Role of Nociceptin/Orphanin FQ and NOP Receptors in the Response to Acute and Repeated Restraint Stress in Rats

Abstract

Central nociceptin/orphanin FQ (N/OFQ)-expressing neurones are abundantly expressed in the hypothalamus and limbic system and are implicated in the regulation of activity of the hypothalamic-pituitary-adrenal axis (HPA) and stress responses. We investigated the role of the endogenous N/OFQ receptor (NOP) system using the nonpeptidic NOP antagonist, JTC-801 [N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxy-methyl)benzamide monohydrochloride], during the HPA axis response to acute physical/psychological stress (60 min of restraint). Although i.v. JTC-801 (0.05 mg/kg in 100 μl) had no significant effect on restraint-induced plasma corticosterone release at 30 or 60 min post-injection, i.v. JTC-801 (0.05 mg/kg in 100 μl) in quiescent rats significantly increased basal plasma corticosterone at the 30-min time-point compared to i.v. vehicle (1% dimethysulphoxide in sterile saline). Central injection of JTC-801 i.c.v. was associated with increased Fos expression in the parvocellular paraventricular nucleus 90 min after infusion compared to vehicle control. These findings contrast to the effects of i.c.v. UFP-101, a NOP antagonist that we have previously shown to have no effect on HPA activity in quiescent rats. To determine whether restraint stress was associated with compensatory changes in N/OFQ precursor (ppN/OFQ) or NOP receptor mRNAs, in a separate study, we undertook reverse transcriptase-polymerase chain reaction and in situ hybridisation analysis of ppN/OFQ and NOP transcripts in the brains of male Sprague–Dawley rats. In support of an endogenous role for central N/OFQ in psychological stress, we found that acute restraint significantly decreased preproN/OFQ transcript expression in the hippocampus 2 h after stress compared to unstressed controls. PpN/OFQ mRNA was also reduced in the mediodorsal forebrain 4 h after stress. NOP mRNA was reduced in the hypothalamus 2 h after restraint and at 4 h in mediodorsal forebrain and hippocampus. In situ hybridisation analysis showed that acute restraint significantly decreased ppNN/OFQ in the central amygdala, with significantly increased expression in bed nucleus and reticular thalamus associated with repeated restraint. There was a strong trend for reduced NOP mRNA in the bed nucleus of acute and repeated restraint groups, although there were no other significant changes seen. Although the exact mechanisms require elucidation, the findings obtained in the present study provide evidence indicating that the endogenous N/OFQ system is involved in both acute and chronic restraint stress responses. In summary, our findings confirm the significant role of endogenous NOP receptors and tonic N/OFQ function in the response to the psychological stress of restraint.

Endogenous Nociceptin System Involvement in Stress Responses and Anxiety Behavior

“…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). Chronic restraint stress is also associated with marked increases in limbic BNST expression of preproN/OFQ, presumably in response to stress-induced release of N/OFQ peptide (Delaney et al, 2012).…”

“…We have also reported significant changes in expression of preproN/OFQ mRNA transcript following acute and repeated restraint stress in rats. Acute restraint significantly reduces preproN/OFQ mRNA expression in the central amygdala (CeA), whereas repeated restraint significantly increases precursor transcript levels in the BNST and dorsal reticular thalamic nucleus (Delaney et al, 2012). In contrast, NOP receptor mRNA expression appears to be quite resistant to stress-induced changes, at least when monitored using in situ hybridization histochemistry (Delaney et al, 2012).…”

“…Acute restraint significantly reduces preproN/OFQ mRNA expression in the central amygdala (CeA), whereas repeated restraint significantly increases precursor transcript levels in the BNST and dorsal reticular thalamic nucleus (Delaney et al, 2012). In contrast, NOP receptor mRNA expression appears to be quite resistant to stress-induced changes, at least when monitored using in situ hybridization histochemistry (Delaney et al, 2012). The impact of chronic stressors on mRNA expression implies that robust changes in N/OFQergic neuronal regulation contribute to habituation to stress.…”

“…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). Chronic restraint stress is also associated with marked increases in limbic BNST expression of preproN/OFQ, presumably in response to stress-induced release of N/OFQ peptide (Delaney et al, 2012). NOP receptor mRNA in BNST is correspondingly reduced by chronic restraint, providing provocative evidence that chronic stress (and associated anxiety) elicits adaptations in the N/OFQ system.…”

Antidepressant-like Effects of Buprenorphine are Mediated by Kappa Opioid Receptors

“…BPN has low affinity for ORL-1 receptors, and we did not observe diminished activity of BPN's effects in the FST following systemic administration of JTC-801. At this dose JTC-801 is known to diminish allodynia and hyperalgesia in mice and reverse stress-induced behavioral deficits (Delaney et al, 2012;Yamada et al, 2002;Zhang et al, 2015). Numerous studies have shown that activation of ORL-1 receptors produces anxiolytic effects, whereas antagonism evokes antidepressant-like responses (Witkin et al, 2014).…”