A neuroactive steroid, dehydroepiandrosterone sulfate, prevents the development of morphine dependence and tolerance via c-fos expression linked to the extracellular signal-regulated protein kinase

Ren, Xiuhai; Noda, Yukihiro; Mamiya, Takayoshi; Nagai, Taku; Nabeshima, Toshitaka

doi:10.1016/j.bbr.2003.10.013

Cited by 59 publications

(41 citation statements)

References 34 publications

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“…In particular, morphine-induced hyperlocomotion and CPP could be modulated by σ 1 -receptor ligands (T. Maurice, unpublished observations). Moreover, the naloxone-precipitated morphine withdrawal symptoms could be blocked by administration of the σ 1 agonist igmesine (T. Maurice, unpublished observations) as well as DHEA in a NE-100-sensitive manner, thus confirming the involvement of the σ 1 -receptor subtype, as stated by Ren et al (207).…”

Section: Neurosteroids and σ Drugs May Influence Abused Drug Intakesupporting

confidence: 68%

The Sigma1 Protein as a Target for the Non-genomic Effects of Neuro(active)steroids: Molecular, Physiological, and Behavioral Aspects

2006

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Abstract. Steroids synthesized in the periphery or de novo in the brain, so called 'neurosteroids', exert both genomic and nongenomic actions on neurotransmission systems. Through rapid modulatory effects on neurotransmitter receptors, they influence inhibitory and excitatory neurotransmission. In particular, progesterone derivatives like 3α-hydroxy-5α-pregnan-20-one (allopregnanolone) are positive allosteric modulators of the γ-aminobutyric acid type A (GABA A ) receptor and therefore act as inhibitory steroids, while pregnenolone sulphate (PREGS) and dehydroepiandrosterone sulphate (DHEAS) are negative modulators of the GABA A receptor and positive modulators of the N-methyl-D-aspartate (NMDA) receptor, therefore acting as excitatory neurosteroids. Some steroids also interact with atypical proteins, the sigma (σ) receptors. Recent studies particularly demonstrated that the σ 1 receptor contributes effectively to their pharmacological actions. The present article will review the data demonstrating that the σ 1 receptor binds neurosteroids in physiological conditions. The physiological relevance of this interaction will be analyzed and the impact on physiopathological outcomes in memory and drug addiction will be illustrated. We will particularly highlight, first, the importance of the σ 1 -receptor activation by PREGS and DHEAS which may contribute to their modulatory effect on calcium homeostasis and, second, the importance of the steroid tonus in the pharmacological development of selective σ 1 drugs.

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Section: Neurosteroids and σ Drugs May Influence Abused Drug Intakesupporting

confidence: 68%

The Sigma1 Protein as a Target for the Non-genomic Effects of Neuro(active)steroids: Molecular, Physiological, and Behavioral Aspects

2006

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“…Chronic morphine treatment causes increases in Ca 2ϩ levels and alterations of ERK (Ren et al, 2004), CaMKII (Lu et al, 2000;Liang et al, 2004), and CREB (Nestler, 2001). Our Western blotting analysis showed that morphine exposure and withdrawal-induced increases of levels of phosphorylation of NR1, NR2B, ERK1/2, CaMKII, and CREB protein were significantly reduced by MMP-9 inhibitor MMP9i (5 g, i.t.)…”

Section: Resultsmentioning

confidence: 65%

Spinal Matrix Metalloproteinase-9 Contributes to Physical Dependence on Morphine in Mice

Li¹,

Han²,

Liu³

et al. 2010

J. Neurosci.

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Preventing and reversing opioid dependence continues to be a clinical challenge and underlying mechanisms of opioid actions remain elusive. We report that matrix metalloproteinase-9 (MMP-9) in the spinal cord contributes to development of physical dependence on morphine. Chronic morphine exposure and naloxone-precipitated withdrawal increase activity of spinal MMP-9. Spinal inhibition or targeted mutation of MMP-9 suppresses behavioral signs of morphine withdrawal and the associated neurochemical alterations. The increased MMP-9 activity is mainly distributed in the superficial dorsal horn and colocalized primarily with neurons and small numbers of astrocytes and microglia. Morphine exposure and withdrawal increase phosphorylation of NR1 and NR2B receptors, ERK1/2, calmodulin-dependent kinase II, and cAMP response element binding proteins; and such phosphorylation is suppressed by either spinal inhibition or targeted mutation of MMP-9. Further, spinal administration of exogenous MMP-9 induces morphine withdrawal-like behavioral signs and mechanical allodynia, activates NR1 and NR2 receptors, and downregulates integrin-␤1, while a function-neutralizing antibody against integrin-␤1 suppresses MMP-9-induced phosphorylation of NR1 and NR2B. Morphine withdrawal-induced MMP-9 activity is also reduced by an nNOS inhibitor. Thus, we hypothesize that spinalMMP-9maycontributetothedevelopmentofmorphinedependenceprimarilythroughneuronalactivationandinteractionwithNR1and NR2B receptors via integrin-␤1 and NO pathways. The other gelatinase, MMP-2, is not involved in morphine dependence. Inhibiting spinal MMP-9 or MMP-2 reduces chronic and/or acute morphine tolerance. This study suggests a novel therapeutic approach for preventing, minimizing, or reversing opioid dependence and tolerance.

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“…Because there is not evidence that PKA activation is required for stimulation of MAPK induced by morphine withdrawal in the heart (Almela et al, 2007b), this study evaluates the cross-talk between cAMP/PKA and ERKs and subsequently phosphorylation of TH at Ser31 in morphine-dependent rats. These two ancient and conserved signaling pathways are involved in various central processes, including drug addiction (Ren et al, 2004) Although several signaling pathways can mediate activitydependent phosphorylation of TH, the only protein kinase reported to phosphorylate TH at Ser31 in vitro was ERK (Haycock et al, 1992;Lindgren et al, 2002). In situ phosphorylation of TH at Ser31 increases TH activity and catecholamine synthesis (Dunkley et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…The ERK signaling pathway could be important as a regulator of cardiac function (for review, see Michel et al, 2001). Recently, several studies have shown that this pathway contributes to naloxone-precipitated withdrawal in morphine-dependent rats (Ren et al, 2004;Almela et al, 2007bAlmela et al, , 2008.…”

mentioning

confidence: 99%

Cross-Talk between Protein Kinase A and Mitogen-Activated Protein Kinases Signalling in the Adaptive Changes Observed during Morphine Withdrawal in the Heart

Almela

Atucha²,

Milanés³

et al. 2009

J Pharmacol Exp Ther

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Our previous studies have shown that morphine withdrawal induced an increase in the expression of protein kinase (PK) A and mitogen-activated extracellular kinase (MAPK) pathways in the heart during morphine withdrawal. The purpose of the present study was to evaluate the interaction between PKA and extracellular signal-regulated kinase (ERK) signaling pathways mediating the cardiac adaptive changes observed after naloxone administration to morphine-dependent rats. Dependence on morphine was induced by a 7-day subcutaneous implantation of morphine pellets. Morphine withdrawal was precipitated on day 8 by an injection of naloxone (2 mg/kg). ERK1/2 and tyrosine hydroxylase (TH) phosphorylation was determined by quantitative blot immunolabeling using phosphorylation statespecific antibodies. Naloxone-induced morphine withdrawal activates ERK1/2 and phosphorylates TH at Ser31 in the right and left ventricle, with an increase in the mean arterial blood pressure and heart rate. When N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004), a PKA inhibitor, was infused, concomitantly with morphine, it diminished the expression of ERK1/2. In contrast, the infusion of calphostin C (a PKC inhibitor) did not modify the morphine withdrawal-induced activation of ERK1/2. The ability of morphine withdrawal to activate ERK that phosphorylates TH at Ser31 was reduced by HA-1004. The present findings demonstrate that the enhancement of ERK1/2 expression and the phosphorylation state of TH at Ser31 during morphine withdrawal are dependent on PKA and suggest cross-talk between PKA and ERK1/2 transduction pathway mediating morphine withdrawal-induced activation (phosphorylation) of TH.

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A neuroactive steroid, dehydroepiandrosterone sulfate, prevents the development of morphine dependence and tolerance via c-fos expression linked to the extracellular signal-regulated protein kinase

Cited by 59 publications

References 34 publications

The Sigma1 Protein as a Target for the Non-genomic Effects of Neuro(active)steroids: Molecular, Physiological, and Behavioral Aspects

The Sigma1 Protein as a Target for the Non-genomic Effects of Neuro(active)steroids: Molecular, Physiological, and Behavioral Aspects

Spinal Matrix Metalloproteinase-9 Contributes to Physical Dependence on Morphine in Mice

Cross-Talk between Protein Kinase A and Mitogen-Activated Protein Kinases Signalling in the Adaptive Changes Observed during Morphine Withdrawal in the Heart

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