Journal
JOURNAL OF NEUROCHEMISTRY
Volume 158, Issue 2, Pages 169-181Publisher
WILEY
DOI: 10.1111/jnc.15355
Keywords
caspase-3; glutamate receptors; JNK; opioid use disorders; p75NTR; TrkB
Categories
Funding
- National Institute of Health [T32 041218]
Ask authors/readers for more resources
Morphine withdrawal induces neuronal apoptosis, with p75NTR potentially playing a role. Experimental results in mice suggest that morphine withdrawal increases the accumulation of p75NTR in hippocampal synapses while decreasing the TrkB receptor, favoring synaptic remodeling and apoptosis. This highlights the importance of preventing opioid withdrawal to reduce neurotoxic mechanisms associated with opioid use disorders.
Morphine withdrawal evokes neuronal apoptosis through mechanisms that are still under investigation. We have previously shown that morphine withdrawal increases the levels of pro-brain-derived neurotrophic factor (BDNF), a proneurotrophin that promotes neuronal apoptosis through the binding and activation of the pan-neurotrophin receptor p75 (p75NTR). In this work, we sought to examine whether morphine withdrawal increases p75NTR-driven signaling events. We employed a repeated morphine treatment-withdrawal paradigm in order to investigate biochemical and histological indicators of p75NTR-mediated neuronal apoptosis in mice. We found that repeated cycles of spontaneous morphine withdrawal promote an accumulation of p75NTR in hippocampal synapses. At the same time, TrkB, the receptor that is crucial for BDNF-mediated synaptic plasticity in the hippocampus, was decreased, suggesting that withdrawal alters the neurotrophin receptor environment to favor synaptic remodeling and apoptosis. Indeed, we observed evidence of neuronal apoptosis in the hippocampus, including activation of c-Jun N-terminal kinase (JNK) and increased active caspase-3. These effects were not seen in saline or morphine-treated mice which had not undergone withdrawal. To determine whether p75NTR was necessary in promoting these outcomes, we repeated these experiments in p75NTR heterozygous mice. The lack of one p75NTR allele was sufficient to prevent the increases in phosphorylated JNK and active caspase-3. Our results suggest that p75NTR participates in the neurotoxic and proinflammatory state evoked by morphine withdrawal. Because p75NTR activation negatively influences synaptic repair and promotes cell death, preventing opioid withdrawal is crucial for reducing neurotoxic mechanisms accompanying opioid use disorders.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available