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Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the NOP opioid receptor (previously referred to as ORL1 or OP4 receptor), exerts a variety of behavioral effects. N/OFQ as well as the synthetic NOP receptor agonist Ro 64-6198 have been reported to possess antistress properties and to elicit a pronounced hyperphagic effect in freely feeding rats. These findings have raised our interest to investigate possible interactions in the control of ingestive behavior between N/OFQ and corticotropin-releasing factor (CRF), which is well known to be a major mediator of stress and to possess anorectic properties. These studies have shown that intracerebroventricular injections of N/OFQ or of Ro 64-6198 reverse the anorectic action evoked by intracerebroventricular administration of CRF. The anti-anorectic effect of N/OFQ or Ro 64-6198 is antagonized by the selective NOP receptor antagonist [Nphe1]N/OFQ1-13NH2, providing evidence that it is mediated by this receptor. The effect occurs at doses that are not hyperphagic per se and is clearly selective versus the anorectic action of CRF since N/OFQ or Ro 64-6198 do not influence the anorectic effect of Escherichia coli lipopolysaccharide (LPS). Neither N/OFQ nor Ro 64-6198 shows affinity for CRF receptors, suggesting that NOP receptor agonists might act as functional antagonists of CRF with regard to its anorectic action. Microinjection studies have revealed that the bed nucleus of the stria terminalis (BNST) is highly sensitive to the anorectic action of CRF, as well as to the anti-anorectic action of N/OFQ; pretreatment with 0.025-0.25 microg/site of N/OFQ into the BNST blocked the anorectic action of 0.1 microg/site of CRF given in the same area. On the other hand, intra-BNST microinjection of 0.025-0.25 microg/site of N/OFQ did not modify basal food intake. Thus, the BNST may be the site where the functional antagonism between N/OFQ and CRF takes place. These findings raise interest for the N/OFQ-NOP receptor system as a pharmacological target to block the anorectic effect of CRF. In comparison to CRF receptor antagonists, NOP receptor agonists may have the advantage of not inhibiting the hypothalamic-pituitary-adrenal (HPA) axis.

Rationale: Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the opioid-like orphan receptor NOP, was shown to reduce home-cage ethanol consumption, ethanol-induced conditioned place preference and stress-induced reinstatement of alcohol-seeking behaviour., Objectives: The present study, using genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, was designed to evaluate the effect of this opioid peptide on 10% ethanol and 10% sucrose self-administration, under a fixed-ratio 1 (FR 1) or a progressive-ratio (PR) schedule of reinforcement. Furthermore, using an experimental model of relapse in which rats were trained to lever press for ethanol in the presence of the discriminative stimulus of an orange odour (S(+)) and a 1-s cue light (CS(+)) or for water in the presence of anise odour (S(-)) and 1-s white noise (CS(-)), the effect of N/oFQ on cue-induced reinstatement of extinguished ethanol responding was investigated., Results: Sub-chronic (6 days) intracerebroventricular (i.c.v.) injection of 0.5 microg or 1.0 microg N/OFQ per rat significantly reduced alcohol self-administration under both the FR 1 and PR schedules of reinforcement. Conversely, i.c.v. administration of 0.5, 1.0 or 4.0 microg of the peptide per rat did not affect sucrose self-administration. In addition, i.c.v. N/OFQ (1.0-2.0 microg per rat) significantly inhibited the reinstatement of extinguished ethanol responding under an S(+)/CS(+) condition, whereas lever pressing under S(-)/CS(-) was not altered., Conclusions: The present study demonstrates that the reinforcing effects of ethanol are markedly blunted by activation of the opioidergic N/OFQ receptor system. Moreover, the data provide evidence of the efficacy of N/OFQ to prevent reinstatement of ethanol-seeking behaviour elicited by environmental conditioned stimuli.

Lyme disease is a multisystem disorder with protean clinical manifestations that is caused by the tick-transmitted spirochete Borrelia burgdorferi. Infection caused by B burgdorferi is known to induce glomerulonephritis in animals. We report a patient with acute postinfection membranoproliferative glomerulonephritis after the clinical multisystem manifestation of Lyme disease, which was confirmed serologically. Although the patient was dialysis dependent for a protracted period of 5 months, the final outcome was excellent.

Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the opioid N/OFQ receptor (NOP), possesses marked functional anti-stress and anti-corticotropin-releasing factor (CRF) actions. We have shown that intracerebroventricular injection of N/OFQ reverses the hypophagic effect induced by stress or by CRF given intracerebroventricularly. To shed new light on the mechanisms involved in the anti-CRF action of N/OFQ, we investigated the ability of N/OFQ to prevent CRF-induced anorexia after microinjection studies into brain areas of potential interest in the control of feeding behavior and coexpressing NOP and CRF receptors. These areas include the bed nucleus of the stria terminalis (BNST), the central amygdala (CeA), the locus ceruleus (LC), the ventromedial hypothalamus (VMH), the paraventricular nucleus (PVN), and the dorsal raphe (DR). The results demonstrated that the anorectic effect of 0.04 nmol of CRF per rat (200 ng per rat) given intracerebroventricularly is reversed by pretreatment with 0.01-0.21 nmol of N/OFQ per rat (25-500 ng per rat) injected into the BNST but not into the CeA, LC, VMH, PVN, or DR. Microinjection of 0.01-0.02 nmol of CRF per site (50-100 ng per site) into the BNST but not into the CeA or the LC induced marked anorexia in food-deprived rats. Pretreatment with 0.01-0.21 nmol of N/OFQ per site (25-500 ng per site) into the BNST also blocked the anorectic action of 0.02 nmol of CRF per site (100 ng per site) given in the same area. Finally, intra-BNST microinjection of 0.01-0.21 nmol of N/OFQ per site (25-500 ng per site) did not modify food intake in either food-sated or food-deprived rats. These data demonstrate that the BNST is involved in the modulation of CRF-induced anorexia, which is prevented by activation of N/OFQ receptors.

The intracerebroventricular administration of the 17 amino acid peptide nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the NOP receptor (previously referred to as ORL-1 or OP4 receptor), reduces voluntary 10% ethanol intake in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats. Studies aimed at the pharmacological characterization of the receptor, which mediates the effect, have shown that the C-terminal 13 amino acid sequence is crucial for activity and that the selective NOP receptor antagonist [Nphe(1)]N/OFQ(1-13)NH(2) blocks the effect of N/OFQ on ethanol drinking. In place conditioning studies, N/OFQ abolishes the conditioned place preference (CPP) induced by ethanol in msP rats, or by morphine in nonselected Wistar rats; these findings suggest that N/OFQ is able to abolish the rewarding properties of ethanol and morphine. Moreover, N/OFQ inhibits reinstatement of alcohol-seeking behavior induced to electric footshock stress, as well as reinstatement of alcohol-seeking behavior induced by ethanol-paired cues. Together, these findings suggest that N/OFQ and its receptor may represent an interesting target for pharmacological treatment of alcohol abuse.

Several evidences indicate altered regulation of brain serotonergic mechanisms in alcohol abuse; changes in 5-HT2A receptor density and functioning have been observed in several lines of alcohol-preferring rats. Using quantitative autoradiography, the present study investigated the influence of chronic intragastric ethanol treatment on forebrain 5-HT2A binding sites in rats. Administration for 7 days of high doses of ethanol, which induced physical dependence, lowered the levels of 5-HT2A binding sites in the cingulate cortex, the frontal cortex and in the agranular insular cortex. The effect was observed immediately after the last ethanol administration, was statistically significant 14 h later, when marked withdrawal signs were observed, and remained significant after 8 days of detoxification, when withdrawal signs were no longer evident. No significant differences were detected in the claustrum, parietal cortex, piriform cortex, caudate putamen, olfactory tubercle, nucleus accumbens, shell and core. Chronic treatment with 6 g/kg of ethanol, which did not induce dependence, did not modify 5-HT2A binding sites. These long-lasting changes in brain 5-HT2A binding sites observed in the present study might contribute to specific aspects of ethanol dependence, such as development of depression and alcohol craving.

Over the last 16 years the evolution of 24 pregnancies in 17 women with biopsy-proven glomerular disease was analyzed. The underlying renal histology was IgA nephropathy in 8 cases, lupus nephritis in 7, mesangiocapillary glomerulonephritis type I in 1, and focal segmental glomerulosclerosis in 1. All but 2 had normal renal function before conception and 3 were hypertensive. Fetal survival rate was 75%. There were 6 preterm deliveries (33.3%), 3 newborns small for gestational age (17%), 1 stillbirth, and 5 therapeutic abortions. The perinatal mortality was 5.5%. De novo hypertension occurred in 8 pregnancies (33.3%). In 11 pregnancies (46%) increased proteinuria was diagnosed and in 6 (25%) a decline in maternal renal function was recorded. Permanent impairment of renal function was seen in 2 women with renal insufficiency before conception. Maternal hypertension and renal function impairment were associated more frequently with obstetric complications. In conclusion, pregnancy is safe for normotensive mothers with glomerular diseases and normal renal function. Hypertension and impaired renal function at conception seem to carry increased risk for mothers and fetuses. Low-dose immunosuppressive treatment during pregnancy is not harmful for the fetus.