Modulation of adenosine concentration by opioid receptor agonists in rat striatum

Halimi, Gilles; Devaux, Christiane; Clot-Faybesse, Olivier; Sampol, J.; Legof, Lydia; Rochat, Hervé; Guieu, Régis

doi:10.1016/s0014-2999(00)00275-2

Cited by 31 publications

(22 citation statements)

References 48 publications

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“…Adenosine is formed from cAMP both inside and outside the cell (Hack and Christie, 2003). Morphine dose dependently increases adenosine release (Sandner-Kiesling et al, 2001), perhaps by inhibition of adenosine uptake (Halimi et al, 2000). Sensitivity to exogenous adenosine is increased at excitatory synapses in the NAc following chronic morphine treatment (Brundege and Williams, 2002), and chronic morphine treatment results in an upregulation of adenosine transporters in the striatum (Kaplan and Leite-Morris, 1997).…”

Section: Discussionmentioning

confidence: 99%

A Differential Role for the Adenosine A2A Receptor in Opiate Reinforcement vs Opiate-Seeking Behavior

Brown

Short²,

Cowen

et al. 2008

Neuropsychopharmacol

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The adenosine A 2A receptor is specifically enriched in the medium spiny neurons that make up the 'indirect' output pathway from the ventral striatum, a structure known to have a crucial, integrative role in processes such as reward, motivation, and drug-seeking behavior. In the present study we investigated the impact of adenosine A 2A receptor deletion on behavioral responses to morphine in a number of reward-related paradigms. The acute, rewarding effects of morphine were evaluated using the conditioned place preference paradigm. Operant self-administration of morphine on both fixed and progressive ratio schedules as well as cue-induced drug-seeking was assessed. In addition, the acute locomotor response to morphine as well as sensitization to morphine was evaluated. Decreased morphine selfadministration and breakpoint in A 2A knockout mice was observed. These data support a decrease in motivation to consume the drug, perhaps reflecting diminished rewarding effects of morphine in A 2A knockout mice. In support of this finding, a place preference to morphine was not observed in A 2A knockout mice but was present in wild-type mice. In contrast, robust cue-induced morphine-seeking behavior was exhibited by both A 2A knockout and wild-type mice after a period of withdrawal. The acute locomotor response to morphine in the A 2A knockout was similar to wild-type mice, yet A 2A knockout mice did not display tolerance to chronic morphine under the present paradigm. Both genotypes display locomotor sensitization to morphine, implying a lack of a role for the A 2A receptor in the drug-induced plasticity necessary for the development or expression of sensitization. Collectively, these data suggest a differential role for adenosine A 2A receptors in opiate reinforcement compared to opiate-seeking.

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Section: Discussionmentioning

confidence: 99%

A Differential Role for the Adenosine A2A Receptor in Opiate Reinforcement vs Opiate-Seeking Behavior

Brown

Short²,

Cowen

et al. 2008

Neuropsychopharmacol

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“…After behavioral testing, rats were anesthetized, and the brain was fixed and sectioned as described to verify infusion sites (47). § § McFarland, K., 34th Annual Meeting of the Society for Neuroscience, Oct. [23][24][25][26][27]2004, San Diego, CA, abstr. 119.2.…”

Section: Methodsmentioning

confidence: 99%

“…Recent evidence suggests that A2a can modify behavioral actions of ethanol, opiates, and cannabinoids (25)(26)(27). In addition, animals treated with A2a agonists or morphine show a similar physical dependence and exhibit bidirectional cross-withdrawal syndromes after blockade by receptor antagonists (28).…”

mentioning

confidence: 99%

Adenosine A2a blockade prevents synergy between μ-opiate and cannabinoid CB1 receptors and eliminates heroin-seeking behavior in addicted rats

Yao

McFarland

Fan

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

101

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Relapse is the most serious limitation of effective medical treatment of opiate addiction. Opiate-related behaviors appear to be modulated by cannabinoid CB1 receptors (CB1) through poorly understood cross-talk mechanisms. Opiate and CB1 receptors are coexpressed in the nucleus accumbens (NAc) and dorsal striatum. These regions also have the highest density of adenosine A2a receptors (A2a) in the brain. We have been investigating the postsynaptic signaling mechanisms of -opiate receptors (MORs) and CB1 receptors in primary NAc͞striatal neurons. In this article, we present evidence that MOR and CB1 act synergistically on cAMP͞PKA signaling in NAc͞striatal neurons. In addition, we find that synergy requires adenosine and A2a. Importantly, an A2a antagonist administered either directly into the NAc or indirectly by i.p. injection eliminates heroin-induced reinstatement in rats trained to self-administer heroin, a model of human craving and relapse. These findings suggest that A2a antagonists might be effective therapeutic agents in the management of abstinent heroin addicts.PKA ͉ addiction ͉ nucleus accumbens ͉ gene activation O piate addiction is a world-wide public health problem with serious socioeconomic ramifications. A major limitation of effective medical treatment is the craving and relapse that develops during attempted abstinence. Opiates bind to three opioid receptors: the ␦-opioid receptor (DOR), -opioid receptor (MOR), and -opioid receptor (KOR) receptors. MOR and DOR are implicated in reward for heroin and morphine, whereas KOR is implicated in aversion (1). MOR antagonists reduce opiate selfadministration, and constitutive deletion of the MOR attenuates opiate-induced conditioned place preference (CPP) (2, 3). Moreover, selective MOR blockade is sufficient to induce conditioned aversion in morphine-dependent animals, presumably because of unopposed activation of KOR (1). The nucleus accumbens (NAc) mediates reward and reinforcement of addictive agents. Thus, inactivation of the NAc core inhibits heroin self-administration (4). We have been investigating postsynaptic signaling mechanisms activated by opiate receptors in NAc͞striatal neurons. We reported that brief exposure of primary NAc͞striatal neurons to MOR agonists for 10 min activates cAMP͞PKA signal transduction followed by stimulation of cAMP response element (CRE)-mediated gene expression hours later (5). We also found that paradoxical stimulation of cAMP͞PKA signaling by G i -coupled MOR depends on preferential binding of the MOR to G␣ i3 ␤␥. Thus, activation of the MOR appears to release ␤␥ subunits from G␣ i3 ; released unbound ␤␥ subunits stimulate adenylyl cyclase (AC) II and IV to increase cAMP production. In turn, this transient increase in cAMP activates PKA and CRE-dependent gene transcription (5).Signaling of G protein-coupled receptors can be modulated by G protein regulators. Recent evidence suggests that an activator of G protein signaling 3 (AGS3), regulates G␣ i3 -coupled receptor signaling by competing with ␤␥ subunits for bin...

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“…In some animal studies, evidence suggests that there may be cross-talk between adenosine and opioid-receptor-mediated neuroprotection (43)(44)(45). In the CNS, adenosine and opioid receptors are physically coupled (46). Morphine is known to elevate adenosine levels via inhibition of adenosine kinase, resulting in locally increased adenosine concentration (46).…”

Section: Discussionmentioning

confidence: 99%

“…In the CNS, adenosine and opioid receptors are physically coupled (46). Morphine is known to elevate adenosine levels via inhibition of adenosine kinase, resulting in locally increased adenosine concentration (46). Although morphine might function in part by increasing the levels of neuroprotective adenosine, the metabolic breakdown of adenosine by xanthine oxidase ultimately to urate generates hydrogen peroxide.…”

Section: Discussionmentioning

confidence: 99%

Use of Opioids in Asphyxiated Term Neonates: Effects on Neuroimaging and Clinical Outcome

et al. 2005

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Perinatal asphyxia is a common cause of neurologic morbidity in neonates who are born at term. Asphyxiated neonates are frequently treated with analgesic medications, including opioids, for pain and discomfort associated with their care. On the basis of previous laboratory studies suggesting that opioids may have neuroprotective effects, we conducted a retrospective review of medical records of 52 neonates who were admitted to our neonatal intensive care unit between 1995 and 2002 and had undergone magnetic resonance imaging (MRI) of the brain. Our review revealed that 33% of neonates received morphine or fentanyl. The neonates who received opioids also had experienced hypoxic/ischemic insults of greater magnitude as suggested by higher plasma lactate levels and lower 5-min Apgar scores. It is interesting that the MRI studies of neonates who were treated with opioids during the first week of life demonstrated significantly less brain injury in all regions studied. More important, follow-up studies of a subgroup of opioid-treated neonates whose MRI scans were obtained in the second postnatal week had better long-term neurologic outcomes. Our results suggest that the use of opioids in the first week of life after perinatal asphyxia have no significant long-term detrimental effects and may increase the brain's resistance to hypoxicischemic insults. Immediately after birth, asphyxiated neonates who are admitted to the neonatal intensive care unit (NICU) experience repetitive invasive and noninvasive procedures, such as endotracheal intubation, arterial line placement, i.v. catheterization, intramuscular injections, and endotracheal suctioning. Although necessary steps in the care of these neonates, such procedures result in pain and prolonged stress during a critical time associated with rapid brain growth and development (1). In addition to causing abnormalities in respiration, heart rate, and blood pressure (2), neonatal pain may alter neuronal and synaptic organization (3) and potentiate the effects of hypoxia (4). Animal studies show that exposure to untreated repetitive pain and stress results in prolonged firing of C-fibers, causing glutamate-induced N-methyl-D-aspartate (NMDA) receptor activation (5). This may augment hypoxia-induced glutamate release, an important mechanism that contributes to neuronal injury or death.Opioid analgesics such as morphine and fentanyl are administered to critically ill neonates in an effort to reduce pain and stress (6). The antinociceptive effects of these medications are mediated through a combined presynaptic and postsynaptic hyperpolarization, leading to reductions in the release of and sensitivity to endogenous mediators such as glutamate (7,8). These data suggest that opioids might confer neuroprotection by decreasing excitotoxicity through reductions in glutamate release, leading to greater overall reductions in neurologic damage. Cell culture studies indicate that both endogenous and exogenous opioids can protect cortical neurons from hypoxiainduced cell death (9,10) an...

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Modulation of adenosine concentration by opioid receptor agonists in rat striatum

Cited by 31 publications

References 48 publications

A Differential Role for the Adenosine A2A Receptor in Opiate Reinforcement vs Opiate-Seeking Behavior

A Differential Role for the Adenosine A2A Receptor in Opiate Reinforcement vs Opiate-Seeking Behavior

Adenosine A2a blockade prevents synergy between μ-opiate and cannabinoid CB1 receptors and eliminates heroin-seeking behavior in addicted rats

Use of Opioids in Asphyxiated Term Neonates: Effects on Neuroimaging and Clinical Outcome

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