Preclinical Toxicity Studies of Naltrexone

Mc, Braude; Jm, Morrison

doi:10.1037/e497452006-006

Cited by 15 publications

(5 citation statements)

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“…Intermittent opioid receptor blockade using daily injections of LDN, at a dosage of NTX that was ;0.01% of the LD 50 and without toxicological symptoms (42), had a remarkable neuroprotective effect on MOGinjected animals. Several lines of evidence support this conclusion.…”

Section: Discussionmentioning

confidence: 93%

“…The results of this study suggest for the first time that endogenous opioid peptides interfere with the autoimmune encephalitogenic process, and influence the onset and progression of EAE. Intermittent opioid receptor blockade using daily injections of LDN, at a dosage of NTX that was ;0.01% of the LD 50 and without toxicological symptoms (42), had a remarkable neuroprotective effect on MOGinjected animals. Several lines of evidence support this conclusion.…”

Section: Discussionmentioning

confidence: 93%

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Endogenous Opioids Regulate Expression of Experimental Autoimmune Encephalomyelitis: A New Paradigm for the Treatment of Multiple Sclerosis

Zagon

Rahn

Turel

et al. 2009

Exp Biol Med (Maywood)

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Preclinical investigations utilizing murine experimental auto-immune encephalomyelitis (EAE), as well as clinical observations in patients with multiple sclerosis (MS), may suggest alteration of endogenous opioid systems in MS. In this study we used the opioid antagonist naltrexone (NTX) to invoke a continuous (High Dose NTX, HDN) or intermittent (Low Dose NTX, LDN) opioid receptor blockade in order to elucidate the role of native opioid peptides in EAE. A mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced EAE was employed in conjunction with daily treatment of LDN (0.1 mg/kg, NTX), HDN (10 mg/kg NTX), or vehicle (saline). No differences in neurological status (incidence, severity, disease index), or neuropathological assessment (activated astrocytes, demyelination, neuronal injury), were noted between MOG-induced mice receiving HDN or vehicle. Over 33% of the MOG-treated animals receiving LDN did not exhibit behavioral signs of disease, and the severity and disease index of the LDN-treated mice were markedly reduced from cohorts injected with vehicle. Although all LDN animals demonstrated neuropathological signs of EAE, LDN-treated mice without behavioral signs of disease had markedly lower levels of activated astrocytes and demyelination than LDN- or vehicle-treated animals with disease. These results imply that endogenous opioids, evoked by treatment with LDN and acting in the rebound period from drug exposure, are inhibitory to the onset and progression of EAE, and suggest that clinical studies of LDN are merited in MS and possibly in other autoimmune disorders.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 93%

Endogenous Opioids Regulate Expression of Experimental Autoimmune Encephalomyelitis: A New Paradigm for the Treatment of Multiple Sclerosis

Zagon

Rahn

Turel

et al. 2009

Exp Biol Med (Maywood)

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“…The specific mechanisms as to how naltrexone regulates growth have yet to be determined. The dosages needed to alter cerebellar ontogeny are exceedingly low, being 0.05-2.5% of the LD50 in adult rats (Braude and Morrison, 1976). It does not appear that naltrexone's effects are a reflection of nutritional status, nor are hormonal changes believed to be responsible for naltrexone's actions on development , although further studies are being conducted to evaluate this possibility.…”

Section: Discussionmentioning

confidence: 99%

Opioid antagonist (naltrexone) modulation of cerebellar development: histological and morphometric studies

Zagon¹,

Pj²

1986

J. Neurosci.

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The role of endogenous opioid systems in preweaning cerebellar development was explored in rats utilizing naltrexone, a potent opioid antagonist. Sprague-Dawley rats were given daily subcutaneous injections of either 1 or 50 mg/kg naltrexone to invoke a temporary or complete blockade, respectively, of opioid receptors throughout the first 3 weeks of postnatal life; animals injected with sterile water served as controls. At weaning (day 21), macroscopic, morphometric, and histological determinations were conducted. In general, 50 mg/kg naltrexone had a stimulatory action on cerebellar development, whereas 1 mg/kg naltrexone had an inhibitory influence. Both sexes were affected comparably. Limits to naltrexone's ability to modulate cerebellar ontogeny were noted, with more latitude existing toward growth enhancement than impairment. The temporal course of ontogeny was generally unaltered in naltrexone-treated rats. Rather, only events that transpired over this period were dramatically affected. The most notable effects in 1 mg/kg naltrexone rats were marked decreases in cerebellar areal dimensions, the content of internal granule neurons, and cellular and tissue differentiation. Characteristics of the 50 mg/kg naltrexone group included increases in cerebellar areal dimensions, neural cell number, content, and size, and structural changes consistent with acceleration in growth and differentiation. Naltrexone influenced both neurons and glia, but only neural cells still being generated during the first 21 d after birth were altered in regard to quantity. Previous evidence has shown the presence of peak levels of endogenous opioids and opioid receptors in the cerebellum during the first weeks of life, as well as demonstrating the presence of enkephalin immunoreactivity on germinative cerebellar cells during postnatal neurogenesis but not in adult counterparts.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Naltrexone levels which affect development are reportedly small (0.05-2.5% of the LD 50 in adult rats) [ 428 ]. With an LD 50 of approximately 2000 mg/kg in adult rats [ 31 , 439 ], the dosages required to induce and effect in rats are 1-50 mg/kg, with 1 mg/kg considered a low dose (Table 5 ), and 50 mg/kg a high dose (Table 4 ) [ 425 ].…”

Section: Animal Studiesmentioning

confidence: 99%

The Effects of Maternally Administered Methadone, Buprenorphine and Naltrexone on Offspring: Review of Human and Animal Data

Farid¹,

Dunlop

Tait³

et al. 2008

139

144

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Most women using heroin are of reproductive age with major risks for their infants. We review clinical and experimental data on fetal, neonatal and postnatal complications associated with methadone, the current "gold standard", and compare these with more recent, but limited, data on developmental effects of buprenorphine, and naltrexone. Methadone is a -opioid receptor agonist and is commonly recommended for treatment of opioid dependence during pregnancy. However, it has undesired outcomes including neonatal abstinence syndrome (NAS). Animal studies also indicate detrimental effects on growth, behaviour, neuroanatomy and biochemistry, and increased perinatal mortality. Buprenorphine is a partial -opioid receptor agonist and a -opioid receptor antagonist. Clinical observations suggest that buprenorphine during pregnancy is similar to methadone on developmental measures but is potentially superior in reducing the incidence and prognosis of NAS. However, small animal studies demonstrate that low doses of buprenorphine during pregnancy and lactation lead to changes in offspring behaviour, neuroanatomy and biochemistry. Naltrexone is a non-selective opioid receptor antagonist. Although data are limited, humans treated with oral or sustained-release implantable naltrexone suggest outcomes potentially superior to those with methadone or buprenorphine. However, animal studies using oral or injectable naltrexone have shown developmental changes following exposure during pregnancy and lactation, raising concerns about its use in humans. Animal studies using chronic exposure, equivalent to clinical depot formulations, are required to evaluate safety. While each treatment is likely to have maternal advantages and disadvantages, studies are urgently required to determine which is optimal for offspring in the short and long term.

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Preclinical Toxicity Studies of Naltrexone

Cited by 15 publications

References 0 publications

Endogenous Opioids Regulate Expression of Experimental Autoimmune Encephalomyelitis: A New Paradigm for the Treatment of Multiple Sclerosis

Endogenous Opioids Regulate Expression of Experimental Autoimmune Encephalomyelitis: A New Paradigm for the Treatment of Multiple Sclerosis

Opioid antagonist (naltrexone) modulation of cerebellar development: histological and morphometric studies

The Effects of Maternally Administered Methadone, Buprenorphine and Naltrexone on Offspring: Review of Human and Animal Data

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