Mu-opioid receptors modulate the stability of dendritic spines

Abstract

Opioids classically regulate the excitability of neurons by suppressing synaptic GABA release from inhibitory neurons. Here, we report a role for opioids in modulating excitatory synaptic transmission. By activating ubiquitously clustered -opioid receptor (MOR) in excitatory synapses, morphine caused collapse of preexisting dendritic spines and decreased synaptic ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Meanwhile, the opioid antagonist naloxone increased the density of spines. Chronic treatment with morphine decreased the density of dendritic spines even in the presence of Tetrodotoxin, a sodium channel blocker, indicating that the morphine's effect was not caused by altered activity in neural network through suppression of GABA release. The effect of morphine on dendritic spines was absent in transgenic mice lacking MORs and was blocked by CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH 2), areceptor antagonist. These data together with others suggest that endogenous opioids and͞or constitutive activity of MORs participate in maintaining normal morphology and function of spines, challenging the classical model of opioids. Abnormal alteration of spines may occur in drug addiction when opioid receptors are overactivated by exogenous opiates. synaptic plasticity T he children of mothers who abuse opiate narcotics during pregnancy are known to exhibit various clinical deficits in brain growth and psychological behaviors (1, 2). Chronic exposure to opiates can impair learning and memory in humans and other mammals (3,4). In the classical model, opioids acutely affect the excitability of neurons by suppressing the presynaptic release of GABAergic inhibitory neurons (5, 6). However, there is an unsolved puzzle for this classical model. In addition to GABAergic neurons, -opioid receptors (MORs) extensively exist in glutamatergic neurons such as pyramidal neurons in the cortex and the hippocampus (7). It has been previously reported that the density of dendritic spines in animals that have been chronically treated with morphine is lower than that in untreated control animals (8, 9). This difference could be caused by altered formation, maturation, plasticity, and͞or stabilization. To distinguish these possibilities, time-lapse, live-imaging experiments are required to examine the temporal dynamics in the morphine-induced changes in dendritic spines. Hence, in this study, we have used a longitudinal live-imaging system to examine opioid-induced changes in dendritic spines in the same neurons for several days. Our live-imaging data together with electrophysiological data revealed additional roles for opioids: destabilizing dendritic spines and decreasing synaptic ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Plasticity of dendritic spines and trafficking of AMPA receptors play important roles in synaptic plasticity, a cellular model for learning and memory (10, 11). Opiate tolerance and dependence have been proposed to present a pathological form of learning and memory (12). Rec...

Effects of Opiate Drugs on Fas-Associated Protein with Death Domain (FADD) and Effector Caspases in the Rat Brain: Regulation by the ERK1/2 MAP Kinase Pathway

“…In the current study, FADD, the adaptor protein that couples Fas to caspase-8 and transmits the death signal, followed an opposite modulation. Together, the results suggest that possible apoptotic signals engaged by Fas activation (see Tegeder and Geisslinger, 2004;Liao et al, 2005) would be offset by decreased signal transduction through FADD and effector caspases-8/3 (not altered by any opiate treatment). Since the activation of ERK1/2 is crucial for various antiapoptotic mechanisms (Wada and Penninger, 2004), including protection against Fas-mediated apoptosis (Holmström et al, 1999(Holmström et al, , 2000, it is tempting to conclude that opiate drugs (and specifically the d-agonists) could promote survival signals in the brain through inhibition of FADD, which in turn is dependent on the activation of ERK1/2 signaling.…”

Cholesterol level influences opioid signaling in cell models and analgesia in mice and humans

“…In addition, the relationship between cholesterol level and opioid signaling was tested in the primary cultures of rat hippocampal neurons that have OPRM1 expressed endogenously ( 15 ). Correlation between cholesterol level and in vivo opioid functions was also tested by manipulating the cholesterol level in mice and by analyzing the clinical records of patients.…”

“…HEK293 cells that stably express OPRM1 and primary cultures of rat hippocampal neurons were prepared as described previously ( 15,16 ). Opioid-induced AC inhibition was quantifi ed by measuring the intracellular cAMP level according to the previous reports ( 17 ).…”

Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction

“…As a measurement of neuronal damage, we focused on loss of dendritic spines, a highly consistent and likely causative event in HAND development (14,15,38,39). Importantly, chronic treatment with morphine reduces spine density and excitatory synaptic activity (40), although the mechanisms involved are complex and not yet defined. Our present observations suggest that opiates and HIV negatively regulate neuronal CXCL12/CXCR4 signaling within human and nonhuman primates and identify decreased dendritic spine density as a consequence of FHC induction.…”