Opioids intrinsically inhibit the genesis of mouse cerebellar granule neuron precursors in vitro: differential impact of μ and δ receptor activation on proliferation and neurite elongation

Abstract

Although opioids are known to affect neurogenesis in vivo, it is uncertain the extent to which opioids directly or indirectly affect the proliferation, differentiation or death of neuronal precursors. To address these questions, the intrinsic role of the opioid system in neurogenesis was systematically explored in cerebellar external granular layer (EGL) neuronal precursors isolated from postnatal mice and maintained in vitro. Isolated neuronal precursors expressed proenkephalin-derived peptides, as well as specific mu and delta, but negligible kappa, opioid receptors. The developmental effects of opioids were highly selective. Morphine-induced mu receptor activation inhibited DNA synthesis, while a preferential delta2-receptor agonist ([D-Ala2]-deltorphin II) or Met-enkephalin, but not the delta1 agonist [D-Pen2, D-Pen5]-enkephalin, inhibited differentiation within the same neuronal population. If similar patterns occur in the developing cerebellum, spatiotemporal differences in endogenous mu and delta opioid ligand-receptor interactions may coordinate distinct aspects of granule neuron maturation. The data additionally suggest that perinatal exposure to opiate drugs of abuse directly interfere with cerebellar maturation by disrupting normal opioid signalling and inhibiting the proliferation of granule neuron precursors.

Modulation of neuronal CXCR4 by the μ-opioid agonist DAMGO

“…These are critical issues because CXCL12 regulates neuronal function in both developing and mature neurons and affects multiple behaviors of neuronal and non-neuronal cells . Of note, CXCL12 plays a crucial role in the proliferation and migration of neural progenitor cells (Klein et al, 2001;Stumm et al, 2003;Belmadani et al, 2005), whereas opiates-including morphine-are known to inhibit neurogenesis in vivo and in vitro (Eisch et al, 2000;Hauser et al, 2000). Furthermore, the activation of MOR by drugs of abuse may exacerbate neurotoxicity of viral proteins, such as the HIV-1 gp120 that acts as a partial CXCR4 agonist (Khan et al, 2004).…”

“…The crucial role of this chemokine/receptor pair in the central nervous system (CNS) in vivo was demonstrated by studies on animals lacking CXCL12 or CXCR4, showing serious deficits in hippocampus/ cerebellum development (Zou et al, 1998;Lu et al, 2002). Interestingly, morphine and other μ-opioid receptor (MOR) agonists inhibit neurogenesis in these brain areas (Eisch et al, 2000;Hauser et al, 2000).…”

Effect of nicotine on cerebellar granule neuron development

“…Neurotransmitters can act as signals to influence neuronal maturation and can differentially regulate cellular proliferation, migration, survival and differentiation (Lipton & Kater, 1989;Schwartz, 1992;Hauser & Mangoura, 1998;Hauser et al, 2000). The abundance of cholinergic synthetic enzymes and receptors in the postnatal cerebellum (Brooksbank et al, 1978;Court et al, 1993;1995) is consistent with the notion that acetylcholine is important during postnatal cerebellar development.…”

“…As noted, [ 3 H]-thymidine incorporation was used to estimate the proportion of dividing neuroblasts, while DNA content was used to estimate EGL cell numbers (all nondividing diploid cells contain the same amount of DNA). DNA content was assessed at 48 h following nicotine treatment to allow sufficient time for changes in DNA synthesis (determined at 24 h) to be manifest as actual changes in cell numbers, as previously determined using other drugs (Hauser et al, 2000). The effect of nicotine on DNA synthesis was concentration-dependent ( Fig.…”

Cognitive Impairments in Drug Addicts

“…The effect of morphine is known to be mediated mainly through the MOP receptor although, at high concentrations, this opiate is known also to interact with both the delta-opioid peptide (DOP) and the KOP receptors. Furthermore, it appears that the opioid receptor subtypes (MOP, DOP, and KOP) may regulate different aspects of neuronal development (Hauser et al, 2000). Evidence suggesting that the MOP receptor could play an important role in regulating progenitor cell survival has recently been described (Harburg et al, 2007).…”