Endogenous opioids upregulate brain‐derived neurotrophic factor mRNA through δ‐ and µ‐opioid receptors independent of antidepressant‐like effects

Abstract

Systemic administration of δ-opioid receptor (DOR) agonists decreases immobility in the forced swim test (FST) and increases brain-derived neurotrophic factor (BDNF) mRNA expression in rats, indicating that DOR agonists may have antidepressant-like effects. The aim of this study was to investigate the effects of central administration of endogenous opioid peptides on behavior in the FST and on brain BDNF mRNA expression in rats. Effects of endogenous opioids were compared with those produced by intracerebroventricular administration of a selective non-peptidic DOR agonist (+)BW373U86. Antidepressant-like effects were measured by decreased immobility in the FST. BDNF mRNA expression was determined by in situ hybridization. Centrally administered (+) BW373U86 decreased immobility and increased BDNF mRNA expression in the frontal cortex through a DOR-mediated mechanism, because these effects were blocked by the DOR antagonist naltrindole, but not by the μ-opioid receptor (MOR) antagonist naltrexone (NTX) or the κ-opioid receptor antagonist nor-binaltorphimine. Of all the endogenous opioids tested, only leuand metenkephalin produced behavioral effects like those of (+)BW373U86 in the FST. Unlike (+) BW373U86, the enkephalins upregulated BDNF mRNA expression in the hippocampus through DOR-and MOR-mediated mechanisms. β-Endorphin, endomorphin-1 and endomorphin-2 significantly increased BDNF mRNA levels in the frontal cortex, hippocampus and amygdala without reducing immobility; and most of these effects were reversed by NTX. This study is the first to provide evidence that endogenous opioids can upregulate BDNF mRNA expression through the DOR and MOR, and that leu-and met-enkephalin have similar pharmacological profiles to synthetic DOR agonists in producing antidepressant-like effects.

Profiling of behavioral changes and hippocampal gene expression in mice chronically treated with the SSRI paroxetine

“…The conflicting results might be explained by several methodological differences, of which the shorter treatment period might be the most critical factor (Boehm et al 2006;Shishinka et al 2007). A recent study reports the effects of enkephalins on behavior and BDNF expression in the hippocampus (Zhang et al 2006). In our study, we also determined a robust increase in Bdnf expression in the hippocampus of paroxetine-treated DBA/2 mice.…”

In vivo BDNF modulation of hippocampal mossy fiber plasticity induced by high frequency stimulation

“…Enhancement in synaptic strength as well synaptic reorganization after HFS at this pathway has been found to be NMDA receptor-independent and dependent on the activation of opioid receptors, which are expressed in high concentrations at this area (Derrick et al, 1991;Escobar et al, 1997). It has also been reported that opioid receptor activation increases BDNF mRNA in hippocampal neurons (Zhang et al, 2006). Some of BDNF's principal targets are the activation of adenylyl cyclase that activates protein kinase A (PKA) and metabotropic glutamate receptors (mGluR), which have been reported to be essential for hippocampal mossy fiber LTP (Henze et al, 2000).…”

The Endomorphin System and Its Evolving Neurophysiological Role

“…Recently, centrally administered endomorphin-1 and -2 were shown to increase BDNF mRNA expressions in hippocampus and amygdala (Zhang et al, 2006). BDNF participates in synaptic plasticity mechanisms, such as long-term potentiation, learning, and memory (Huang and Reichardt, 2001;Malcangio and Lessmann, 2003).…”

“…Zhang et al (2006) examined the effects of i.c.v. administered endomorphins, at doses active in other behavioral studies (30 and 90 nmol/animal, i.e., ϳ20 and 50 g/animal), on animal behavior in the FST and on brain-derived neurotrophic factor (BDNF) gene expression in rats.…”

“…Zhang et al (2006) performed the FST 30 min after central administration of endomorphins, which is far too late. As was shown in our report, endomorphins, because of rapid enzymatic degradation, produced a significant antidepressant effect only 10 to 15 min after i.c.v.…”