Naloxone prevents microglia-induced degeneration of dopaminergic substantia nigra neurons in adult rats.
Resident microglia are involved in immune responses of the central nervous system and may contribute to neuronal degeneration and death. Here, we tested in adult rats whether injection of bacterial lipopolysaccharide (which causes inflammation and microglial activation) just above the substantia nigra, results in the death of dopaminergic substantia nigra pars compacta neurons. Two weeks after lipopolysaccharide injection, microglial activation was evident throughout the nigra and the number of retrogradely-labeled substantia nigra neurons was reduced to 66% of normal. This suggests that inflammation and/or microglial activation can lead to neuronal cell death in a well-defined adult animal model. The opioid receptor antagonist naloxone reportedly reduces release of cytotoxic substances from microglia and protects cortical neurons in vitro. Here, a continuous two-week infusion of naloxone at a micromolar concentration close to the substantia nigra, prevented most of the neuronal death caused by lipopolysaccharide, i.e. 85% of the neurons survived. In addition, with systemic (subcutaneous) infusion of 0. 1mg/d naloxone, 94% of the neurons survived. Naloxone infusions did not obviously affect the morphological signs of microglial activation, suggesting that naloxone reduces the release of microglial-derived cytotoxic substances. Alternatively, microglia might not cause the neuronal loss, or naloxone might act by blocking opioid receptors on (dopaminergic or GABAergic) neurons.Thus, local inflammation induces and the opioid antagonist naloxone prevents the death of dopaminergic substantia nigra neurons in adult rats. This may be relevant to the understanding of the pathology and treatment of Parkinson's disease, where these neurons degenerate.
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Department of Anatomy and Neurobiology, Dalhousie University, Halifax, Canada.
Bing
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Hagg
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D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D009270:Naloxone / Q000494:pharmacology*; D009410:Nerve Degeneration; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000166:cytology* / Q000502:physiology
D008070:Lipopolysaccharides; D009270:Naloxone; D004298:Dopamine