Traumatic Brain Injury Induces Nociceptin/Orphanin FQ and Nociceptin Opioid Peptide Receptor Expression within 24 Hours.

Traumatic brain injury (TBI) is a major cause of mortality and disability around the world, for which no treatment has been found. Nociceptin/Orphanin FQ (N/OFQ) and the nociceptin opioid peptide (NOP) receptor are rapidly increased in response to fluid percussion, stab injury, and controlled cortical impact (CCI) TBI. TBI-induced upregulation of N/OFQ contributes to cerebrovascular impairment, increased excitotoxicity, and neurobehavioral deficits. Our objective was to identify changes in N/OFQ and NOP receptor peptide, protein, and mRNA relative to the expression of injury markers and extracellular regulated kinase (ERK) 24 h following mild (mTBI) and moderate TBI (ModTBI) in wildtype (WT) and NOP receptor-knockout (KO) rats. N/OFQ was quantified by radioimmunoassay, mRNA expression was assessed using real-time PCR and protein levels were determined by immunoblot analysis. This study revealed increased N/OFQ mRNA and peptide levels in the CSF and ipsilateral tissue of WT, but not KO, rats 24 h post-TBI; NOP receptor mRNA increased after ModTBI. Cofilin-1 activation increased in the brain tissue of WT but not KO rats, ERK activation increased in all rats following ModTBI; no changes in injury marker levels were noted in brain tissue at this time. In conclusion, this study elucidates transcriptional and translational changes in the N/OFQ-NOP receptor system relative to TBI-induced neurological deficits and initiation of signaling cascades that support the investigation of the NOP receptor as a therapeutic target for TBI.

Acute single non-sedative doses of NOP receptor agonists affect acquisition of object location memory but repeated high doses do not induce long-lasting deficits.

The Nociceptin/Orphanin FQ (N/OFQ) system has been shown to modulate various aspects of long-term memory. It is therefore important to study the effects on memory impairment by nociceptin receptor (NOP) agonists under preclinical development. In the present study, we investigated the effect of systemic injection of two small molecule selective NOP agonists, AT-202 and AT-524, in the object location memory task in male and female mice. Since high doses of NOP agonists have been shown to induce sedation, we first determined the sedative doses for the two compounds and found them to be higher in female than in male mice. We then observed that sub-sedative doses of NOP agonists administered before learning, induced memory impairment during a test session performed 24 h later. Again, female mice were less sensitive to the amnesic effects than males. On the contrary, in male mice, NOP agonists did not produce amnesia when they were injected after learning, suggesting that they do not affect the consolidation of object location memory. Finally, repeated administration of high doses of NOP agonists over 7 days did not impair long-term spatial memory. Together, our data show for the first time that NOP receptor agonists impair the acquisition of object location memory with sex-dependent potency but do not affect memory consolidation, and that repeated stimulation of the receptor does not compromise long-term episodic-like spatial memory.

Endometriosis and Opioid Receptors: Are Opioids a Possible/Promising Treatment for Endometriosis?

Endometriosis (EM), defined as the presence of endometrial-like tissue with surrounding smooth muscle cells outside the uterus, is a disregarded gynecological disease reported to affect 6-10% of women of reproductive age, with 30-50% of them suffering from chronic pelvic pain and infertility. Since the exact pathogenic mechanisms of EM are still unclear, no curative therapy is available. As pain is an important factor in EM, optimal analgesia should be sought, which to date has been treated primarily with non-steroidal anti-inflammatory drugs (NSAIDs), metamizole or, in extreme cases, opioids. Here, we review the pain therapy options, the mechanisms of pain development in EM, the endogenous opioid system and pain, as well as the opioid receptors and EM-associated pain. We also explore the drug abuse and addiction to opioids and the possible use of NOP receptors in terms of analgesia and improved tolerability as a target for EM-associated pain treatment. Emerging evidence has shown a promising functional profile of bifunctional NOP/MOP partial agonists as safe and nonaddictive analgesics. However, until now, the role of NOP receptors in EM has not been investigated. This review offers a thought which still needs further investigation but may provide potential options for relieving EM-associated pain.

Opioid-Modulated Receptor Localization and Erk1/2 Phosphorylation in Cells Coexpressing µ-Opioid and Nociceptin Receptors.

We attempted to examine the alterations elicited by opioids via coexpressed µ-opioid (MOP) and nociceptin/orphanin FQ (NOP) receptors for receptor localization and Erk1/2 (p44/42 MAPK) in human embryonic kidney (HEK) 293 cells. Through two-photon microscopy, the proximity of MOP and NOP receptors was verified by fluorescence resonance energy transfer (FRET), and morphine but not buprenorphine facilitated the process of MOP-NOP heterodimerization. Single-particle tracking (SPT) further revealed that morphine or buprenorphine hindered the movement of the MOP-NOP heterodimers. After exposure to morphine or buprenorphine, receptor localization on lipid rafts was detected by immunocytochemistry, and phosphorylation of Erk1/2 was determined by immunoblotting in HEK 293 cells expressing MOP, NOP, or MOP+NOP receptors. Colocalization of MOP and NOP on lipid rafts was enhanced by morphine but not buprenorphine. Morphine stimulated the phosphorylation of Erk1/2 with a similar potency in HEK 293 cells expressing MOP and MOP+NOP receptors, but buprenorphine appeared to activate Erk1/2 solely through NOP receptors. Our results suggest that opioids can fine-tune the cellular localization of opioid receptors and phosphorylation of Erk1/2 in MOP+NOP-expressing cells.

Therapeutic potentials of NOP and MOP receptor coactivation for the treatment of pain and opioid abuse.

Following the identification of the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) as an endogenous ligand for the NOP receptor, ample evidence has revealed unique functional profiles of the N/OFQ-NOP receptor system. NOP receptors are expressed in key neural substrates involved in pain and reward modulation. In nonhuman primates (NHPs), NOP receptor activation effectively exerts antinociception and anti-hypersensitivity at the spinal and supraspinal levels. Moreover, NOP receptor activation inhibits dopaminergic transmission and synergistically enhances mu-opioid peptide (MOP) receptor-mediated analgesia. In this article, we have discussed the functional profiles of ligands with dual NOP and MOP receptor agonist activities and highlight their optimal functional efficacy for pain relief and drug abuse treatment. Through coactivation of NOP and MOP receptors, bifunctional NOP/MOP receptor "partial" agonists (e.g., AT-121, BU08028, and BU10038) reveal a wider therapeutic window with fewer side effects. These newly developed ligands potently induce antinociception without MOP receptor agonist-associated side effects such as abuse potential, respiratory depression, itching sensation, and physical dependence. In addition, in both rodent and NHP models, bifunctional NOP/MOP receptor agonists can attenuate reward processing and/or the reinforcing effects of opioids and other abused drugs. While a mixed NOP/opioid receptor "full" agonist cebranopadol is undergoing clinical trials, bifunctional NOP/MOP "partial" agonists exhibit promising therapeutic profiles in translational NHP models for the treatment of pain and opioid abuse. This class of drugs demonstrates the therapeutic advantage of NOP and MOP receptor coactivation, indicating a greater potential for future development.

Opioidergic Signaling-A Neglected, Yet Potentially Important Player in Atopic Dermatitis.

Atopic dermatitis (AD) is one of the most common skin diseases, the prevalence of which is especially high among children. Although our understanding about its pathogenesis has substantially grown in recent years, and hence, several novel therapeutic targets have been successfully exploited in the management of the disease, we still lack curative treatments for it. Thus, there is an unmet societal demand to identify further details of its pathogenesis to thereby pave the way for novel therapeutic approaches with favorable side effect profiles. It is commonly accepted that dysfunction of the complex cutaneous barrier plays a central role in the development of AD; therefore, the signaling pathways involved in the regulation of this quite complex process are likely to be involved in the pathogenesis of the disease and can provide novel, promising, yet unexplored therapeutic targets. Thus, in the current review, we aim to summarize the available potentially AD-relevant data regarding one such signaling pathway, namely cutaneous opioidergic signaling.

Spotlight on Nociceptin/Orphanin FQ Receptor in the Treatment of Pain.

In our society today, pain has become a main source of strain on most individuals. It is crucial to develop novel treatments against pain while focusing on decreasing their adverse effects. Throughout the extent of development for new pain therapies, the nociceptin/orphanin FQ receptor (NOP receptor) has appeared to be an encouraging focal point. Concentrating on NOP receptor to treat chronic pain with limited range of unwanted effects serves as a suitable alternative to prototypical opioid morphine that could potentially lead to life-threatening effects caused by respiratory depression in overdose, as well as generate abuse and addiction. In addition to these harmful effects, the uprising opioid epidemic is responsible for becoming one of the most disastrous public health issues in the US. In this article, the contributing molecular and cellular structure in controlling the cellular trafficking of NOP receptor and studies that support the role of NOP receptor and its ligands in pain management are reviewed.

Role of Nociceptin/Orphanin FQ-NOP Receptor System in the Regulation of Stress-Related Disorders.

Nociceptin/orphanin FQ (N/OFQ) is a 17-residue neuropeptide that binds the nociceptin opioid-like receptor (NOP). N/OFQ exhibits nucleotidic and aminoacidics sequence homology with the precursors of other opioid neuropeptides but it does not activate either MOP, KOP or DOP receptors. Furthermore, opioid neuropeptides do not activate the NOP receptor. Generally, activation of N/OFQ system exerts anti-opioids effects, for instance toward opioid-induced reward and analgesia. The NOP receptor is widely expressed throughout the brain, whereas N/OFQ localization is confined to brain nuclei that are involved in stress response such as amygdala, BNST and hypothalamus. Decades of studies have delineated the biological role of this system demonstrating its involvement in significant physiological processes such as pain, learning and memory, anxiety, depression, feeding, drug and alcohol dependence. This review discusses the role of this peptidergic system in the modulation of stress and stress-associated psychiatric disorders in particular drug addiction, mood, anxiety and food-related associated-disorders. Emerging preclinical evidence suggests that both NOP agonists and antagonists may represent a effective therapeutic approaches for substances use disorder. Moreover, the current literature suggests that NOP antagonists can be useful to treat depression and feeding-related diseases, such as obesity and binge eating behavior, whereas the activation of NOP receptor by agonists could be a promising tool for anxiety.

Potent and selective NOP receptor activation reduces cocaine self-administration in rats by lowering hedonic set point.

Developing new medications for the treatment of cocaine dependence continues to be a research priority. Compelling evidence indicates that mixed opioid receptor agonists, particularly bifunctional compounds that target nociceptin/orphanin FQ peptide (NOP) and mu opioid receptors, may be useful for the treatment of cocaine addiction. Here, we verify that potent and selective pharmacological activation of NOP receptors is sufficient to reduce relevant facets of cocaine addiction in animal models. Accordingly, we determined whether systemic injections of the small molecule AT-312 (0, 1, 3 mg/kg) could reduce operant cocaine self-administration, motivation for cocaine, and vulnerability to cocaine relapse in rats. Results indicate that a potent and selective NOP receptor agonist was equally efficacious in reducing the number of cocaine infusions in short (1-hour), as well as long (6-hour) access sessions. When tested on an economic-demand reinforcement schedule, AT-312 reduced Q0 , the parameter that describes the amount of drug consumed at zero price, while leaving the parameter α, a measure of motivation for drug consumption, unaltered. Furthermore, AT-312 successfully reduced conditioned reinstatement of cocaine seeking. In contrast, the NOP receptor agonist did not modify food self-administration. Blockade of the NOP receptor with the antagonist SB-612111 prevented the effect of AT-312 in decreasing cocaine-reinforced responding under a 2-hour fixed ratio 1 schedule, suggesting a NOP receptor-mediated mechanism. This work demonstrates that potent and selective activation of NOP receptors is sufficient to decrease cocaine taking and seeking behaviors in rats.

Nociceptin impairs acquisition of novel object recognition memory in perirhinal cortex.

Nociceptin/Orphanin FQ (N/OFQ) plays an important role in the regulation of spatial, fear and recognition memories. N/OFQ receptors are highly distributed in the perirhinal cortex, which is a key brain area involved in modulating novel object recognition (NOR) memory. However, the role of N/OFQ in NOR memory in the perirhinal cortex was still unknown. Moreover, the effects of N/OFQ on different stages of NOR memory were still unclear. In NOR task, we found that pre-training intracerebroventricular (icv) injection of N/OFQ (0.3 and 1 nmol) impaired long-term memory in a dose-dependent manner. However, icv infusion of N/OFQ immediately after training did not affect NOR memory consolidation even at a high dose of 3 nmol. Pre-test icv injection of N/OFQ (1 nmol) also did not influence NOR memory retrieval. These data indicate that N/OFQ negatively modulates long-term NOR memory during the acquisition phase. Furthermore, the amnesia effect of N/OFQ (1 nmol, icv) could be antagonist by pre-treatment with the selective N/OFQ receptor antagonist [Nphe1]N/OFQ(1-13)NH2 (10 nmol, icv), indicating pharmacological specificity. Then, we found that pre-training infusion of N/OFQ (0.1 and 0.3 nmol/side) into the bilateral perirhinal cortex impaired long-term NOR memory, suggesting the perirhinal cortex is a critical brain structure in mediating the amnesic effect of N/OFQ in NOR task. In conclusion, our data, for the first time, indicate that N/OFQ in the perirhinal cortex impairs NOR memory acquisition through the NOP receptors.