Orphanin FQ acts as an anxiolytic to attenuate behavioral responses to stress

Abstract

Orphanin FQ (OFQ, Nociceptin) is a recently discovered 17-amino acid neuropeptide that is structurally related to the opioid peptides but does not bind opioid receptors. OFQ has been proposed to act as an anti-opioid peptide, but its widespread sites of action in the brain suggest that it may have more general functions. Here we show that OFQ plays an important role in higher brain functions because it can act as an anxiolytic to attenuate the behavioral inhibition of animals acutely exposed to stressful͞anxiogenic environmental conditions. OFQ anxiolytic-like effects were consistent across several behavioral paradigms generating different types of anxiety states in animals (light-dark preference, elevated plus-maze, exploratory behavior of an unfamiliar environment, pharmacological anxiogenesis, operant conf lict) and were observed at low nonsedating doses (0.1-3 nmol, intracerebroventricular). Like conventional anxiolytics, OFQ interfered with regular sensorimotor function at high doses (>3 nmol). Our results show that an important role of OFQ is to act as an endogenous regulator of acute anxiety responses. OFQ, probably in concert with other major neuropeptides, exerts a modulatory role on the central integration of stressful stimuli and, thereby, may modulate anxiety states generated by acute stress.Orphanin FQ (OFQ, Nociceptin) is a 17-amino acid neuropeptide that is structurally related to the opioid peptides but does not act on , ␦, or opioid receptor subtypes (1, 2). OFQ selectively binds its own receptor (OFQR), which is also sequentially related to the opioid receptors, yet does not bind opioid ligands (3-8). The OFQR couples to G proteins to modulate second messenger systems and cell excitability (9-11). When delivered intracerebroventricularly (i.c.v.) in a large dose range (0.1-10 nmol), OFQ was found to block stress and opioid-mediated antinociception (12, 13), to stimulate feeding in satiated rats (14), and to increase or decrease, depending on dosage, locomotion (1, 15) or nociception (16, 17) in rodents. OFQ, its precursor, and OFQR are present in several brain regions involved in integration of the emotional components of fear and stress such as the amygdaloid complex, thalamic and hypothalamic regions, or central gray regions (1-8, 18, 19). This has led us to investigate whether OFQ might also have a role in higher brain functions and would control behavioral responses to stress that relate to anxiety states. To investigate this hypothesis, a battery of behavioral models of anxiety and fear (light-dark aversion, elevated plus-maze, exploratory behavior of an unfamiliar environment, pharmacological anxiogenesis, operant conflict) were used on mice and rats. In these assays, fear-like responses of a composite nature are generated by exposure to various stressful environmental conditions (20-27). These paradigms have been established for their sensitivity to conventional anxiolytic tranquilizers and anxiogenic compounds of various structural classes and mechanisms of action. They were pha...

Nociceptin/Orphanin FQ Modulates Motor Behavior and Primary Motor Cortex Output Through Receptors Located in Substantia Nigra Reticulata

“…N/OFQ (0.1-1 nmol) inhibited motor behavior by inducing akinesia and bradykinesia, by slowing the time to initiate and to execute a movement. The specificity of these effects is also confirmed by reports that these doses of N/OFQ did not affect other motor parameters such as righting reflex (Devine et al, 1996) or muscle strength (Jenck et al, 1997) and tone (Devine et al, 1996;Marti et al, 2004a). Moreover, akinesia and bradykinesia, were replicated by N/OFQ injections in SNr, the motor output of basal ganglia.…”

“…In particular, i.c.v. injections of N/OFQ or systemic administration of Ro 64-6198 (a synthetic NOP receptor agonist) facilitated spontaneous locomotion at low doses (Florin et al, 1996;Jenck et al, 1997;Higgins et al, 2001;Kuzmin et al, 2004) and inhibited it at higher ones (Reinscheid et al, 1995;Devine et al, 1996;Rizzi et al, 2001;Higgins et al, 2001;Kuzmin et al, 2004). NOP receptor agonists also inhibited exercise-induced locomotion (as in the rotarod test) although in a monophasic way (Jenck et al, 2000;Higgins et al, 2001;Marti et al, 2004a).…”

The Mouse Defense Test Battery: pharmacological and behavioral assays for anxiety and panic

“…The neuroanatomical distribution of nociceptin/orphanin FQ and its receptor in brain areas known to play a role in the modulation of emotional processes (Anton et al, 1996) has led several groups to investigate the effects of central administration of nociceptin/orphanin FQ in anxiety models. The neuropeptide was found to exert anxiolyticlike action in the elevated plus-maze and light/dark tests (Jenck et al, 1997) and prevented stress-induced anorexia (Ciccocioppo et al, 2001). In the Mouse Defense Test Battery, nociceptin/orphanin FQ attenuated some, but not all, defensive behaviors, thereby confirming that it may modulate emotional behaviors (Table 3).…”

Conditioned Opioid Withdrawal Decreases Nociceptin/Orphanin FQ Levels in the Frontal Cortex and Olfactory Tubercle

“…Because both the Acb and frontal cortex are involved in responses to stressful stimuli, and as nociceptin may be an endogenous anxiolytic-like agent, it was necessary to determine if stress altered nociceptin levels in these brain regions (Jenck et al 1997;Jenck et al 2000;Horger and Roth 1996). Rats were repeatedly exposed to mild footshock stress in operant chambers, and footshock was unpredictably reapplied after several weeks of no footshock.…”

“…Because the frontal cortex is involved in stress and nociceptin has been implicated as an endogenous anxiolytic, we sought to determine whether the change in nociceptin peptide levels might be a response to a stressful component of conditioned withdrawal (Horger and Roth 1996;Jenck et al 1997). Repeated footshock stress in a stimulus pattern similar to our conditioned withdrawal protocol did not, however, induce changes in nociceptin in the frontal cortex.…”