neuronal (eNOS, iNOS and nNOS, respectively). The l-arginine metabolite asymmetric dimethylarginine (ADMA) is a potent, noncompetitive inhibitor of nNOS, while its congener N^G-monomethyl-l-arginine (l-NMMA) is a less potent, competitive inhibitor. In rat neurons large amounts of ADMA are found, suggesting its importance in modulating neuronal activity.
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Nitric oxide (NO) plays pivotal roles in controlling physiological functions, participates in pathophysiological intervention, and is involved in mechanisms underlying beneficial or untoward actions of therapeutic agents. Endogenous nitric oxide is formed by three isoforms of nitric oxide synthase: endothelial, neurogenic and inducible. The former two are constitutively present mainly in the endothelium and nervous system, respectively, and the latter one is induced by lipopolysaccharides or cytokines mainly in mitochondria and glial cells. Constitutively formed nitric oxide modulates the actions of morphine and related analgesics by either enhancing or reducing antinociception. Tolerance to and dependence on morphine or its withdrawal syndrome are likely prevented by nitric oxide synthase inhibition. Information concerning modulation of morphine actions by nitric oxide is undoubtedly useful in establishing new strategies for efficient antinociceptive treatment and for minimizing noxious and unintended reactions.
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Differential effects of morphine- and cocaine-induced nNOS immunoreactivity in the dentate gyrus of hippocampus of mice lacking μ-opioid receptors

Abstract

Section snippets

Acknowledgements

Neurosci. Res.

Neuron

Neurosci. Biobehav. Rev.

Eur. J. Pharmacol.

Neuron

Biochem. Pharmacol.

Neuropharmacology

Eur. J. Pharmacol.

Mol. Brain Res.

Brain Res. Dev. Brain Res.

Brain Res. Brain Res. Rev.

Neurosci. Lett.

Brain Res. Bull.

Neurosci. Lett.