Expression of BDNF and TrkB Phosphorylation in the Rat Frontal Cortex During Morphine Withdrawal are NO Dependent

Abstract

Nitric oxide (NO) mediates pharmacological effects of opiates including dependence and abstinence. Modulation of NO synthesis during the induction phase of morphine dependence affects manifestations of morphine withdrawal syndrome, though little is known about mechanisms underlying this phenomenon. Neurotrophic and growth factors are involved in neuronal adaptation during opiate dependence. NO-dependent modulation of morphine dependence may be mediated by changes in expression and activity of neurotrophic and/or growth factors in the brain. Here, we studied the effects of NO synthesis inhibition during the induction phase of morphine dependence on the expression of brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and insulin-like growth factor 1 (IGF1) as well as their receptors in rat brain regions after spontaneous morphine withdrawal in dependent animals. Morphine dependence in rats was induced within 6 days by 12 injections of morphine in increasing doses (10-100 mg/kg), and NO synthase inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) (10 mg/kg) was given 1 h before each morphine injection. The expression of the BDNF, GDNF, NGF, IGF1, and their receptors in the frontal cortex, striatum, hippocampus, and midbrain was assessed 40 h after morphine withdrawal. L-NAME treatment during morphine intoxication resulted in an aggravation of the spontaneous morphine withdrawal severity. Morphine withdrawal was accompanied by upregulation of BDNF, IGF1, and their receptors TrkB and IGF1R, respectively, on the mRNA level in the frontal cortex, and only BDNF in hippocampus and midbrain. L-NAME administration during morphine intoxication decreased abstinence-induced upregulation of these mRNAs in the frontal cortex, hippocampus and midbrain. L-NAME prevented from abstinence-induced elevation of mature but not pro-form of BDNF polypeptide in the frontal cortex. While morphine abstinence did not affect TrkB protein levels as well as its phosphorylation status, inhibition of NO synthesis decreased levels of phosphorylated TrkB after withdrawal. Thus, NO signaling during induction of dependence may be involved in the mechanisms of BDNF expression and processing at abstinence, thereby affecting signaling through TrkB in the frontal cortex.

Naringenin induces laxative effects by upregulating the expression levels of c-Kit and SCF, as well as those of aquaporin 3 in mice with loperamide-induced constipation

“…NOS is a key factor which produces endogenous NO that widely exists in gastrointestinal tissues and plays an important role in modulating gastrointestinal movements. The increasing level of NO has been shown to be involved in colonic motility disorders of constipation ( 33 ). The downregulation of NOS can reduce the production of NO, which is a feasible way to relieve constipation ( 34 ).…”

Update of neurotrophic factors in neurobiology of addiction and future directions

“…Nitric oxide (NO) signaling can also regulate the expression of BDNF, GDNF and their receptors in different brain regions of morphine-dependent rats after spontaneous morphine withdrawal (Peregud et al, 2015). In these experiments morphine withdrawal was accompanied by an increased expression of BDNF mRNA in the frontal cortex, hippocampus, and midbrain, while the mRNA levels of the BDNF receptor TrkB were increased only in the frontal cortex.…”

“…In these experiments morphine withdrawal was accompanied by an increased expression of BDNF mRNA in the frontal cortex, hippocampus, and midbrain, while the mRNA levels of the BDNF receptor TrkB were increased only in the frontal cortex. Interestingly, the authors showed that administration of the NO synthase inhibitor L-N G -nitroarginine methyl ester (L-NAME) during morphine intoxication prevented the increase in BDNF and TrkB mRNA expression, suggesting that NO signaling during the development of morphine dependence can modulate the BDNF/TrkB pathway (Peregud et al, 2015). …”

The Ameliorative Effects of Isorhynchophylline on Morphine Dependence Are Mediated Through the Microbiota-Gut-Brain Axis

“…This indicates that the GM is connected to the CNS through BDNF. Morphine use has been shown to increase the expression of BDNF and NTRK2 in the brain ( Numan et al, 1998 ; Akbarian et al, 2002 ; Bolanos and Nestler, 2004 ; Vargas-Perez et al, 2009 ; Koo et al, 2012 ; Mashayekhi et al, 2012 ; Peregud et al, 2016 ; Naghshvarian et al, 2017 ). In our study, the mRNA expression of bndf and ntrk2 in zebrafish increased significantly after morphine administration, while isorhynchophylline reversed this change.…”