Nociceptin/Orphanin FQ and Its Receptor—Potential Targets for Pain Therapy?

Abstract

The neuropeptide nociceptin, also called orphanin FQ (N/OFQ), is the endogenous agonist of the N/OFQ peptide receptor (NOP receptor). Both N/OFQ and the NOP receptor share a high degree of homology with classical opioid peptides and opioid receptors, respectively, and use similar signal transduction pathways as classical opioids. The NOP receptor has thus been regarded as the fourth member of the opioid receptor family. Despite this close relationship, 7 years of research have demonstrated that the N/OFQ system has a distinct pharmacological profile and serves different physiological functions. In particular, its role in the control of pain and analgesia at different levels of integration appears quite different from that of classical opioids. The recent development of specific antagonists at the NOP receptor and of NOP receptor or N/OFQ precursor knock-out mice have generated new insights into the role of N/OFQ in pain processing and help to evaluate the N/OFQ-NOP system as a potential target for new analgesic drugs.While acute-particularly post-traumatic and postsurgical pain can be treated satisfactorily with available analgesics in most cases-chronic inflammatory and neuropathic pain often responds only poorly. The identification of novel targets for analgesic therapy is therefore a major focus in current pharmacological research. Chronic pain states are frequently accompanied by an increased pain sensitivity, which can appear as hyperalgesia, an increased sensitivity to noxious stimuli, or allodynia, a painful sensation of usually innocuous stimuli. N/OFQ has repeatedly been implicated in the development and/or modulation of both phenomena and has thus attracted significant attention in current pain research.The discovery of N/OFQ is a prominent example of so called reverse pharmacology in which a receptor was known before the corresponding ligand could be identified (Civelli et al., 1998). Soon after the discovery of the ␦ opioid (DOP) receptor by expression cloning molecular biologists have not only identified the expected and (MOP and KOP) opioid receptors, but also a fourth unperceived receptor, which does not bind classical opioids. The human homolog of this receptor has therefore been termed opioid receptor-like 1 receptor (Mollereau et al., 1994). Only 1 year after its discovery, a 17 amino acid neuropeptide was identified as the endogenous agonist by two independent groups and called nociceptin (Meunier et al., 1995) or orphanin FQ (Reinscheid et al., 1995). Both the peptide and its receptor, now called N/OFQ peptide (NOP) receptor, share a high degree of homology with classical opioid peptides (namely dynorphin A) and classical opioid receptors (namely the opioid peptide receptor). A first series of behavioral tests has suggested that this peptide was pro-rather than antinociceptive, when injected intracerebroventricularly (i.c.v.). This effect led Meunier et al. (1995) to coin the term nociceptin. Reinscheid et al. (1995) called the peptide orphanin FQ, indicating that the peptide activat...

Acute and subchronic antinociceptive effects of nociceptin/orphanin FQ receptor agonists infused by intrathecal route in rats

“…Spinal morphine produced a dose dependent and robust antinociceptive effect in line with previous findings (Kosson et al, 2008). A similar antinociceptive action has been promoted by the spinal injection of N/OFQ accordingly to (Schroder et al, 2014;Zeilhofer and Calò, 2003;). Compared to morphine, N/OFQ displayed similar potency but reduced maximal effects.…”

“…NOP( þ/þ ) and NOP( À / À) rats displayed similar pain threshold in the Paw pressure test. This is in line with studies performed in NOP knockout mice (Depner et al, 2003;Nishi et al, 1997) suggesting that the endogenous N/OFQ -NOP receptor system does not tonically control nociceptive transmission (Zeilhofer and Calò, 2003). The spinal injection of morphine in NOP( À / À ) rats produced a clear antinociceptive effect while N/OFQ, UFP-112 and UFP-113 were completely inactive.…”

“…N/OFQ has been shown to cause hyperalgesia, allodynia or analgesia depending on the dose and the route of administration. In most of the studies, N/OFQ supraspinal administration elicits pronociceptive effects in rodents and is able to counteract the antinociceptive effects of opioids (Zeilhofer and Calò, 2003). On the contrary N/OFQ administered i.t.…”

In vitro and in vivo studies on UFP-112, a novel potent and long lasting agonist selective for the nociceptin/orphanin FQ receptor

“…These pharmacological features are highly desirable especially for investigating those conditions and states in which a selective and prolonged stimulation of NOP receptor is beneficial, including anxiety states [21,28], drug addiction [15,48], anorectic conditions [16], spinal analgesia (as indicated by laboratory animals [54] as well as primate [35] studies), cough and possibly other respiratory diseases [40], acute heart failure [26,34], and, as indicated by clinical studies, urinary incontinence due to overactive bladder [37][38][39]. Peak changes in mean arterial pressure and heart rate produced immediately following i.v.…”

Pharmacological Studies of NOP Receptor Agonists as Novel Analgesics

“…30,39 It has been suggested that intrathecal N/OFQ-induced hyperalgesia may be mediated by tachykinin NK1 receptors in the mouse spinal cord. 39,40 Although intrathecal N/OFQ did not produce hyperalgesic effects like intrathecal substance P in monkeys, more studies are warranted to elucidate the relationship of intrathecal substance P with other neurotransmitter systems in the modulation of nociceptive processing of the primate spinal cord.In contrast, intrathecal administration of DAMGO 10 nmol significantly produced antinociceptive effects, manifested as elevated tail-withdrawal latencies in 50 C water. These effects are consistent with rodent studies, indicating that intrathecal DAMGO is a potent m-opioid antinociceptive agent.…”