The formation of long-term memory requires protein synthesis, particularly during initial memory consolidation. This process also seems to be dependant upon protein degradation, particularly degradation by the ubiquitin-proteasome system. The aim of this study was to investigate the temporal requirement of protein synthesis and degradation during the initial consolidation of allocentric spatial learning. As memory returns to a labile state during reactivation, we also focus on the role of protein synthesis and degradation during memory reconsolidation of this spatial learning. Male CD1 mice were submitted to massed training in the spatial version of the Morris water maze. At various time intervals after initial acquisition or after a reactivation trial taking place 24 h after acquisition, mice received an injection of either the protein synthesis inhibitor anisomycin or the protein degradation inhibitor lactacystin. This injection was performed into the hippocampal CA3 region, which is specifically implicated in the processing of spatial information. Results show that, in the CA3 hippocampal region, consolidation of an allocentric spatial learning task requires two waves of protein synthesis taking place immediately and 4 h after acquisition, whereas reconsolidation requires only the first wave. However, for protein degradation, both consolidation and reconsolidation require only one wave, taking place immediately after acquisition or reactivation, respectively. These findings suggest that protein degradation is a key step for memory reconsolidation, as for consolidation. Moreover, as protein synthesis-dependent reconsolidation occurred faster than consolidation, reconsolidation did not consist of a simple repetition of the initial consolidation.

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A site-directed mutagenesis approach has been used to gain insight into the molecular events whereby the heptadecapeptide nociceptin binds and activates the opioid receptor-like 1 (ORL1) receptor, a G protein-coupled receptor. Alanine mutation, in the human ORL1 receptor, of transmembrane amino acid residues that are conserved in opioid receptors, Asp(130) and Tyr(131) in transmembrane segment (TM) III, Phe(220) and Phe(224) in TM V, and Trp(276) in TM VI, yields mutant receptors with reduced affinity, and proportionally decreased reactivity, toward nociceptin. Least to most deleterious in this respect are Ala substitutions of Phe(220) approximately W276A < Tyr(131) << Phe(224) 10,000 nM compared with 0.8 nM at the wild-type receptor). In all respects, this mutant receptor appears to be functionally inactive, indicating that residue Gln(286) may play a pivotal role in ORL1 receptor-mediated transduction of the nociceptin signal.

These data provide compelling evidence that central apelin participates in the regulation of glucose homeostasis and suggest a novel pathophysiological mechanism involved in the transition from normal to diabetic state.

BACKGROUND AND PURPOSEOpiates remain the most effective compounds for alleviating severe pain across a wide range of conditions. However, their use is associated with significant side effects. Neuropeptide FF (NPFF) receptors have been implicated in several opiate-induced neuroadaptive changes including the development of tolerance. In this study, we investigated the consequences of NPFF receptor blockade on acute and chronic stimulation of opioid receptors in mice by using RF9, a potent and selective antagonist of NPFF receptors that can be administered systemically. EXPERIMENTAL APPROACHThe effects of RF9 were investigated on opioid pharmacological responses including locomotor activity, antinociception, opioid-induced hyperalgesia, rewarding properties and physical dependence. KEY RESULTSRF9 had no effect on morphine-induced horizontal hyperlocomotion and slightly attenuated the decrease induced in vertical activity. Furthermore, RF9 dose-dependently blocked the long-lasting hyperalgesia produced by either acute fentanyl or chronic morphine administration. RF9 also potentiated opiate early analgesic effects and prevented the development of morphine tolerance. Finally, RF9 increased morphine-induced conditioned place preference without producing any rewarding effect by itself and decreased naltrexone-precipitated withdrawal syndrome following chronic morphine treatment. CONCLUSION AND IMPLICATIONSThe NPFF system is involved in the development of two major undesirable effects: tolerance and dependence, which are clinically associated with prolonged exposure to opiates. Our findings suggest that NPFF receptors are interesting therapeutic targets to improve the analgesic efficacy of opiates by limiting the development of tolerance, and for the treatment of opioid dependence. AbbreviationsCPP, conditioned place preference; HMA, horizontal motor activity; NPFF, neuropeptide FF; OIH, opioid-induced hyperalgesia; VMA, vertical motor activity BJP British Journal of Pharmacology