Morphine Withdrawal Increases Brain-Derived Neurotrophic Factor Precursor

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 hr. 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 -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 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.

Conditioned aversive memory associated with morphine withdrawal increases brain‐derived neurotrophic factor in dentate gyrus and basolateral amygdala

“…In agreement with our results, it has been described that formation of aversive memories associated with conditioned morphine withdrawal requires BDNF signaling pathway in the rat amygdala . Moreover, morphine treatment and morphine withdrawal increased both pro‐BDNF and BDNF levels in frontal cortex . However, the molecular mechanism by which BDNF elicits the formation of aversive memories associated with conditioned morphine withdrawal remains poorly understood.…”

“…47 Moreover, morphine treatment and morphine withdrawal increased both pro-BDNF and BDNF levels in frontal cortex. 48 However, the molecular mechanism by which BDNF elicits the formation of aversive memories associated with conditioned morphine withdrawal remains poorly understood. In our present study, we found that BDNF expression significantly increased after FIGURE 5 Western blotting analysis of pERK, pCREB, pro-brain-derived neurotrophic factor (BDNF), and BDNF in dentate gyrus (DG) after conditioned place aversion (CPA) extinction.…”

A central role for glial CCR5 in directing the neuropathological interactions of HIV-1 Tat and opiates

“…For example, morphine exposures in vivo appear to increase the extracellular protease tissue plasminogen activator, thus increasing cleavage of proBDNF to mBDNF. Withdrawal from morphine had the opposite effect [ 69 ]. Intracellular conversion of proBDNF to mBDNF in neurons is reduced by the HIV surface envelope protein gp120, which reduces levels of the intracellular protease furin [ 47 ].…”

Amyloid beta soluble forms and plasminogen activation system in Alzheimer’s disease: Consequences on extracellular maturation of brain‐derived neurotrophic factor and therapeutic implications

“…It has been shown that exogenous tPA administration increases hippocampal BDNF levels and the conversion of pro‐BDNF to BDNF by plasmin is essential for LTP late‐phases . In addition, a defective tPA/plasmin/PAI‐1‐mediated BDNF maturation has been claimed to be involved in the manifestation of some brain pathologies, such as substance abuse and addiction, depression, and stress …”