Regular paperNeurohumoral effects of orphanin FQ/nociceptin: relevance to cardiovascular and renal function☆
Introduction
The discovery of the endogenous opioid-like peptide, orphanin FQ/nociceptin (OFQ/N) in brain tissue has stimulated considerable interest in the potential physiological roles that this novel compound may have. Research initially demonstrated that OFQ/N acts selectively to activate the ORL1 (opioid receptor-like 1) receptor to produce either nociceptive and/or analgesic effects, depending on the experimental conditions of the study. Based on these and subsequent investigations, OFQ/N has been shown to have a complex pharmacology with a pattern of physiological responses that are either similar, or in opposition to those elicited by classic opioid peptide systems (i.e. the endorphins).
In addition to exhibiting a unique profile of effects on analgesic/nociceptive processes, it is clear that OFQ/N evokes marked changes in other biologic systems. OFQ/N modulates second messenger pathways, alters neurotransmitter and hormonal release, and evokes end organ responses in central and peripheral tissues. From these observations, OFQ/N has been suggested to mediate a wide variety of physiological processes. The wide distribution of OFQ/N and ORL1 in neuronal tissue suggests that this novel system may exert many of its biologic effects by modulating neurotransmission and the activity of hormonal pathways. The purpose of this article is to review what is known regarding the neural and humoral effects of OFQ/N on cardiovascular and renal function. For those areas where information is available, a brief overview of the neural and humoral effects of OFQ/N on other biologic systems will also be presented.
OFQ/N is a heptadecapeptide that has been isolated from brain tissue and shown to be the endogenous ligand of the orphan ORL1 receptor [85], [100]. The amino acid sequence of OFQ/N most closely resembles that of endogenous opioid peptides with particular similarity to dynorphin A(1–17), a proposed endogenous ligand of the κ-opioid receptor [26]. ORL1 shares a high degree of nucleotide sequence homology with each of the cloned μ, δ, and κ-opioid receptors, but most notably resembles the κ-1 subtype [86].
The structural resemblance of OFQ/N to that of endogenous opioid peptides suggests that these two systems may share common features in regards to function and/or mechanisms of action. Opioid agonists produce profound alterations in cardiovascular and renal function, respiratory rate, and gastrointestinal motility [93]. These and other biologic responses are mediated by the action of opioids to alter a broad range of neural and humoral systems. These include opioid-induced changes in central sympathetic outflow [62], [63] and the secretion/release of hormones from the pituitary [7], [8], [96], heart [41], adrenal glands [58], [96], and kidneys [58].
Neuroanatomical studies have demonstrated that OFQ/N, prepro-OFQ/N (the precursor of OFQ/N), and ORL1 are distributed throughout the CNS in regions known to participate in the regulation of autonomic and cardiovascular function, and fluid and electrolyte balance (refer to other articles in this issue for complete review). This includes expression of OFQ/N, prepro-OFQ/N, and ORL1 transcripts in regions such as the nucleus of the solitary tract, the central amygdala, the hypothalamus, the dorsal and ventral horns of the spinal cord, and in pre-vertebral and para-vertebral ganglia [2], [10], [13], [37], [42], [54], [71], [82], [86], [87], [89], [91]. In addition to the CNS, OFQ/N has been identified in neural tissue innervating the lung [40] and in several peripheral organs, including the kidneys [115].
Section snippets
OFQ/N and cardiovascular function
Arterial blood pressure is controlled by a complex interaction of neural and humoral mechanisms that act collectively to determine the level of heart rate, cardiac contractility, arterial resistance, and water and sodium balance. An alteration in one or more of these controlling systems can result in a change in arterial blood pressure. The autonomic nervous system expresses the activity of neurogenic arcs received from afferent baroreceptor inputs that innervate the nucleus of the solitary
OFQ/N and renal function
Synthetic or endogenous opioid agonists evoke profound changes in renal function (for review see ref. 58). The effects of opioids on the renal handling of water and electrolytes (e.g. sodium) can occur from a peripheral, direct renal, or CNS site of action. From these locations, opioids evoke multiple integrated neural and humoral mechanisms that act collectively to affect renal hemodynamics and/or the renal tubular reabsorption of sodium and water. OFQ/N shares a number of structural,
Conclusions
The studies summarized above demonstrate that OFQ/N can evoke profound cardiovascular responses by pathways that affect the autonomic nervous system. There is good evidence that OFQ/N affects heart rate and arterial blood pressure by interacting with pathways that affect central parasympathetic (heart) and sympathetic outflow (heart, vasculature, and kidneys). OFQ/N exerts a unique profile of physiological responses, including hypotension, bradycardia, diuresis and antinatriuresis. The neural
Acknowledgements
I thank Velga A. Kenigs and Lisa A. Dayan for their valuable technical support in the research performed in my laboratory.
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2016, NeuropeptidesCitation Excerpt :In agreement to these results, the i.c.v. administration of N/OFQ induced depressor and bradycardiac responses, as well as a reduction in urinary sodium excretion and an increase in urine flow rate(Kapusta et al., 1999). Depressor and bradycardiac responses were also observed after intravenous administration of this peptide (Champion et al., 1997; Giuliani et al., 1997; Kapusta, 2000), due to parasympathetic activation and sympathetic indirect inhibition. In addition, the increase in plasma corticosterone induced by RS was higher after i.c.v. administration of NOP antagonist (Leggett et al., 2007).
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2015, Vitamins and HormonesCitation Excerpt :Intracerebroventricular (i.c.v.) injection of N/OFQ causes a variety of behavioral effects in rodents (Calò et al., 1998; Gavioli & Calò, 2006; Meunier et al., 1995; Reinscheid et al., 1995) consistent with a broad central nervous system distribution of the peptide and its receptor (Boom et al., 1999; Mollereau et al., 1996; Neal et al., 1999a, 1999b; Nothacker et al., 1996). Diverse central actions of N/OFQ have been reported including regulation of locomotor activity (Rizzi et al., 2001), feeding (Polidori, de Caro, & Massi, 2000), cognition (Higgins et al., 2002; Nabeshima, Noda, & Mamiya, 1999), the response to psychoactive drugs (Ciccocioppo, Angeletti, Panocka, & Massi, 2000; Martin-Fardon, Ciccocioppo, Massi, & Weiss, 2000), and regulation of cardiovascular and renal function (Kapusta, 2000; Kapusta, Dayan, & Kenigs, 2002). As its name suggests, N/OFQ also regulates pain but in a complex way reflecting the intriguing pharmacology of this peptide system.
Nociceptin/Orphanin FQ-NOP Receptor System in Inflammatory and Immune-Mediated Diseases
2015, Vitamins and HormonesCitation Excerpt :The cardiovascular dysfunction in septic patients is characterized by severe hypotension, which may be mediated at least in part by NO, a potent vasodilator (Bateman, Sharpe, & Ellis, 2003). It was demonstrated that N/OFQ induces hypotension and bradycardia (Kapusta, 2000; Malinowska, Godlewski, & Schlicker, 2002), decreasing heart rate and mean arterial pressure in mice (Burmeister, Ansonoff, Pintar, & Kapusta, 2008). Using the cecal ligation and puncture (CLP) model of sepsis in rats, our group has demonstrated that the mortality rate of septic animals was significantly reduced by the treatment with a single dose of the NOP antagonist UFP-101 (Carvalho et al., 2008).
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2013, Pharmacology and TherapeuticsNociceptin/orphanin FQ in inflammation and sepsis
2011, British Journal of AnaesthesiaCitation Excerpt :Endogenous and exogenous opioids have important cardiovascular effects.30 Similarly, N/OFQ causes hypotension and bradycardia when administered i.v. and intracerebroventricularly, as demonstrated by various in vitro and in vivo animal studies and this has been covered extensively.6 31 Different mechanisms of action have been proposed and here we concentrate on the data which suggest an immunovascular link.
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This work was supported in part by United States Grants DK43337 and DK02605 from the National Institute of Diabetes and Digestive and Kidney Diseases.