Modulation of Opiate-Related Signaling Molecules in Morphine-Dependent Conditioned Behavior: Conditioned Place Preference to Morphine Induces CREB Phosphorylation

Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology (Impact Factor: 7.05). 12/2009; 35(4):955-66. DOI: 10.1038/npp.2009.199
Source: PubMed


Opiate addiction is a chronic, relapsing behavioral disorder where learned associations that develop between the abused opiate and the environment in which it is consumed are brought about through Pavlovian (classical) conditioning processes. However, the signaling mechanisms/pathways regulating the mechanisms that underlie the responses to opiate-associated cues or the development of sensitization as a consequence of repeated context-independent administration of opiates are unknown. In this study we examined the phosphorylation levels of various classic signaling molecules in brain regions implicated in addictive behaviors after acute and repeated morphine administration. An unbiased place conditioning protocol was used to examine changes in phosphorylation that are associated with (1) the expression of the rewarding effects of morphine and (2) the sensitization that develops to this effect. We also examined the effects of a delta-receptor antagonist on morphine-induced conditioned behavior and on the phosphorylation of classic signaling molecules in view of data showing that blockade of delta-opioid receptor (deltaOR) prevents the development of sensitization to the rewarding effects of morphine. We find that CREB phosphorylation is specifically induced upon the expression of a sensitized response to morphine-induced conditioned behavior in brain areas related to memory consolidation, such as the hippocampus and cortex. A similar effect is also observed, albeit to a lesser extent, in the case of the GluR1 subunit of AMPA glutamate receptor. These increases in the phosphorylation levels of CREB and pGluR1 are significantly blocked by pretreatment with a deltaOR antagonist. These results indicate a critical role for phospho-CREB, AMPA, and deltaOR activities in mediating the expression of a sensitized response to morphine-dependent conditioned behavior.

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Available from: Srinivas Gullapalli,
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    • "Exogenous opioids, ranging from opiate derivatives (e.g., morphine) to prescription opioid analgesics (e.g., oxycodone), interact with opioid receptors in the body to produce effects ranging from therapeutic to pathological (Shurman et al., 2010). Similar to alcohol, morphine (5 mg/kg, 20 min pretreatment) acutely elicits ERK phosphorylation in the rodent extended amygdala through a dopamine D1 receptor-dependent process (Valjent et al., 2004), while higher doses (10–50 mg/kg) produce no changes or even decreases in neuronal pERK levels, depending on brain region (Eitan et al., 2003; Muller and Unterwald, 2004; Valjent et al., 2004; Moron et al., 2010). In striatal neurons, mu-opioid receptor activation of the ERK cascade also appears to require receptor phosphorylation by G protein-coupled receptor kinase (GRK3) and arrestin3 recruitment (Macey et al., 2006). "
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    ABSTRACT: Early pioneering work in the field of biochemistry identified phosphorylation as a crucial post-translational modification of proteins with the ability to both indicate and arbitrate complex physiological processes. More recent investigations have functionally linked phosphorylation of extracellular signal-regulated kinase (ERK) to a variety of neurophysiological mechanisms ranging from acute neurotransmitter action to long-term gene expression. ERK phosphorylation serves as an intracellular bridging mechanism that facilitates neuronal communication and plasticity. Drugs of abuse, including alcohol and opioids, act as artificial yet powerful rewards that impinge upon natural reinforcement processes critical for survival. The graded progression from initial exposure to addiction (or substance dependence) is believed to result from drug- and drug context-induced adaptations in neuronal signaling processes across brain reward and stress circuits following excessive drug use. In this regard, commonly abused drugs as well as drug-associated experiences are capable of modifying the phosphorylation of ERK within central reinforcement systems. In addition, chronic drug and alcohol exposure may drive ERK-regulated epigenetic and structural alterations that underlie a long-term propensity for escalating drug use. Under the influence of such a neurobiological vulnerability, encountering drug-associated cues and contexts can produce subsequent alterations in ERK signaling that drive relapse to drug and alcohol seeking. Current studies are determining precisely which molecular and regional ERK phosphorylation-associated events contribute to the addiction process, as well as which neuroadaptations need to be targeted in order to return dependent individuals to a healthy state.
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    • "Induction of immediate early genes (IEGs) is viewed as an important step in the formation of long-lasting neuroadaptations underlying learning and memory as well as the persistence of some psychoactive drugs [12] [13]. Much attention has been paid to the effects of psychostimulants on the transcription factorcoding IEGs, such as c-fos and cAMP response element binding protein (CREB), but less is known about their influence on the effector IEGs [14] [15]. Among the effector IEGs, activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) "
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    • "nges have also been explored . While acute morphine attenuates prefrontal cortical cell activation by excitatory afferents ( Giacchino and Henriksen , 1998 ) , following chronic exposure , morphine withdrawal significantly upregulates glutamatergic synaptic transmission via presynaptic mechanisms involving the cAMP pathway ( Bie , et al . , 2005 , Moron , et al . , 2010 ) , PKC activation ( Bie , et al . , 2005 , Chen and Huang , 1991 ) . Ionotropic glutamate receptors have important regulatory roles related to opioid system function in the amygdala , particularly through their contribution to learning and memory . Opioid exposure leads to definitive effects on both the AMPAR and NMDAR systems that can"
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