The nociceptin/orphanin FQ antagonist UFP-101 differentially modulates the glucocorticoid response to restraint stress in rats during the peak and nadir phases of the hypothalamo–pituitary–adrenal axis circadian rhythm

Endogenous Nociceptin System Involvement in Stress Responses and Anxiety Behavior

“…These two physiological systems can be considered as major effector pathways for maintenance of homeostasis during stress. On the basis of the preproN/OFQ knockout phenotype, N/OFQ was proposed as an endogenous antistress peptide opposing the stress-promoting effects of the HPA axis (Koster et al, 1999), however, we and others have provided evidence indicating that central N/OFQ in fact activates the HPA axis in rats (Devine, Watson, & Akil, 2001;Leggett, Harbuz, Jessop, & Fulford, 2006;Leggett, Jessop, & Fulford, 2007). i.c.v.…”

“…Many brain regions associated with stressor responding also mediate anxiety-like behavior and are most notably high in N/OFQ expression. Our in vivo studies using peptide infusions have shown that N/OFQ regulates hypothalamic CRH expression, and NOP antagonists prolong HPA axis responses to acute restraint (Leggett et al, 2007). Recently, we reported that stress modulates endogenous N/OFQ and decreases NOP mRNA expression (Delaney et al, 2012;Leggett et al, 2009), whereas acute glucocorticoid treatment completely suppresses N/OFQ action on BNST neuronal activity (Dawe, Wakerley, & Fulford, 2010).…”

“…Identification of novel candidates involved in fear regulation will benefit understanding of the basis of mental disorders associated with intense fear such as post-traumatic stress and anxiety disorders, in addition to other disorders associated with aberrant behavior like schizophrenia and drug addiction (Sato, 1992;Sinha, Catapano, & O'Malley, 1999). Recent research into the role of N/OFQ in the amygdala (Roozendaal, Lengvilas, McGaugh, Civelli, & Reinscheid, 2007;Uchiyama, Toda, Hiranita, Watanabe, & Eyanagi, 2008), in memory (Higgins et al, 2002), anxiety (Fernandez et al, 2004;Green, Barbieri, Brown, Chen, & Devine, 2008;Jenck et al, 2000;Uchiyama et al, 2008;Varty et al, 2005;Vitale, Arletti, Ruggieri, Cifani, & Massi, 2006), and stress (Dawe et al, 2010;Delaney et al, 2012;Devine et al, 2001;Leggett et al, 2006Leggett et al, , 2007Leggett et al, , 2009Rodi et al, 2008) demonstrates the clear potential of this peptidergic system with regard to emotional functions. The emerging data is compelling, demanding further investigation of N/OFQ's contribution to the basic fear network and fear learning.…”

Nociceptin/orphanin FQ and the regulation of neuronal excitability in the rat bed nucleus of the stria terminalis: Interaction with glucocorticoids

“…We have recently shown that N/OFQ regulates the hypophysiotropic CRF neurones in rats, and potently regulates the basal HPA axis activity (Leggett et al 2006). In response to the predominantly psychological stress of restraint, our recent evidence suggests that central NOP receptors are necessary for the normal termination of HPA axis activity (Leggett et al 2007). N/OFQmediated activation of NOP receptors in the BNST is important for the acute activation of the HPA axis in response to intracranial N/OFQ peptide infusion (Green et al 2007) and N/OFQ infusion i.c.v., or intra-BNST attenuates CRF-induced anxiety in the elevated plus maze test in rats (Rodi et al 2008).…”

Role of spinal GABAA receptor reduction induced by stress in rat thermal hyperalgesia

“…Animals were securely immobilized to restrict, but not prevent, body movements. This model has been validated to elicit physical/psychogenic stress responses associated with stimulation of the hypothalamic-pituitary-adrenal axis (Leggett et al 2007). …”