Nociceptin/Orphanin FQ Increases Anxiety-Related Behavior and Circulating Levels of Corticosterone During Neophobic Tests of Anxiety

Abstract

Intracranial administration of nociceptin/orphanin FQ (N/OFQ) increases circulating concentrations of adrenocorticotrophic hormone and corticosterone in unstressed rats, and elevates the responsiveness of these hormones during mild stress. Furthermore, N/OFQ and its cognate receptor are both abundant in a variety of limbic nuclei, and stress exposure decreases neuronal N/OFQ content in forebrain neurons. In light of these and other findings, we examined the potential involvement of N/OFQ in regulation of anxiety-related behaviors in rats. In the open field, elevated plus maze, and dark-light neophobic tests, intracerebroventricular N/OFQ (1.0 pmole-1.0 nmole) increased the expression of anxiety-related behaviors. Specifically, N/OFQ increased the latency to enter, decreased the number of entries into, and decreased the time spent in the exposed or brightly lit environments of all three tests. N/OFQ also enhanced thigmotactic responses in the open field test. The effects of diazepam and of the benzodiazepine inverse agonist FG 7142 were also assessed in independent groups of rats. In all three tests, the behavioral effects of N/OFQ resembled the anxiogenic actions of FG 7142, and contrasted with the anxiolytic actions of diazepam. N/OFQ administration also increased circulating concentrations of corticosterone during anxiety testing, in comparison with the concentrations in vehicle-treated controls. We conclude that N/OFQ administration is anxiogenic, and elevates responsiveness of the hypothalamic pituitary-adrenal axis during neophobic tests of anxiety. This supports the possibility that N/OFQ neurotransmission participates in processing of emotionally-salient and stressful stimuli, and suggests that normal functioning of the N/OFQ system may be important in physiological and psychological well-being.

The Anxiolytic-Like Effects of the Novel, Orally Active Nociceptin Opioid Receptor Agonist 8-[bis(2-Methylphenyl)methyl]-3-phenyl-8-azabicyclo[3.2.1]octan-3-ol (SCH 221510)

“…Finally, the OFQ/N knockout mice did not adapt to repeated swim stress. However, the (Fernandez et al, 2004) and rats (Green et al, 2007) in the elevated plus-maze, open field, and light-dark box models. The present experiments with SCH 221510 are consistent, however, with previous findings with both OFQ/N (Jenck et al, 1997;Griebel et al, 1999) and the nonpeptide agonist Ro64-6198 (Jenck et al, 2000;Varty et al, 2005) that demonstrated robust anxiolytic-like profiles in multiple species and across a larger number of behavioral models.…”

Characterization of the nociceptin receptor (ORL-1) agonist, Ro64-6198, in tests of anxiety across multiple species

“…Thus, at least three independent groups (Jenck et al 1997;Griebel et al 1999;Gavioli et al 2002) have reported an anxiolytic-like profile in a variety of unconditioned tests of anxiety based on exploration of aversive environments (elevated plus maze, light/dark test) and an ethological test battery based on measurement of behavioral responses to a natural threat. It is against this body of evidence that the recent findings of Fernandez et al (2004) need to be placed into context. Although reduced exploration of the elevated plus maze and light/dark box after OFQ/N pretreatment seems consistent with an anxiogenic state, elevations in blood corticosterone levels seem uninterpretable in terms of heightened stress level, given that diazepam produces a similar change (Fernandez et al 2004; see also McElroy et al 2002).…”

“…However, interpretation of an anxiolytic potential of ORL-1 receptor agonists has recently been challenged by Fernandez et al (2004), who reported i.c.v. OFQ/N (1 pmol to 1 nmol) to reduce rodent exploration within a number of test environments, in a manner similar to the benzodiazepine inverse agonist FG-7142, a standard anxiety-provoking drug (Dorow 1987).…”

Anxiolytic-like effects of morphine and buprenorphine in the rat model of fear-potentiated startle: tolerance, cross-tolerance, and blockade by naloxone

“…κ-opioid receptor (Privette and Terrian 1995;Wright and Ingenito 2001;Wall and Messier 2000), and ORL 1 receptor (Jenck et al 1997;Jenck et al 2000;Wichmann et al 2000, but see Fernandez et al 2004) have been shown to increase the percentage of entries and time spent in the open arms of a plus maze, indicating an anxiolytic-like action.…”