Effect of chronic morphine on the dentate gyrus neurogenic microenvironment

Abstract

Opiates, such as morphine, decrease neurogenesis in the postnatal hippocampal subgranular zone (SGZ) by inhibiting progenitor proliferation and maturation. However, it is not known how morphine influences the growth factors and vasculature that encompass the neurogenic SGZ microenvironment. We examined morphine’s effect on pro- and anti-proliferative factors in the dentate gyrus (DG; Experiment 1) as well as the DG neurovasculature itself (Experiment 2). For Experiment 1, mice were implanted with sham or morphine pellets subcutaneously (s.c.; 0 and 48 hrs) and were decapitated 24 or 96 hrs later. One brain hemisphere was post fixed to examine proliferation by immunohistochemistry, and a DG-enriched sample was dissected from the other hemisphere to examine the neurogenic microenvironment via immunoblotting for known pro- and anti-proliferative factors. Consistent with previous results, morphine decreased the number of proliferating cells in the SGZ, as the number of Ki67-immunoreactive (IR) cells was decreased at 96 hrs. Morphine did not alter DG levels of the pro-proliferative factor BDNF, anti-proliferative factor IL1β, or their receptors TrkB and IL1R1 at either time point. However, morphine increased the pro-proliferative factor VEGF at 96 hrs. Given that VEGF is also a potent angiogenic factor, Experiment 2 examined whether the morphine-induced increase in VEGF correlated with altered DG neurovasculature. Mice were implanted with morphine pellets as in Experiment 1, and two hrs before perfusion (24 or 96 hrs) were administered bromodeoxyuridine intraperitoneally (BrdU, i.p.; 150 mg/kg). Tissue was co-stained for BrdU and the endothelial cell marker endoglin to enable examination of DG vessels and proximity of BrdU-IR cells to endoglin-IR vessels. At 96 hrs, endoglin-IR vessel area and perimeter were increased, but proximity of BrdU-IR cells to endoglin-IR vessels remained unchanged. These data suggest that following chronic morphine exposure, factors within the neurogenic microenvironment are maintained or upregulated to compensate for decreased SGZ proliferation.

The Noradrenergic Component in Tapentadol Action Counteractsμ-Opioid Receptor–Mediated Adverse Effects on Adult Neurogenesis

“…7A, we observed no significant difference in the absolute number of BrdU 1 cells in the SGZ or GCL of mice treated with 20 mg/kg tapentadol in the 24-hour group compared with vehicle (mean 588 6 87.5 and 488 6 186.1 BrdU 1 cells in the SGZ in vehicle-and tapentadoltreated mice, respectively; mean 888 6 297.3 and 637 6 165.4 BrdU 1 cells in the GCL in vehicle-and tapentadol-treated mice, respectively). These data confirm that, unlike morphine (Eisch et al, 2000;Arguello et al, 2009), chronic tapentadol treatment has no negative effects on the proliferative rate of adult hippocampal neural progenitors. In the 21-day group, we phenotypically characterized BrdU 1 cells by performing a triple immunolabeling with antibodies raised against BrdU, NeuN (a marker of mature neurons), and GFAP (a marker of astrocytes).…”

“…In rodents, hippocampal adult neurogenesis is profoundly affected by chronically administered opiates. Adult in vivo exposure to m-opioid receptor (MOR) agonists decreases SGZ progenitor proliferation, maturation, and survival of new neurons (Eisch et al, 2000;Mandyam et al, 2004;Kahn et al, 2005;Eisch and Harburg, 2006;Arguello et al, 2009). On the basis of these observations, it can be hypothesized that alteration in hippocampal neurogenesis may represent one mechanism by which opiates may exert long-lasting effects on the neural circuitry involved in learning, memory, and cognition.…”

Brain-Derived Neurotrophic Factor and Neuropsychiatric Disorders

“…BDNF mRNA expression is also enhanced after long-term withdrawal from self-administered heroin (Kuntz-Melcavage et al, 2009). Longterm morphine administration does not seem to affect BDNF or TrkB protein expression in hippocampus (Arguello et al, 2009).…”

Alterations of neuronal precursor cells in stages of human adult neurogenesis in heroin addicts

“…Actually, none of these dealt with the consequences of chronic drug addiction in human brains. While several animal studies suggested a negative influence of drug addiction on adult neurogenesis (Arguello et al, 2009Chambers, 2013;Eisch et al, 2000;Fischer et al, 2008;Kahn et al, 2005;Mandyam and Koob, 2012), human data in this context are still not available. The present study describes, for the first time, qualitative and quantitative changes of immunohistochemical staining patterns associated with adult neurogenesis in human healthy controls compared to cases of drug addicts with known heroin abuse, in early and middle adulthood.…”