PMID- 28776309
OWN - NLM
STAT- MEDLINE
DCOM- 20180806
LR  - 20191008
IS  - 1476-3524 (Electronic)
IS  - 1029-8428 (Print)
IS  - 1029-8428 (Linking)
VI  - 32
IP  - 3
DP  - 2017 Oct
TI  - Morphine Withdrawal Increases Brain-Derived Neurotrophic Factor Precursor.
PG  - 509-517
LID - 10.1007/s12640-017-9788-8 [doi]
AB  - 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.
FAU - Bachis, Alessia
AU  - Bachis A
AD  - Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown 
      University Medical Center, 3970 Reservoir Rd NW, Washington, DC, 20057, USA.
FAU - Campbell, Lee A
AU  - Campbell LA
AD  - Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown 
      University Medical Center, 3970 Reservoir Rd NW, Washington, DC, 20057, USA.
AD  - Medical Development Program, National Institute on Drug Abuse, Intramural 
      Research Program, National Institute of Health, DHHS, Baltimore, MD, 21224, USA.
FAU - Jenkins, Kierra
AU  - Jenkins K
AD  - Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown 
      University Medical Center, 3970 Reservoir Rd NW, Washington, DC, 20057, USA.
FAU - Wenzel, Erin
AU  - Wenzel E
AD  - Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown 
      University Medical Center, 3970 Reservoir Rd NW, Washington, DC, 20057, USA.
AD  - Department of Pharmacology, Georgetown University Medical Center, Washington, DC, 
      20057, USA.
FAU - Mocchetti, Italo
AU  - Mocchetti I
AD  - Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown 
      University Medical Center, 3970 Reservoir Rd NW, Washington, DC, 20057, USA. 
      moccheti@georgetown.edu.
LA  - eng
GR  - 1F31DA032282/National Institute on Drug Abuse/
GR  - R01 NS079172/NS/NINDS NIH HHS/United States
GR  - T32 NS041218/NS/NINDS NIH HHS/United States
GR  - R21 NS102121/NS/NINDS NIH HHS/United States
GR  - T32 NS041218/National Institutes of Health/
GR  - F31 DA032282/DA/NIDA NIH HHS/United States
GR  - NS079172/National Institute of Neurological Disorders and Stroke/
GR  - 1R21 NS102121/National Institutes of Health/
PT  - Journal Article
DEP - 20170803
PL  - United States
TA  - Neurotox Res
JT  - Neurotoxicity research
JID - 100929017
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Narcotics)
RN  - 0 (Protein Precursors)
RN  - 0 (brain-derived neurotrophic factor precursor)
RN  - 76I7G6D29C (Morphine)
RN  - EC 3.4.21.68 (Tissue Plasminogen Activator)
RN  - EC 3.4.21.75 (Furin)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
RN  - EC 3.4.24.23 (Matrix Metalloproteinase 7)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*metabolism
MH  - Cells, Cultured
MH  - Corpus Striatum/drug effects/*metabolism/pathology
MH  - Frontal Lobe/drug effects/*metabolism/pathology
MH  - Furin/metabolism
MH  - Male
MH  - Matrix Metalloproteinase 3/metabolism
MH  - Matrix Metalloproteinase 7/metabolism
MH  - Morphine/toxicity
MH  - Morphine Dependence/*metabolism/pathology
MH  - Narcotics/toxicity
MH  - Neurons/drug effects/metabolism/pathology
MH  - Protein Precursors/*metabolism
MH  - Rats, Sprague-Dawley
MH  - Substance Withdrawal Syndrome/*metabolism/pathology
MH  - Tissue Plasminogen Activator/metabolism
PMC - PMC5711538
MID - NIHMS897634
OTO - NOTNLM
OT  - BDNF
OT  - Furin
OT  - Opioid abuse
OT  - Tissue plasminogen activator
OT  - proBDNF
EDAT- 2017/08/05 06:00
MHDA- 2018/08/07 06:00
PMCR- 2018/10/01
CRDT- 2017/08/05 06:00
PHST- 2017/03/09 00:00 [received]
PHST- 2017/07/21 00:00 [accepted]
PHST- 2017/06/28 00:00 [revised]
PHST- 2017/08/05 06:00 [pubmed]
PHST- 2018/08/07 06:00 [medline]
PHST- 2017/08/05 06:00 [entrez]
PHST- 2018/10/01 00:00 [pmc-release]
AID - 10.1007/s12640-017-9788-8 [pii]
AID - 10.1007/s12640-017-9788-8 [doi]
PST - ppublish
SO  - Neurotox Res. 2017 Oct;32(3):509-517. doi: 10.1007/s12640-017-9788-8. Epub 2017 
      Aug 3.