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Morphine Withdrawal Increases Brain-Derived Neurotrophic Factor Precursor

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Abstract

Morphine has been shown to increase the expression of brain-derived neurotrophic factor (BDNF) in the brain. However, little is known about the effect of morphine withdrawal on BDNF and its precursor protein, or proBDNF, which induces neuronal apoptosis. In this work, we examined whether BDNF and proBDNF levels change in rats chronically injected with escalating doses of morphine and those who undergo spontaneous withdrawal for 60 h. We observed, in the frontal cortex and striatum, that the ratio of BDNF to proBDNF changed depending upon the experimental paradigm. Morphine treatment and morphine withdrawal increased both BDNF and proBDNF levels. However, the increase in proBDNF immunoreactivity in withdrawal rats was more robust than that observed in morphine-treated rats. proBDNF is processed either intracellularly by furin or extracellularly by the tissue plasminogen activator (tPA)/plasminogen system or matrix metalloproteases (MMPs). To examine the mechanisms whereby chronic morphine treatment and morphine withdrawal differentially affects BDNF/proBDNF, the levels MMP-3 and MMP-7, furin, and tPA were analyzed. We found that morphine increases tPA levels, whereas withdrawal causes a decrease. To confirm the involvement of tPA in the morphine-mediated effect on BDNF/proBDNF, we exposed cortical neurons to morphine in the presence of the tPA inhibitor plasminogen activator inhibitor-1 (PAI-1). This inhibitor reversed the morphine-mediated decrease in proBDNF, supporting the hypothesis that morphine increases the availability of BDNF by promoting the extracellular processing of proBDNF by tPA. Because proBDNF could negatively influence synaptic repair, preventing withdrawal is crucial for reducing neurotoxic mechanisms associated with opioid abuse.

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Acknowledgements

This work was supported by HHS grants 1R01 NS079172 and 1R21 NS102121 to I.M., 1F31DA032282 to L.A.C., T32 NS041218 to E.W., and Georgetown University Music for the Mind award to A.B.

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  1. Lee A. Campbell

    Present address: Medical Development Program, National Institute on Drug Abuse, Intramural Research Program, National Institute of Health, DHHS, Baltimore, MD, 21224, USA

Authors and Affiliations

  1. Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Rd NW, Washington, DC, 20057, USA

    Alessia Bachis, Lee A. Campbell, Kierra Jenkins, Erin Wenzel & Italo Mocchetti

  2. Department of Pharmacology, Georgetown University Medical Center, Washington, DC, 20057, USA

    Erin Wenzel

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  1. Alessia Bachis
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Correspondence to Italo Mocchetti.

Electronic Supplementary Material

Supplementary Fig. A

Representative proBDNF standard curve obtained using the ELISA kit, as described in Materials and Methods. B. Cross reactivity of different concentrations (ng/ml) of BDNF as detected by the proBDNF ELISA. (PSD 88 kb)

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Bachis, A., Campbell, L.A., Jenkins, K. et al. Morphine Withdrawal Increases Brain-Derived Neurotrophic Factor Precursor. Neurotox Res 32, 509–517 (2017). https://doi.org/10.1007/s12640-017-9788-8

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