Anxiety is a key consequence of ethanol withdrawal and important risk factor for relapse. The neuropeptide nociceptin/orphanin FQ (N/OFQ), or agonists at this peptide’s receptor (NOP), exert anxiolytic-like and anti-stress actions. N/OFQ dysfunction has been linked to both a high-anxiety behavioral phenotype and excessive ethanol intake. Recent studies suggest a possible link between genetic polymorphisms of the NOP transcript and alcoholism. Thus, in the present study, the effects of intracerebroventricularly (ICV) administered N/OFQ were tested for modification of anxiety-like behaviors, using the shock-probe defensive burying and elevated plus maze tests, in ethanol-dependent vs. nondependent rats, one and three weeks following termination of ethanol exposure. Additionally, Prepro-N/OFQ (ppN/OFQ) and NOP receptor gene expression was measured in the central nucleus of the amygdala, in the bed nucleus of the stria terminalis, and in the lateral hypothalamus at the same time points in separate subjects. One week post-ethanol, N/OFQ dose-dependently attenuated elevated anxiety-like behavior in ethanol-dependent rats and produced anxiolytic-like effects in nondependent controls in both behavioral tests. However, three weeks post-ethanol, N/OFQ altered behavior consistent with anxiogenic-like actions in ethanol-dependent rats, but continued to exert anxiolytic-like actions in nondependent controls. These findings were paralleled by ethanol history-dependent changes of ppN/OFQ and NOP gene expression that showed a distinctive time-course in the examined brain structures. The results demonstrate that ethanol dependence and withdrawal are associated with neuroadaptive changes in the N/OFQ-NOP system suggesting a role of this neuropeptidergic pathway as a therapeutic target for the treatment of alcohol abuse.

In addition to its traditional role in reproduction, progesterone (PROG) has demonstrated neuroprotective and promyelinating effects in lesions of the peripheral and central nervous systems, including the spinal cord. The latter is a target of PROG, as nuclear receptors, as well as membrane receptors, are expressed by neurons and/or glial cells. When spinal cord injury (SCI) is produced at the thoracic level, several genes become sensitive to PROG in the region caudal to the lesion site. Although the cellular machinery implicated in PROG neuroprotection is only emerging, neurotrophins, their receptors, and signaling cascades might be part of the molecules involved in this process. In rats with SCI, a 3-d course of PROG treatment increased the mRNA of brain-derived neurotrophic factor (BDNF) and BDNF immunoreactivity in perikaryon and processes of motoneurons, whereas chromatolysis was strongly prevented. The increased expression of BDNF correlated with increased immunoreactivity for the BDNF receptor TrkB and for phosphorylated cAMP-responsive element binding in motoneurons. In the same SCI model, PROG restored myelination, according to measurements of myelin basic protein (MBP) and mRNA levels, and further increased the density of NG2+-positive oligodendrocyte progenitors. These cells might be involved in remyelination of the lesioned spinal cord. Interestingly, similarities in the regulation of molecular parameters and some cellular events attributed to PROG and BDNF (i.e., choline acetyltransferase, Na,K-ATPase, MBP, chromatolysis) suggest that BDNF and PROG might share intracellular pathways. Furthermore, PROG-induced BDNF might regulate, in a paracrine or autocrine fashion, the function of neurons and glial cells and prevent the generation of damage.

Several studies demonstrated a cross-talk between the opioid and cannabinoid system. The NOP receptor and its endogenous ligand nociceptin/orphanin FQ represent an opioid-related functional entity that mediates some non-classical opioid effects. The relationship between cannabinoid and nociceptin/NOP system is yet poorly explored. In this study, we used the neuroblastoma SH-SY5Y cell line to investigate the effect of delta-9-tetrahydrocannabinol (∆(9)-THC) on nociceptin/NOP system. Results revealed that the exposure to ∆(9)-THC (100, 150, and 200 nM) for 24 h produces a dose-dependent NOP receptor B (max) down-regulation. Moreover, ∆(9)-THC caused a dose-dependent decrease in NOP mRNA levels. The selective cannabinoid receptor CB1 antagonist AM251 (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide) reduces both effects, suggesting that ∆(9)-THC activation of CB1 receptor is involved in the observed effects. These data show evidence of a cross-talk between NOP and CB1 receptors, thus suggesting a possible interplay between cannabinoid and nociceptin/NOP system.

Nociceptin (N/OFQ) is involved in neuronal excitability and in certain types of seizures. Kainate-induced seizures are associated with increased N/OFQ release in the rat thalamus and hippocampus, causing down-regulation of the N/OFQ receptor (NOP). In this study, we used the neuroblastoma SH-SY5Y cell line as a model to investigate the effects of kainate on NOP receptor density and gene expression. Exposure to kainate (10-50 microM) for 3 h did not affect NOP receptor density. In contrast, a NOP Bmax down-regulation was detected in cells exposed to 10 microM kainate for both 6 and 24 h. Moreover, our data show that kainate causes a decrease in NOP mRNA levels after 3, 6, and 24 h, an effect blocked by the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). These findings show that kainate is able to affect the NOP system, both at biosynthesis and receptor density levels in SH-SY5Y cells, and that the kainate ionotropic receptor can contribute to the regulation of the NOP receptor. These data are in agreement with data obtained in vivo and provide new evidence concerning the existence of a cross-talk between NOP and kainate receptors, leading to an interplay between glutamate and N/OFQ circuits.

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