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

Abstract

Nociceptin (N/OFQ) peptide has regulatory roles in neuroendocrine responses to stress. We sought to clarify the roles of nociceptin and its receptors (NOP receptors) in the regulation of rat bed nucleus of the stria terminalis (BNST) neurones in vitro. The effect of nociceptin (75 nM) across subregions of the anterior BNST was determined using extracellular single-unit recordings in rat brain slices. Firing patterns of the neurones were recorded in the presence of N-methyl-D-aspartate (NMDA, 10 μm) for the classification of putative cell types. Based on the firing patterns, four cell types were identified. The distribution of cell types differed between the dorsal and ventral BNST. Nociceptin inhibited the activity of 53.2% of all the neurones tested (n = 47), regardless of the cell type or subregion. The duration of nociceptin-mediated inhibition of cell firing was significantly attenuated by pre-treatment with the NOP receptor antagonist, UFP-101 (750 nM), indicating that nociceptin-induced suppression of firing rate involves NOP receptor activation in the BNST. Pre-treatment of slices with 100-nM corticosterone (CORT) vs. dimethylsulphoxide (DMSO) for 20 min significantly abolished the nociceptin-induced inhibition of firing rate (P < 0.001) when tested 2 h later. We did not, however, observe a significant effect of CORT on baseline firing rate or pattern in BNST neurones. We suggest that the interaction between nociceptin and glucocorticoids in the BNST may be essential for normal adaptive stress responses.

The role of orphanin FQ/nociceptin in neuroplasticity: relationship to stress, anxiety and neuroinflammation

“…Importantly, OFQ/N neurotransmission and stimulation of NOP-R in the BNST is thought to reduce GABAergic input to the PVN, which ultimately would prolong activation of the HPA axis and stress-induced elevations of CORT. Consistent with this hypothesis, OFQ/N elicits strong inhibition of BNST neuronal firing in vitro (Dawe et al, 2010). Moreover, unilateral, intra-BNST infusion of OFQ/N in rats dose-dependently enhanced the CORT response to mild psychogenic stress (exposure to an OF; Green et al, 2007).…”

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).…”

“…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.…”

“…This raises the question that N/OFQ-mediated impairments in memory may involve effects on 5-HT neurotransmission in the BLA or NAcc, both sites of major dorsal raphe inputs. NOP activation has also been shown to tonically inhibit noradrenaline release in the BLA (Kawahara, Hesselink, van Scharrenburg, & Westerink, 2004), glutamate and GABA release in rat lateral amygdala (LA) (Meis & Pape, 2001), and neuronal excitability in the BNST (Dawe et al, 2010). Despite this, very little is known about neurotransmitter substrates underpinning N/OFQ effects specifically on conditioned fear.…”

Further characterization of the prototypical nociceptin/orphanin FQ peptide receptor agonist Ro 64-6198 in rodent models of conflict anxiety and despair

“…The NOP receptor is highly expressed in cortical and limbic regions involved in the integration of the emotional responses of anxiety, fear, and stress such as the amygdala, the bed nucleus of the stria terminalis and the septo-hippocampal region, but also in midbrain areas including the periaqueductal gray matter, the locus coeruleus, and the dorsal raphe nucleus (Meunier 1997;Mollereau and Mouledous 2000;Neal et al 1999). NOP receptor activation decreases neuronal excitability (Chee et al 2011;Dawe et al 2010), neurotransmitter release (Cavallini et al 2003;Kawahara et al 2004;Meis 2003;Schlicker and Morari 2000), as well as neuronal plasticity in cortico-limbic structures (Bongsebandhu-phubhakdi and Manabe 2007;Manabe et al 1998;Wei and Xie 1999) and therefore likely acts via inhibition of neural activity. Activation of NOP receptors induces anxiolytic-like and anti-stress effects across multiple species (reviewed in Chiou et al 2007;Duzzioni et al 2011 ;Fernandez et al 2004;Shoblock 2007) whereas blockade of NOP receptors, by genetic (Gavioli et al 2003;Rizzi et al 2011) or pharmacological means (Gavioli et al 2004;Goeldner et al 2010 ;Redrobe et al 2002;Rizzi et al 2007), has antidepressant-like properties in despair and chronic mild stress-induced anhedonia models (Vitale et al 2009).…”