Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A growing body of evidence supports an important role of the transcription factor cAMP responsive element binding protein (CREB) in mediating opioid-induced changes in the cAMP pathway. Regulation of CREB and subsequent changes in gene expression may underlie some long-term cellular adaptations associated with the administration of opioid drugs. The effect of morphine on the level of the transcription factor CREB, as well as CREB phosphorylation, was investigated in NG108-15 cells. Morphine and the delta-opioid receptor agonist [D-Pen(2,5)]enkephalin (DPDPE) produced a dose-dependent increase in CREB phosphorylation. The effect was reversed by naloxone and naltrindole, respectively. The calmodulin antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7), the protein kinase inhibitor staurosporine, as well as 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7), an inhibitor of protein kinase C and cAMP-dependent protein kinase, but not N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride (H-8), an inhibitor of cAMP- and cGMP-dependent protein kinase, blocked the opioid-induced CREB phosphorylation. The obtained results suggest that in the cells studied opioids affect, via the delta-opioid receptor, stimulatory intracellular mediator systems involving Ca(2+)/calmodulin and the protein kinase C pathway.
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PMID:Acute delta-opioid receptor activation induces CREB phosphorylation in NG108-15 cells. 1070

Morphine-3-glucuronide (M3G), a main metabolite of morphine, has been proposed as a responsible factor when patients present with the neuroexcitatory side effects (allodynia, hyperalgesia, and myoclonus) observed following systemic administration of large doses of morphine. Indeed, both high-dose morphine (60 nmol/5 microl) and M3G (3 nmol/5 microl) elicit allodynia when administered intrathecally (i.t.) into mice. The allodynic behaviors are not opioid receptor mediated. This chapter reviews the potential mechanism of spinally mediated allodynia evoked by i.t. injection of M3G in mice. We discuss a possible presynaptic release of nociceptive neurotransmitters/neuromodulators such as substance P, glutamate, and dynorphin in the primary afferent fibers following i.t. M3G. It is possible to speculate that i.t. M3G injection could activate indirectly both NK(1) receptor and glutamate receptors that lead to the release of nitric oxide (NO) in the dorsal spinal cord. The NO plays an important role in M3G-induced allodynia. The phosphorylation of extracellular signal-regulated protein kinase (ERK) in the dorsal spinal cord evoked via NO/cGMP/PKG pathway contributes to i.t. M3G-induced allodynia. Furthermore, the increased release of NO observed after i.t. injection of M3G activates astrocytes and induces the release of the proinflammatory cytokine, interleukin-1beta. Taken together, these findings suggest that M3G may induce allodynia via activation of NO-ERK pathway, while maintenance of the allodynic response may be triggered by NO-activated astrocytes in the dorsal spinal cord. The demonstration of the cellular mechanisms of neuronal-glial interaction underlying M3G-induced allodynia provides a fruitful strategy for improved pain management with high doses of morphine.
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PMID:Mechanism of allodynia evoked by intrathecal morphine-3-glucuronide in mice. 1960 72

The nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cGMP-dependent protein kinase (PKG) signaling pathway has been reported to play a key role in memory processing. However, little is known about its role in drug-associated reward memory. Here, we report the following. 1) The NO pathway in the CA1 is critical for the retrieval of morphine-associated reward memory. Specifically, the nNOS, sGC and PKG protein levels in the CA1 were increased after the expression of morphine conditioned place preference (CPP). Intra-CA1 injection of an NOS, sGC or PKG inhibitor prevented morphine CPP expression. 2) The involvement of the NO pathway in morphine CPP requires NR2B-containing NMDA receptors (NR2B-NMDARs). NR2B-NMDAR expression was elevated in the CA1 following morphine CPP expression, and intra-CA1 injection of the NR2B-NMDAR antagonist Ro25-6981 not only blocked morphine CPP expression but also inhibited the up-regulation of nNOS, sGC and PKG. Moreover, the Ro25-6981-induced blockade of morphine CPP was abolished by intra-CA1 injection of a NOS substrate or an sGC activator. 3) The NR2B-NMDAR stimulated the NO pathway by up-regulating the phosphorylation of Akt(Ser473). Morphine CPP expression enhanced the pAkt(Ser473) level, which has been corroborated to regulate nNOS activity, and this effect was reversed by intra-CA1 injection of Ro25-6981. 4) GluR1 acted downstream of the NO pathway. The membrane level of GluR1 in the CA1 was increased after morphine CPP expression, and this effect was prevented by pre-injection of a PKG inhibitor into the CA1. Additionally, co-immunoprecipitation revealed an interaction between PKG and GluR1; this result further indicated a role of PKG in regulating GluR1 trafficking. Collectively, the results of our study demonstrated that the activation of the NR2B-NMDAR/NO/sGC/PKG signaling pathway is necessary for the retrieval of morphine-associated reward memory.
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PMID:Essential role of the NO signaling pathway in the hippocampal CA1 in morphine-associated memory depends on glutaminergic receptors. 2659 57