Morphine is a poor inducer of l-opioid receptor (MOR) internalization, but a potent inducer of cellular tolerance. Here we show that, in contrast to full agonists such as [D-Ala 2 -MePhe 4 -Gly-ol]enkephalin (DAMGO), morphine stimulated a selective phosphorylation of the carboxyterminal residue 375 (Ser 375 ). Ser 375 phosphorylation was sufficient and required for morphine-induced desensitization of MOR. In the presence of full agonists, morphine revealed partial agonistic properties and potently inhibited MOR phosphorylation and internalization. Upon removal of the drug, DAMGO-desensitized receptors were rapidly dephosphorylated. In contrast, morphine-desensitized receptors remained at the plasma membrane in a Ser 375 -phosphorylated state for prolonged periods. Thus, morphine promotes terminal MOR desensitization by inducing a persistent modification of Ser 375 .

The relief from an aversive event is rewarding. Since organisms are able to learn which environmental cues can cease an aversive event, relief learning helps to better cope with future aversive events. Literature data suggest that relief learning is affected in various psychopathological conditions, such as anxiety disorders. Here, we investigated the role of the mesolimbic dopamine system in relief learning. Using a relief learning procedure in Sprague Dawley rats, we applied a combination of behavioral experiments with anatomical tracing, c-Fos immunohistochemistry, and local chemogenetic and pharmacological interventions to broadly characterize the role of the mesolimbic dopamine system. The present study shows that a specific part of the mesolimbic dopamine system, the projection from the posterior medial ventral tegmental area (pmVTA) to the nucleus accumbens shell (AcbSh), is activated by aversive electric stimuli. 6-OHDA lesions of the pmVTA blocked relief learning but fear learning and safety learning were not affected. Chemogenetic silencing of the pmVTA-AcbSh projection using the DREADD approach, as well as intra-AcbSh injections of the dopamine D2/3 receptor antagonist raclopride inhibited relief learning. Taken together, the present data demonstrate that the dopaminergic pmVTA-AcbSh projection is critical for relief learning but not for similar learning phenomena. This novel finding may have clinical implications since the processing of signals predicting relief and safety is often impaired in patients suffering from anxiety disorders. Furthermore, it may help to better understand psychological conditions like non-suicidal self-injury, which are associated with pain offset relief.

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Neuropeptide S (NPS) is a neuropeptide involved in the regulation of fear. Because safety learning is impaired in patients suffering from anxiety‐related psychiatric disorders, and polymorphisms of the human neuropeptide S receptor (NPSR) gene have also been associated with anxiety disorders, we wanted to investigate whether NPSR‐deficiency interferes with safety learning, and how prior stress would affect this type of learning. We first investigated the effect of pre‐exposure to two different types of stressors (electric stimuli or immobilization) on safety learning in female and male C57Bl/6 mice, and found that while stress induced by electric stimuli enhanced safety learning in males, there were no differences in safety learning following immobilization stress. To further investigate the role of the NPS system in stress‐induced modulation of safety learning, we exposed NPSR‐deficient mice to stress induced by electric stimuli 10 days before safety learning. In nonstressed male mice, NPSR‐deficiency enhanced safety learning. As in male C57Bl/6 mice, pre‐exposure to electric stimuli increased safety learning in male NPSR +/+ mice. This pre‐exposure effect was blocked in NPSR‐deficient male mice showing impaired, but still intact, safety learning in comparison to their NPSR +/+ and NPSR +/− littermates. There was neither a pre‐exposure nor a genotype effect in female mice. Our findings provide evidence that pre‐exposure to stress induced by electric stimuli enhances safety learning in male mice, and that NPSR‐deficiency prevents the beneficial effect of stress exposure on safety learning. We propose an inverted U‐shape relationship between stress and safety learning.

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Relief learning is the association of environmental cues with the cessation of aversive events. While there is increasing knowledge about the neural circuitry mediating relief learning, the respective molecular pathways are not known. Therefore, the aim of the present study was to examine different putative molecular pathways underlying relief learning. To this purpose, male rats were subjected either to relief conditioning or to a pseudo conditioning procedure. Forty-five minutes or 6 h after conditioning, samples of five different brain regions, namely the prefrontal cortex, nucleus accumbens (NAC), dorsal striatum, dorsal hippocampus, and amygdala, were collected. Using quantitative Western blots, the expression level of CREB, pCREB, ERK1/2, pERK1/2, CaMKIIα, MAP2K, PKA, pPKA, Akt, pAkt, DARPP-32, pDARPP-32, 14-3-3, and neuroligin2 were studied. Our analyses revealed that relief conditioned rats had higher CREB phosphorylation in NAC 6 h after conditioning than pseudo conditioned rats. The data further revealed that this CREB phosphorylation was mainly induced by dopamine D1 receptor-mediated activation of PKA, however, other kinases, downstream of the NMDA receptor, may also contribute. Taken together, the present study suggests that CREB phosphorylation, induced by a combination of different molecular pathways downstream of dopamine D1 and NMDA receptors, is essential for the acquisition and consolidation of relief learning.

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