Abstract
Different reports suggest that nociceptin/orphanin FQ (N/OFQ) may have either anxiolytic- or anxiogenic-like effect in rodents. Since N/OFQ elicits hypolocomotion, which undergoes rapid tolerance, and hypolocomotion may be associated to emotional consequences, the present study was designed to investigate the effect of N/OFQ on anxiety after development of tolerance to its hypolocomotor effect. The effect of single or double intracerebroventricular (i.c.v.) injection of N/OFQ was evaluated on anxiety-related behaviors in rats, in the elevated plus maze (EPM) and conditioned defensive burying (CDB) tests. After single administration, N/OFQ displayed an anxiogenic-like pattern of response on the elevated plus maze but hypolocomotion was also observed. Conversely, in the CDB test, N/OFQ induced a clear-cut anxiolytic pattern. To produce tolerance to N/OFQ-induced hypolocomotion the peptide was administered by two i.c.v. injections separated by 120 min; in these conditions it decreased the expression of anxiety-related behaviors in both tests without affecting locomotor activity. The nociceptin/orphanin FQ peptide (NOP) receptor antagonist UFP-101 significantly reduced the effects of N/OFQ to control values in either tests. Corticosterone levels were significantly increased after a single N/OFQ administration (not in a dose-dependent manner) but this increase did not reach significance after double administration (1 nmol/rat). Our results support the idea that N/OFQ may act as an anxiolytic-like agent in the rat; the apparent anxiogenic-like effect observed following its single administration in the EPM may be consequent to its effect on locomotion.
Highlights
First identified in 1995, the 17-amino acid peptide nociceptin/ orphanin FQ (N/OFQ) is the endogeous ligand for the ‘‘orphan’’ opioid receptor ORL-1 ( nociceptin/orphanin FQ peptide (NOP)) [32,45]
N/OFQ is quite selective for NOP receptor, while showing no appreciable affinity for m opioid (MOP), d opioid (DOP) or k opioid (KOP) receptors [34,51,53,24,31]
N/OFQ and NOP receptors are abundantly expressed in limbic and limbic-associated brain structures [16,15,39,40] that are involved in processing of emotionally relevant stimuli, raising the hypothesis that N/OFQ might contribute to regulation of the hypothalamic–pituitary–adrenal (HPA) axis, and to regulation of emotional states
Summary
First identified in 1995, the 17-amino acid peptide nociceptin/ orphanin FQ (N/OFQ) is the endogeous ligand for the ‘‘orphan’’ opioid receptor ORL-1 ( NOP) [32,45]. N/OFQ inhibits adenylate cyclase and calcium currents and hyperpolarizes neurons by opening potassium channels [20,35]. N/OFQ administration inhibits locomotor activity after intracerebroventricular (i.c.v.) injection of doses of 1–10 nmol [45,9], while it has been reported to increase locomotion at. I.c.v. injection of N/OFQ or of the NOP receptor agonist Ro 646198 were shown to decrease behavioral responses to stress [18,21,22,23,50]. N/OFQ was reported to elicit anxiogeniclike responses, to increase plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone (CORT) in unstressed rats and to augment hormonal responses in mildly stressed rats [11]
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