Dextro-Naloxone Counteracts Amphetamine-Induced Hyperactivity

doi:10.1016/S0091-3057(97)00528-5

Pharmacology Biochemistry and Behavior

Volume 59, Issue 2, February 1998, Pages 271-274

https://doi.org/10.1016/S0091-3057(97)00528-5 Get rights and content

Abstract

The locomotor stimulating effect of d-amphetamine in mice was counteracted by the administration of l-naloxone [(−)-naloxone], a known opiate receptor antagonist. Mice injected with amphetamine reached a peak locomotor activity within 30 min. When treated simultaneously with amphetamine and l-naloxone, these subjects showed low motility. Furthermore, when mice were treated not with l-naloxone but with its mirror image, d-naloxone [(+)-naloxone], a compound that by itself does not antagonize opiates and does not affect spontaneous motility, they showed no amphetamine-induced hyperactivity. The finding that an enantiomer of naloxone, with no opiate antagonist activity, is able to block the excitatory action of amphetamine, suggests the existence of a hitherto unknown mechanism of counteracting some of the effects of stimulants and euphoriants like amphetamine and cocaine.

Section snippets

Animals

A total of 110 Swiss–Webster albino male mice, 25–35 g, purchased from Charles River Laboratories (Wilmington, MA), was used in these experiments. The mice were housed four to six per cage and given tap water and Purina Chow ad lib. The animal colony was on a 12 h on–12 h off light cycle. All injections were administered intraperitoneally. Animals were treated in accord with the NIH guidelines. The only invasive treatment that they received consisted of drug injections.

Chemicals

In this study d

Results

Animals given amphetamine increased their locomotor activity significantly. They moved continuously, and displayed repeated grooming and circling motions and some vocalization. They resisted handling more than controls. The hyperactivity was reflected in the quantitative data. Peak motor activity was reached between 30 and 50 min following injection and waned thereafter. Control subjects showed a motility of 57.3 ± 3.0 crossings per min. Treatment with 0.5 mg/kg amphetamine led to a minimal

Discussion

Among the known effects of amphetamine is its interference with dopamine and norepinephrine pathways in the CNS 5, 11, 12, 17. We have used amphetamine to lower the levels of brain norepinephrine and thereby decrease susceptibility to convulsive seizures in rodents 1, 2. The relationship between amphetamine and opiate antagonists has been explored in a large number of studies over the years, with a consensus that the two compounds counteract each other 3, 5, 12, 14, 15, 16, 17.

The primary mode

Acknowledgements

The authors wish to thank Dr. Henry Wisniewski, Director of the New York State Institute for Basic Research in Developmental Disabilities, without whose help and encouragement this work would not have been possible. We thank the Mallinckrodt Corporation for their generous donation of l-naloxone for this study. This work was supported in part by The New York State Research Foundation for Mental Hygiene, Inc. (No. 914-4333A).

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The study found that (−)-naloxone and (+)-naloxone significantly attenuated β-amyloid peptide-induced superoxide production in microglia cells and that the anti-inflammatory effect of naloxone may not be directly related to opioid receptors18 because (+)-naloxone, which does not bind to opioid receptors, had a marked anti-inflammatory effect. Furthermore, (+)-naloxone reduced cocaine-induced19 and amphetamine-induced20 hyperactivity in mice. A recent study also found that naloxone (100pM) inhibited opioid-dependent microglia migration by downregulating the ionotropic purinergic receptor P2X4.21
Microglia have a crucial role in maintaining neuronal homeostasis in the central nervous system. Immune factors released from microglia have important roles in nociceptive signal transduction. Activation of microglia seems to be a shared mechanism in pathological pain and morphine tolerance because pharmacological attenuation of microglia activation provides satisfactory management in both situations.
In the present study, we investigated the effect of 1nM (+)-naloxone, which is not an opioid receptor antagonist, on morphine-induced activation of microglia EOC13.31 cells.
Our results showed that 1μM morphine enhanced microglia activation and migration, decreased α-tubulin acetylation, and induced heat shock protein 90 (HSP90) fragmentation and histone deacetylase 6 (HDAC6) expression. Morphine-induced α-tubulin deacetylation and HSP90 fragmentation were HDAC6-dependent. Pretreatment with (+)-naloxone (1nM) inhibited morphine-evoked microglia activation and chemotaxis and prevented α-tubulin deacetylation and HSP90 fragmentation by inhibiting HDAC6 expression.
Based on the findings of the present study, we suggest that (+)-naloxone inhibits morphine-induced microglia activation by regulating HDAC6-dependent α-tubulin deacetylation and HSP90 fragmentation.
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However, both the (+) and (−) forms of each drug are antagonists at the Toll-like receptor 4 (TLR4; Hutchinson et al., 2008). Interestingly, despite its inability to antagonize opioid receptors, (+) naloxone was found to reduce stimulant-induced locomotor activity (Chatterjie, Alexander, Sechzer, & Lieberman, 1996; Chatterjie, Sechzer, Lieberman, & Alexander, 1998), which is congruent with findings suggesting that TLR4 contributes to the acute effects of drugs of abuse (Hutchinson et al., 2012) and the ability of opioid receptor antagonists to affect such responses (Wu et al., 2012). The activation of TLR4 predominantly contributes to glial activation and the subsequent release of numerous proinflammatory cytokines (Mayfield et al., 2013).
Studies have implicated neuroinflammatory processes in the pathophysiology of various psychiatric conditions, including addictive disorders. Neuroimmune signaling represents an important and relatively poorly understood biological process in drug addiction. The objective of this review is to update the field on recent developments in neuroimmune therapies for addiction. First, we review studies of neuroinflammation in relation to alcohol and methamphetamine dependence followed by a section on neuroinflammation and accompanying neurocognitive dysfunction in HIV infection and concomitant substance abuse. Second, we provide a review of pharmacotherapies with neuroimmune properties and their potential development for the treatment of addictions. Pharmacotherapies covered in this review include ibudilast, minocycline, doxycycline, topiramate, indomethacin, rolipram, anakinra (IL-1Ra), peroxisome proliferator-activated receptor agonists, naltrexone, and naloxone. Lastly, summary and future directions are provided with recommendations for how to efficiently translate preclinical findings into clinical studies that can ultimately lead to novel and more effective pharmacotherapies for addiction.
Ultra-low dose (+)-naloxone restores the thermal threshold of morphine tolerant rats
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Citation Excerpt :
Studies had found that both (−)-naloxone and (+)-naloxone significantly attenuated β-amyloid peptide-induced superoxide production in microglia cells and that the anti-inflammatory effect of naloxone may not be directly related to opioid receptors,26 as (+)-naloxone, which does not bind to opioid receptors, also had a remarkable anti-inflammatory effect. Moreover, (+)-naloxone was found to reduce cocaine-induced and amphetamine-induced hyperactivity in mice27,28. Our present study demonstrated that 15 pg (+)-naloxone not only prevented morphine tolerance development but also enhanced the antinociceptive effect of morphine in morphine-tolerant rats.
As known, long-term morphine infusion leads to tolerance. We previously demonstrated that both co-infusion and post-administration of ultra-low dose (±)-naloxone restores the antinociceptive effect of morphine in morphine-tolerant rats. However, whether the mechanism of the action of ultra-low dose (±)-naloxone is through opioid receptors or not. Therefore, in the present study, we further investigated the effect of ultra-low dose (+)-naloxone, it does not bind to opioid receptors, on the antinociceptive effect of morphine.
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Our results showed that, both co-infusion and post-treatment of ultra-low dose (+)-naloxone with morphine preserves the antinociceptive effect of morphine. Moreover, in the post administration rats, ultra-low dose (+)-naloxone further enhances the antinociceptive effect of morphine.
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An inflammatory response in the CNS mediated by activation of microglia is a key event in the early stages of the development of neurodegenerative diseases. Using mouse cortical mixed glia cultures, we have previously demonstrated that the bacterial endotoxin lipopolysaccharide induces the activation of microglia and the production of proinflammatory factors. Naloxone, an opioid receptor antagonist, inhibits the lipopolysaccharide-induced activation of microglia and the production of proinflammatory factors. Using neuron–glia co-cultures, we extended our study to determine if naloxone has a neuroprotective effect against lipopolysaccharide-induced neuronal damage and analysed the underlying mechanism of action for its potential neuroprotective effect. Pretreatment of cultures with naloxone (1 μM) followed by treatment with lipopolysaccharide significantly inhibited the lipopolysaccharide-induced production of nitric oxide and the release of tumor necrosis factor-α, and significantly reduced the lipopolysaccharide-induced damage to neurons. More importantly, both naloxone and its opioid-receptor ineffective enantiomer (+)-naloxone were equally effective in inhibiting the lipopolysaccharide-induced generation of proinflammatory factors and the activation of microglia, as well as in the protection of neurons.
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ArticlesDextro-Naloxone Counteracts Amphetamine-Induced Hyperactivity

Abstract

Section snippets

Animals

Chemicals

Results

Discussion

Acknowledgements

Eur. J. Pharmacol.

Life Sci.

Life Sci.

Lethality of pentylenetetrazol in rats after depletion of brain norepinephrine

Fed. Proc.

Effects of 6-hydroxydopamine. Delayed motor manifestation associated with high mortality in rodents

Neurochem. Res.

Spontaneous motility in SW miceAmphetamine/naloxone antagonism

FASEB J.

Non-opiate effects of naloxoneAntagonism of amphetamine-induced spontaneous activity in SW mice

FASEB J.

Long-term influence of d-amphetamine on mesolimbic brain-stimulation rewardComparison of chronic haloperolidol and naloxone effects

Pharmacol. Biochem. Behav.

Influence of optical isomers of (+)- and (−)-naloxone on beating frequency, contractile force and action potentials of guinea pig isolated cardiac preparation

Br. J. Pharmacol.

Articles
Dextro-Naloxone Counteracts Amphetamine-Induced Hyperactivity