Nociceptin and the NOP Receptor in Pain Management: From Molecular Insights to Clinical Applications

Abstract

Nociceptin/orphanin FQ (N/OFQ) is a neuropeptide that activates the nociceptin opioid peptide (NOP) receptor, a G protein-coupled receptor structurally similar to classical opioid receptors but with distinct pharmacological properties. Unlike μ-opioid receptor (MOR) agonists, NOP receptor agonists provide analgesia with a reduced risk of respiratory depression, tolerance, and dependence. This review synthesizes current evidence from molecular studies, animal models, and clinical trials to evaluate the therapeutic potential of the N/OFQ–NOP system in pain management and anesthesia. A literature review was conducted through a PubMed search of English language articles published between 2015 and 2025 using keywords such as “nociceptin,” “NOP receptor,” “bifunctional NOP/MOR agonists,” and “analgesia.” Primary research articles, clinical trials, and relevant reviews were selected based on their relevance to NOP pharmacology and therapeutic application. Additional references were included through citation tracking of seminal papers. Comparisons with classical opioid systems were made to highlight key pharmacological differences, and therapeutic developments involving NOP-selective and bifunctional NOP/MOR agonists were examined. In preclinical models of chronic inflammatory and neuropathic pain, NOP receptor ago-nists reduced hyperalgesia by 30–70%, while producing minimal effects in acute pain as-says. In healthy human volunteers, bifunctional NOP/MOR agonists such as cebrano-padol provided significant pain relief, achieving ≥30% reduction in pain intensity in up to 70% of subjects, with lower incidence of respiratory depression compared with morphine. Sunobinop, another NOP/MOR agent, demonstrated reduced next-day residual effects and a favorable cognitive safety profile. Clinical data also suggest that co-activation of NOP and MOR may attenuate opioid-induced hyperalgesia and tolerance. However, challenges remain, including variability in receptor signaling and limited human trial data. The N/OFQ–NOP receptor system represents a promising and potentially safer target for analgesia and perioperative care. Future efforts should focus on developing optimized NOP ligands, incorporating personalized approaches based on receptor variability, and advancing clinical trials to integrate these agents into multimodal pain management and enhanced recovery protocols.

1. Introduction

Nociceptin, also known as orphanin FQ, is a 17-amino acid neuropeptide that was first identified in 1995 as the endogenous ligand for the nociceptin/orphanin FQ peptide receptor (NOP), previously termed the opioid receptor-like 1 (ORL1) receptor [1,2]. Although structurally similar to classical opioid peptides such as dynorphin and enkephalins, nociceptin binds to a distinct receptor system that is phylogenetically related to—but pharmacologically distinct from—the traditional opioid receptors: mu opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR) [1,2].

Since its discovery, NOP receptor research has rapidly evolved from basic receptor characterization to translational applications [1,3]. Early pharmacologic studies estab-lished that, despite its structural homology to classical opioid receptors, NOP displays distinct binding affinities and signaling mechanisms, particularly through Gi/o protein coupling without typical opioid-induced side effects [1,2]. These foundational insights have driven exploration of NOP-targeting agents as promising alternatives in pain and anesthesia therapeutics [3,4].

Unlike MOR, DOR, and KOR, which are potently antagonized by naloxone and mediate well-characterized opioid effects such as euphoria, sedation, and respiratory depression [3,4], the NOP receptor is not antagonized by naloxone and displays a complex pharmacologic profile. Activation of NOP receptors may produce either pronociceptive or antinociceptive effects, depending on the dose, site of action, and physiological context [5]. This bidirectional modulation of pain makes the nociceptin system a particularly compelling target in the development of novel analgesics and anesthetic adjuvants.

The urgent need for alternatives to conventional opioids arises from their well-documented limitations: high risk of respiratory depression, rapid development of tolerance, potential for dependence and addiction, and limited efficacy in certain chronic pain states [5,6]. These issues have fueled the ongoing opioid crisis and underscored the demand for safer, non-addictive analgesics [6].

Recent research suggests that NOP agonists can provide analgesia with minimal risk of respiratory depression, tolerance, or addiction [6]—side effects commonly associated with MOR-targeted opioids [3,7]. In non-human primates, the NOP agonist SCH 221510 produced dose-dependent antinociception comparable to morphine without inducing respiratory depression, even at doses five times the effective analgesic dose [6]. Notably, cebranopadol also delayed the onset of tolerance by more than two-fold compared with morphine when administered over multiple days [7]. In a randomized, double-blind, placebo-controlled trial, it significantly reduced pain intensity in patients with chronic low back pain, with a least-squares mean difference of –1.1 on a 0–10 numerical rating scale versus placebo (p < 0.01), and demonstrated a tolerability profile comparable to classical opioids, but with a lower incidence of nausea and no reported cases of respiratory depression [8]. These properties have spurred growing interest in the integration of nociceptin-based therapies into multimodal analgesia and perioperative pain protocols, especially amid the ongoing opioid crisis.

The relevance of the nociceptin system to anesthesiology extends beyond analgesia. Preclinical and emerging clinical studies have demonstrated that NOP receptor modulation may influence sedation depth, stress response, and even cognitive recovery following anesthesia, highlighting its potential role in enhanced recovery after surgery (ERAS) pathways and critical care sedation strategies [3,4]. This paper aims to review current preclinical and clinical evidence on the N/OFQ–NOP receptor system and evaluate its therapeutic potential in pain management and anesthesia, particularly its role in enhancing perioperative care while minimizing opioid-related adverse effects.

2. Molecular and Pharmacological Profile

2.1. Structure and Function of Nociceptin and NOP Receptors

Nociceptin is derived from a larger precursor protein known as prepronociceptin. The amino acid sequence of nociceptin (FGGFTGARKSARKLANQ) is highly conserved across mammalian species and shares structural homology with endogenous opioid peptides, particularly dynorphin A, despite displaying distinct pharmacological properties [4,5].

The NOP receptor is a G protein-coupled receptor (GPCR) that belongs to the opioid receptor family. Structurally, the NOP receptor exhibits the characteristic seven-transmembrane domain architecture common to class A GPCRs and shares approximately 60% amino acid sequence homology with classical opioid receptors (mu, delta, and kappa) [8]. However, it diverges significantly in regions crucial for ligand binding, particularly within the binding pocket, which accounts for its insensitivity to traditional opioid ligands such as morphine or naloxone [7]. Crystal structures of the human NOP have been instrumental in elucidating its ligand-binding pocket and conformational states. These structural insights facilitate molecular docking and structure-based design of selective and biased ligands with optimized therapeutic profiles.

Upon binding of nociceptin, the NOP receptor primarily couples to the inhibitory G protein G_i/o, leading to a cascade of downstream signaling events [9]. This coupling results in the inhibition of adenylyl cyclase activity, suppression of cyclic AMP (cAMP) production, and subsequent modulation of protein kinase A (PKA) activity [10]. Additionally, NOP receptor activation leads to the opening of G protein-gated inwardly rectifying potassium (GIRK) channels and inhibition of voltage-gated calcium channels, particularly in neuronal tissues, contributing to reduced neuronal excitability and neurotransmitter release [11,12].

Beyond canonical G protein-mediated pathways, NOP receptors can also engage β-arrestin-dependent signaling pathways, influencing receptor desensitization and internalization and potentially contributing to biased agonism [13,14]. Compared with the mu opioid receptor (MOR), which rapidly recruits β-arrestin following high-efficacy agonist binding—leading to desensitization, internalization, and down-stream side effects such as respiratory depression—NOP receptors exhibit slower and more variable β-arrestin recruitment [13,14,15]. This suggests a more favorable G protein-to-β-arrestin signaling bias in the NOP system, which is a key consideration in developing biased agonists aimed at preserving therapeutic benefits (e.g., analgesia) while minimizing side effects [13,15]. This dual signaling capacity has significant implications for the development of NOP-targeting therapeutics, particularly in pain, anxiety, and substance use disorders, where dissociation between analgesic efficacy and side-effect profile is desirable [15].

Together, the structural and functional characteristics of nociceptin and the NOP receptor delineate a distinct neuromodulatory system within the broader opioid family, offering unique pharmacological opportunities such as bifunctional MOP/NOP agonists for chronic pain management [6,7] and biased NOP agonists that preferentially activate G protein pathways while minimizing β-arrestin recruitment—an approach shown to re-duce side effects like respiratory depression and tolerance [13,15]. Figure 1 illustrates the intracellular signaling pathway activated by nociceptin through GPCRs.

2.2. Comparison with Classical Opioid Receptors

The NOP shares substantial structural homology with classical opioid receptors—MOR, DOR, and KOR—yet displays several distinct pharmacological and physiological properties [7,8]. These differences underscore the unique role of the NOP system in neuromodulation and its potential therapeutic implications [15].

Although the NOP receptor is structurally homologous to classical opioid receptors (approximately 60% amino acid identity in the transmembrane domains), it exhibits low or negligible affinity for typical opioid ligands such as morphine, fentanyl, or endogenous enkephalins [16]. Instead, its endogenous ligand nociceptin/orphanin FQ (N/OFQ) binds with high affinity and selectivity to the NOP receptor (Ki ≈ 0.1–1 nM), without activating MOR, DOR, or KOR receptors [17,18].

In terms of anatomical distribution, NOP receptor mRNA and protein are broadly expressed throughout the central nervous system, including regions involved in pain modulation (e.g., periaqueductal gray, spinal cord dorsal horn), emotion and stress (e.g., amygdala, hippocampus), and reward (e.g., ventral tegmental area, nucleus accumbens) [19,20]. Peripheral expression of NOP receptors has also been observed in dorsal root ganglia, sympathetic ganglia, and immune cells, suggesting a role in modulating peripheral nociceptive signaling and neuroimmune interactions [19]. While there is partial overlap with classical opioid receptors, the distribution patterns and expression levels differ, which may contribute to the distinct pharmacological responses seen with NOP-targeting agents [19,20].

One of the defining pharmacological characteristics of the NOP receptor is its insensitivity to naloxone and other opioid antagonists that effectively block classical opioid receptors. Naloxone, a non-selective antagonist at MOR, DOR, and KOR, exhibits minimal antagonistic activity at NOP receptors even at high concentrations (up to micromolar range) [13]. This pharmacological distinction has important clinical implications, particularly in the design of analgesics or anxiolytics with reduced risk of naloxone-reversible respiratory depression and abuse potential [3,6].

N/OFQ remains the only well-characterized endogenous ligand for the NOP receptor, though alternative peptide fragments of prepronociceptin may exert weak or modulatory activity [5]. Unlike classical opioids, which are subject to rapid receptor desensitization and internalization largely mediated by β-arrestin recruitment, NOP receptor desensitization appears to be ligand- and context-dependent. Prolonged exposure to high concentrations of N/OFQ leads to receptor phosphorylation, β-arrestin recruitment, and subsequent internalization, but with slower kinetics compared with MOR or DOR [3].

In MOR systems, β-arrestin 2 recruitment is robust and plays a key role in receptor internalization, MAPK (ERK/JNK) signaling, and the development of analgesic tolerance, respiratory depression, and constipation [13,14]. In contrast, NOP receptors exhibit weaker and more delayed β-arrestin recruitment, leading to reduced internalization and less engagement of β-arrestin-mediated ERK/JNK pathways [15,16,17]. This divergence in downstream signaling is clinically significant. MOR agonists that strongly activate β-arrestin 2 tend to produce rapid tolerance and adverse effects. Meanwhile, NOP agonists that preferentially activate G_i/o pathways (G protein-biased agonists) can provide analgesia with diminished β-arrestin-mediated side effects, such as respiratory depression or physical dependence [15,16,17,18]. Functionally, this suggests that MOR signaling is “balanced” (involving both G protein and β-arrestin), which contributes to both analgesia and adverse effects. NOP receptor signaling, by contrast, is often “G protein-biased,” promoting analgesia while minimizing liabilities like sedation, abuse potential, or overdose risk [18,19].

Thus, NOP receptors may display functional tolerance without the same degree of physical dependence or withdrawal syndromes observed with MOR agonists [7].

This unique pharmacological profile—marked by selective ligand binding, naloxone insensitivity, and distinct desensitization kinetics—positions the NOP receptor as a promising target for developing novel therapeutics aimed at treating pain, anxiety, addiction, and mood disorders without the liabilities associated with classical opioid receptor activation [17,18].

Table 1. Comparison of NOP receptors and classical opioid receptors. Key differences between NOP receptors and classical opioid receptors in terms of ligand specificity, pharmacological effects, therapeutic potential, and mechanisms of receptor desensitization and internalization.

Feature	NOP Receptor	Classical Opioid Receptors (MOR, DOR, KOR)
Endogenous Ligand	Nociceptin/orphanin FQ [5]	Endorphins, enkephalins, dynorphins [3]
Drug Binding	Not activated by morphine or traditional opioids [13,16,17,18]	Activated by opioids like morphine, fentanyl, heroin [16]
Analgesic Effect	Complex: pro- or anti-nociceptive depending on site and context [16,17,18]	Primarily analgesic via inhibition of pain pathways [17,18]
Respiratory Depression	Minimal or none [7]	Significant, especially with MOR agonists [7]
Abuse Potential	Low [7]	High (especially with MOR activation) [7]
Therapeutic Interest	Novel analgesics, anxiety, depression, substance use disorders [17,18]	Pain relief, sedation, anesthesia, opioid use disorder treatment [17,18]
Desensitization and Internalization	Ligand- and context-dependent, slower β-arrestin recruitment and internalization with prolonged N/OFQ exposure [3]	Rapid desensitization and internalization largely via β-arrestin recruitment, especially with high-efficacy agonists [3]
G-Protein vs. β-Arrestin Signaling	Primarily Gi/o; minimal β-arrestin recruitment—G protein bias is therapeutically exploitable [13,15]	Strong β-arrestin recruitment, especially with high-efficacy agonists—associated with side effects [13,15]
Distribution (CNS/Peripheral)	Widespread in CNS: PAG, thalamus, hippocampus, amygdala, VTA, SC; present in DRG, immune cells [19,20]	Widespread in CNS: thalamus, PAG, spinal cord, nucleus accumbens; lower in periphery [19]
Downstream Signaling Pathways	Activates Gi/o proteins leading to inhibition of adenylyl cyclase, reduction of cAMP, activation of inward-rectifier K+ channels, inhibition of voltage-gated Ca2+ channels; minimal β-arrestin pathway activation; limited ERK1/2 and MAPK phosphorylation [7,8,15]	Activates Gi/o proteins inhibiting adenylyl cyclase, modulating ion channels (K+ and Ca2+), but also strongly recruits β-arrestins that mediate receptor internalization and activate additional signaling cascades including ERK1/2, MAPK, and other kinase pathways linked to tolerance and side effects [7,8,15]

CNS = central nervous system; PAG = periaqueductal gray; VTA = ventral tegmental area; SC = spinal cord; DRG = dorsal root ganglion; ERK = extracellular signal-regulated kinase; MAPK = mitogen-activated protein kinase.

highlights the main differences between the NOP receptor and classical opioid receptors.

3. Nociceptin in Pain Modulation

3.1. Central vs. Peripheral Effects

The N/OFQ system exhibits complex roles in pain modulation, with effects varying based on the site of action within the nervous system. At the spinal level, activation of NOP receptors generally leads to antinociceptive outcomes [19]. This is achieved through mechanisms such as inhibition of neurotransmitter release and modulation of ion channel activity, which collectively reduce neuronal excitability and dampen pain transmission [19]. In animal studies, intrathecal administration of NOP agonists like N/OFQ and UFP-112 has demonstrated analgesic effects in acute nociceptive assays such as tail-flick and formalin tests, and these effects are further enhanced when combined with morphine [21,22]. However, it is important to note that very low doses of spinal N/OFQ may paradoxically induce hyperalgesia, indicating a narrow therapeutic window [21,22].

In contrast, supraspinal activation of NOP receptors can yield pronociceptive effects. When N/OFQ is administered intracerebroventricularly, it has been observed to decrease pain thresholds, suggesting an enhancement of pain perception [21,22]. This effect is consistent with observations that supraspinal NOP agonists can counteract opioid analgesia and induce hyperalgesia, possibly through activity in brain regions like the periaqueductal gray (PAG) [21]. Conversely, supraspinal NOP antagonists have been shown to relieve inflammatory allodynia in rodent models, implying that endogenous NOP activity may be pronociceptive in this region [19,21,23,24]. This dichotomy between spinal and supraspinal effects underscores the complexity of the N/OFQ–NOP system in pain regulation.

Peripherally, NOP receptors are also expressed on primary afferent neurons and immune cells and in the dorsal root ganglia (DRG) [19,20]. Local application of NOP agonists, such as intraplantar N/OFQ or Ro64-6198, has produced analgesic effects in some models of acute and neuropathic pain [25,26,27,28]. However, the peripheral analgesic effects tend to be modest and sometimes mediated through naloxone-sensitive, non-NOP mechanisms, suggesting an incomplete understanding of their action outside the CNS [25].

3.2. Animal Models of Nociceptin and Pain

Animal studies have been instrumental in elucidating the role of the N/OFQ–NOP system in various pain states. In models of acute pain, such as the tail-flick or hot-plate tests, NOP receptor activation has shown minimal efficacy when administered systemically, although intrathecal administration can enhance analgesia [23,24]. Systemic NOP agonists like Ro64-6198 have limited effect in acute nociceptive models, further underscoring the site-dependent complexity of NOP pharmacology [28,29].

In inflammatory pain models—for example, those induced by complete Freund’s adjuvant (CFA) or carrageenan—intrathecal NOP agonists significantly attenuate hyperalgesia [19,30]. However, very low doses may paradoxically exacerbate inflammatory pain. Supraspinal NOP antagonists in these models have relieved allodynia, further supporting the concept of a pronociceptive role for supraspinal NOP tone in inflammatory contexts [3,30].

In neuropathic pain models such as chronic constriction injury (CCI) and spinal nerve ligation (SNL), NOP receptor agonists have demonstrated robust antinociceptive effects. Intrathecal delivery of agents like UFP-112 effectively reduces allodynia and hyperalgesia [21,24,28]. Additionally, supraspinal administration of certain non-peptide NOP agonists (e.g., Ro65-6570) has shown efficacy in reducing neuropathic pain, although results are mixed—some studies indicate that blocking supraspinal NOP receptors may also provide analgesia [19]. Peripherally, agents like intraplantar Ro64-6198 have reduced pain behaviors in nerve-injury models, although systemic administration is generally ineffective without targeted delivery [31].

3.3. Interactions with the Endogenous Opioid System

The N/OFQ–NOP system interacts intricately with the endogenous opioid system, particularly the MOR pathway. Co-activation of NOP and MOR has been shown to produce synergistic analgesic effects while potentially mitigating adverse effects associated with MOR activation, such as tolerance and hyperalgesia [27,28]. For instance, NOP agonists have been observed to suppress the development of opioid-induced hyperalgesia by modulating downstream signaling pathways, including β-arrestin recruitment and MAPK activation, implicated in opioid tolerance [29,30].

Moreover, bifunctional NOP/MOR agonists such as cebranopadol and AT-121 have demonstrated the ability to maintain analgesia without inducing classic MOR-related side effects. In preclinical studies, these agents not only provided effective analgesia in inflammatory and neuropathic models but also reduced opioid-seeking behaviors and respiratory depression [30]. These interactions highlight the potential of targeting the N/OFQ–NOP system to enhance opioid analgesia and reduce associated side effects.

Table 2. Advantages and disadvantages of NOP receptor targeting in preclinical (animal) pain models. Summary of the analgesic potential and limitations of NOP receptor-targeting agents across various animal models and anatomical sites of action.

Pain Type	Site of Action	Advantages	Disadvantages
Acute Pain	Spinal	Intrathecal NOP agonists (e.g., N/OFQ, UFP-112) produce analgesia in rodent nociceptive assays (tail-flick, formalin) and potentiate morphine analgesia [22].	Very low doses of spinal N/OFQ can cause hyperalgesia (pronociception) in rodents [22]. Systemic NOP agonists have limited efficacy in acute pain models (rodent studies) [26].
	Supraspinal	(No robust analgesic effect observed in rodents)	Supraspinal NOP agonists in rodents induce hyperalgesia and counteract opioid analgesia (e.g., intracerebroventricular N/OFQ causes pronociception) [22].
	Peripheral	Peripheral NOP agonists can reduce acute nociception in some models (e.g., intraplantar N/OFQ produces tail-flick analgesia) [26].	Peripheral analgesic effects are modest and may involve non-NOP mechanisms (analgesia often naloxone-sensitive) [26].
Inflammatory Pain	Spinal	Intrathecal NOP agonists attenuate inflammatory hyperalgesia (e.g., CFA- or carrageenan-induced) in rodents [22].	Very low-dose spinal N/OFQ may paradoxically enhance inflammatory pain [22].
	Supraspinal	(Rodents) Supraspinal NOP antagonists (e.g., in PAG) relieve inflammatory allodynia, implying NOP tone is pronociceptive [19].	Supraspinal NOP agonists exacerbate inflammatory pain (hyperalgesia, anti-opioid effects) in rodents [19].
	Peripheral	Local NOP agonists (e.g., injected at inflammation site) may reduce inflammatory pain (by analogy to neuropathic models) [32].	Systemic/peripheral NOP agonist analgesia requires high doses; efficacy is limited without central delivery [31].
Neuropathic Pain	Spinal	Intrathecal NOP agonists relieve neuropathic allodynia/hyperalgesia (e.g., CCI or SNL models) in rodents [22].	High doses are often needed; long-term efficacy and tolerance are not fully characterized [22].
	Supraspinal	Some non-peptide NOP agonists (e.g., Ro65-6570) reduce neuropathic allodynia when given intracerebroventricularly in rodents [19].	Blocking supraspinal NOP also relieves neuropathic pain (mixed findings); net supraspinal effect is unclear [19].
	Peripheral	Local NOP agonists (e.g., intraplantar Ro64-6198) produce antiallodynia in nerve-injury models [33].	Systemic or peripheral administration (e.g., subcutaneous) is generally ineffective without targeted delivery [33].

CCI = chronic constriction injury; SNL = spinal nerve ligation.

summarizes the advantages and disadvantages of targeting the NOP receptor in preclinical (animal) pain models.

4. Clinical Implications in Anesthesia

4.1. Anesthetic-Sparing Effects

N/OFQ and its receptor NOP have garnered attention for their potential to reduce the required doses of conventional anesthetics. Preclinical studies suggest that NOP receptor agonists can enhance analgesic and sedative effects, thereby lowering the necessary concentrations of agents like isoflurane or propofol [7,33]. This anesthetic-sparing effect is attributed to the modulation of nociceptive pathways and the promotion of non-rapid eye movement (NREM) sleep states. By activating NOP receptors, these agonists inhibit excitatory neurotransmitter release and hyperpolarize neurons, leading to decreased neuronal excitability [34,35]. Consequently, patients may achieve adequate anesthesia with reduced exposure to traditional anesthetics, potentially minimizing associated side effects and improving recovery profiles.

4.2. Role in Multimodal Analgesia

Incorporating NOP receptor agonists into multimodal analgesia regimens offers a promising strategy to enhance pain control while mitigating opioid-related adverse effects. These agonists exhibit synergistic interactions with both opioid and non-opioid analgesics, allowing for lower doses of each agent to achieve effective analgesia [36]. This synergy not only enhances pain relief but also reduces the incidence of side effects such as respiratory depression, nausea, and constipation commonly associated with higher doses of opioids. Furthermore, NOP receptor agonists have been shown to attenuate the development of opioid tolerance and dependence, addressing significant challenges in chronic pain management [32]. By modulating distinct yet complementary pain pathways, the integration of NOP receptor agonists into multimodal analgesic approaches holds the potential to improve patient outcomes and satisfaction.

4.3. Effects on Respiratory Drive and Consciousness

A critical concern in anesthesia is the risk of respiratory depression and altered consciousness associated with opioid use. NOP receptor agonists present a distinct profile in this regard. Unlike traditional MOR agonists, NOP receptor activation does not significantly suppress respiratory drive [3]. This characteristic makes NOP receptor agonists particularly valuable in procedural sedation, where maintaining spontaneous ventilation is essential. Additionally, while NOP receptor agonists can induce sedation, they tend to preserve arousability and cognitive function to a greater extent than classical opioids [31]. This balance between sedation and consciousness is advantageous in settings requiring patient cooperation or rapid recovery after procedure. The unique effects of NOP receptor agonists on respiratory and cognitive functions underscore their potential as safer alternatives in anesthesia and sedation practices.

Table 3. Advantages and disadvantages of NOP receptor targeting in clinical pain conditions and in co-administration with opioids. Potential advantages and disadvantages of NOP-targeting agents in treating acute and chronic pain, as well as their use alongside traditional opioids.

Clinical Condition	Advantages	Disadvantages
Acute Pain	Dual NOP/MOP agonists (e.g., cebranopadol) provide strong analgesia comparable to opioids [22]. NOP agonists produce analgesia with minimal respiratory depression and reduced pruritus (observed in primate studies) [22].	Pure NOP agonists alone have only modest efficacy in acute pain (no approved drugs yet) [26]. High doses can cause side effects (nausea, hypotension) requiring careful titration [26].
Chronic Pain	Cebranopadol significantly reduces chronic low-back and neuropathic pain and improves function [22]. NOP agonism is expected to control chronic pain with fewer opioid-like side effects (lower tolerance/dependence risk) [22].	Higher doses of NOP-based drugs can cause adverse effects (dizziness, nausea), requiring slow titration [26]. Long-term safety and efficacy of pure NOP agonists in chronic pain are not yet established [26].
Co-Administration with Opioids	NOP agonists synergize with opioids: spinal co-administration enhances analgesia without worsening pruritus (animal studies) [22]. NOP activation may reduce opioid reward and dependence (preclinical models) [22].	Human co-administration effects are uncertain; potential for unexpected interactions [26]. Central NOP activation might oppose opioid analgesia (as seen in rodent supraspinal studies) [26].

summarizes the advantages and disadvantages of targeting the NOP receptor in clinical pain management and in combination with opioids.

5. Therapeutic Agents Targeting the NOP Receptor

5.1. NOP Agonists

Therapeutic targeting of the NOP receptor has advanced significantly with the development of selective and mixed NOP agonists. Compounds such as SCH 221510, Ro 64-6198, and cebranopadol represent distinct classes of NOP receptor ligands that demonstrate promising analgesic properties. SCH 221510 is a selective nonpeptidic NOP agonist with potent antinociceptive effects in rodent models; however, its clinical utility is limited by poor oral bioavailability (<20%) and a short half-life (~1.5 h) [37]. Ro 64-6198, another selective nonpeptidic agonist, exhibits anxiolytic and antinociceptive effects in animals. Despite good brain penetration, its low oral activity and adverse effects at higher doses—such as sedation and hypothermia—have hindered clinical translation [38,39].

Cebranopadol is a notable example of a bifunctional agent, acting as a mixed NOP and MOR agonist. It has advanced to Phase II and III clinical trials for the treatment of chronic pain. Clinical data indicate that cebranopadol provides effective analgesia in neuropathic and cancer-related pain while potentially reducing opioid-related side effects such as respiratory depression and tolerance [40]. Its dual receptor activity is believed to contribute to a broader and more balanced analgesic profile [40]. Pharmacokinetic studies in humans reveal that cebranopadol has favorable oral bioavailability (~80%) and a prolonged half-life of approximately 15 h, enabling once-daily dosing [41,42]. Trial outcomes showed significant reductions in pain scores with fewer adverse events than classical opioids [41,42]. Despite these advantages, cebranopadol still carries a risk of dependence and abuse, albeit potentially lower than classical opioids, and requires careful monitoring in long-term use [40]. Another promising bifunctional ligand, AT-121, a mixed NOP/MOR partial agonist, has demonstrated morphine-comparable analgesia in non-human primates while minimizing respiratory depression, reward liability, and tolerance [43]. It possesses favorable pharmacokinetics (half-life ~8–10 h) and is progressing through early clinical stages [43]. Additionally, computational modeling, including molecular docking, plays a critical role in screening and optimizing NOP-targeting ligands. Structural models of the NOP receptor, combined with ligand docking, can predict receptor–ligand interactions and guide rational drug design. The development of NOP-targeting agents continues to be a dynamic field, with the goal of producing analgesics that retain efficacy while minimizing the drawbacks of traditional opioids [39,40].

5.2. NOP Antagonists

NOP receptor antagonists are a relatively underexplored but increasingly important class of compounds with potential applications beyond pain management. These agents block the action of endogenous N/OFQ, thereby modulating a range of physiological processes, including arousal, mood regulation, and stress response [44]. One emerging area of interest is the use of NOP antagonists to counteract the sedative and cognitive-impairing effects of NOP agonists or conditions characterized by excessive NOP system activity [44,45]. For example, antagonism at the NOP receptor may facilitate recovery of consciousness or alertness following procedural sedation, offering a pharmacologic tool akin to how naloxone reverses mu-opioid effects [41].

Beyond their potential in anesthetic reversal, NOP antagonists show promise in neuropsychiatric contexts. Preclinical studies suggest that these agents may exert antidepressant and anxiolytic effects by enhancing monoaminergic transmission, particularly in the prefrontal cortex and limbic structures [42]. Dysregulation of the NOP system has been implicated in disorders such as depression, anxiety, and schizophrenia, and NOP antagonists may normalize neurotransmission in these conditions [46]. Additionally, NOP antagonists are being explored for their cognitive-enhancing properties, especially in models of stress-induced cognitive deficits or neurodegenerative diseases [43]. BTRX-246040 (LY 2940094), a selective NOP antagonist, has shown favorable pharmacokinetics (oral bioavailability >60%, half-life 6–12 h) and CNS penetration in Phase II trials for major depressive disorder and alcohol use disorder [47,48]. While efficacy was modest, it was well tolerated and provides proof-of-concept for this class [47,48]. Their ability to improve executive function and memory without the stimulant profile of traditional cognitive enhancers makes them attractive candidates for further investigation in both psychiatric and neurologic disorders [46,47,48].

5.3. Bifunctional NOP/MOR Ligands

Bifunctional ligands that simultaneously activate the NOP receptor and the MOR represent a novel pharmacological strategy aimed at achieving effective analgesia with an improved safety profile [49,50,51]. Among these, cebranopadol is the most clinically advanced compound, exhibiting high affinity and agonist activity at both NOP and MOR [44,45]. This dual mechanism allows cebranopadol to engage multiple pain-modulating pathways, resulting in potent and sustained analgesia across various models of acute and chronic pain [32,44,45].

The therapeutic rationale behind bifunctionality lies in leveraging the complementary actions of NOP and MOR receptors: while MOR activation provides strong analgesic effects, NOP receptor activation can counterbalance many of the opioid-related adverse effects such as respiratory depression, tolerance, and dependence [49,51]. This synergistic action aims to maximize pain relief while minimizing side effects, potentially offering a safer alternative to traditional opioids [7,51].

The primary therapeutic advantage of bifunctional NOP/MOR ligands lies in their ability to balance analgesic efficacy with a reduction in the typical side effects associated with traditional opioids [7,49,51]. MOR activation provides robust pain relief, while concurrent NOP receptor activation appears to modulate several MOR-mediated adverse effects, including respiratory depression, tolerance, and physical dependence [51]. In preclinical and clinical studies, cebranopadol has demonstrated a lower incidence of respiratory suppression and a delayed development of tolerance compared with conventional opioids, despite offering comparable or superior analgesic potency [40,45].

However, the presence of MOR agonist activity also carries inherent risks, especially in dependence-prone populations [6,7]. The resurgence or predominance of MOR signaling could potentially reintroduce classical opioid liabilities such as addiction, abuse, and overdose risk, particularly if the balance between NOP and MOR activation is not optimally maintained [6]. Therefore, careful dose titration and patient monitoring are critical to minimize these risks in clinical use [6,7].

Other investigational bifunctional ligands are under development, exploring different ratios of NOP to MOR activity to fine-tune therapeutic outcomes [50,51]. These compounds aim to optimize the synergy between receptors, tailoring drug profiles to specific clinical contexts such as cancer pain, neuropathic pain, or postoperative analgesia [39,49]. The challenge remains in achieving the ideal balance—maximizing analgesia while minimizing sedation, cognitive impairment, and addiction potential. AT-121 exemplifies this approach. Its partial agonism at both NOP and MOR reduces abuse liability while maintaining robust analgesia, positioning it as a leading next-generation pain therapeutic [43]. As research progresses, bifunctional NOP/MOR ligands hold considerable promise as next-generation analgesics in the pursuit of safer, more effective pain management solutions [49].

Table 4. Novel NOP-receptor targeting agents in human clinical and preclinical development. Novel NOP-receptor targeting agents and their current clinical and preclinical trials, including drug type and key indications.

Drug (Code)	Drug Type	Phase	Indication	Sponsor/Company	Trial ID/Source	Status	Pharmacokinetics and Trial Outcomes	References
SCH 221510	Selective NOP agonist	Preclinical	Pain (preclinical)	Schering-Plough	N/A	Abandoned	Short half-life (~1.5 h), low oral bioavailability; effective in rodents, poor developability	[37]
Ro 64-6198	Selective NOP agonist	Preclinical	Anxiety, pain (preclinical)	F. Hoffmann-La Roche	N/A	Abandoned	Good CNS penetration, poor oral activity; sedative effects at higher doses	[38,39]
BTRX-246040 (LY-2940094)	Selective NOP antagonist	Phase II	Major depressive disorder, alcohol use disorder	BlackThorn/Lundbeck	NCT03193398, NCT01798303	Completed	Oral bioavailability >60%, half-life 6–12 h; well tolerated; modest efficacy	[47,48]
Cebranopadol (GRT600)	Mixed NOP/MOR agonist	Phase III	Moderate-to-severe acute pain (e.g., post-surgical, back pain)	Grünenthal (licensed to Tris)	NCT06545097, NCT06423703	Completed	Oral bioavailability ~80%, half-life ~15 h; reduced opioid side effects, strong analgesia	[41,42]
Un-named Grünenthal NOP agonist (oral)	Peripherally restricted NOP agonist	Phase I	Chronic peripheral neuropathic pain	Grünenthal	Not publicly registered	Completed	Likely minimal CNS exposure; efficacy and PK not disclosed	[52]
Un-named Grünenthal NOP agonist (systemic)	Systemic NOP agonist	Phase I	Chronic pain (broad POC study)	Grünenthal	Not publicly registered	Ongoing (Recruiting)	Data not disclosed	[53]
Sunobinop (IMB-115; V117957)	Selective NOP agonist	Phase 1b–2	AUD, overactive bladder, IC/BPS	Imbrium/Purdue	NCT06024642, NCT06285214	Completed	Good CNS penetration; early efficacy in neuropsychiatric indications; well tolerated	[54,55]
Sunobinop (V117957)	Selective NOP agonist	Phase II (Completed)	Insomnia in patients recovering from AUD	Imbrium/Purdue	Internal company report	Completed	Improved sleep parameters; limited published data	[56]
AT-121	Mixed NOP/MOR partial agonist	Early clinical	Analgesia with low abuse/tolerance/respiratory depression	Academia/Industry (NIH-supported)	Preclinical + Phase I planned	In Development	Good CNS penetration, t½ ~8–10 h; no reward in NHPs, comparable efficacy to morphine	[43]

PK = pharmacokinetics; POC = proof-of-concept; IC = interstitial cystitis; BPS = bladder pain syndrome; AUD = alcohol use disorder.

presents novel NOP receptor-targeting agents currently in human clinical and preclinical development.

6. Nociceptin in Specific Clinical Scenarios

6.1. Perioperative Pain Management

The N/OFQ system offers promising applications in the perioperative setting, where the management of acute surgical pain and opioid-related side effects remains a significant clinical challenge. NOP receptor agonists have the potential to serve as adjuncts or alternatives to traditional opioids, providing effective analgesia while minimizing risks such as respiratory depression, constipation, and postoperative nausea [22,45]. Their unique mechanism of action, distinct from that of classical opioids, may be particularly beneficial for opioid-tolerant patients who often require higher analgesic doses and are more prone to side effects [44,45]. By targeting NOP receptors, these agents can bypass desensitized mu-opioid pathways and restore analgesic efficacy in individuals with opioid-induced tolerance [22]. Furthermore, their reduced liability for dependence and abuse makes them attractive options for surgical patients with a history of substance use disorders [3,22].

6.2. Intensive Care Unit (ICU) and Sedation Applications

In critical care settings, NOP receptor agonists have emerged as candidates for sedation and analgesia that preserve respiratory drive—an especially valuable characteristic in the management of mechanically ventilated patients [7]. These agents offer the potential to fine-tune sedation depth without compromising airway protection or delaying ventilator weaning, which is a common concern with traditional sedatives and opioids [22,35]. The preservation of spontaneous breathing under NOP agonist sedation may facilitate more flexible and safer management of patients during prolonged ICU stays or procedural interventions [34,35]. Additionally, the relatively mild cognitive impairment and maintained responsiveness observed with NOP agonists could allow for better neurologic monitoring and faster recovery following sedation [35].

6.3. Chronic Pain and Opioid Use Disorder

Chronic pain management and opioid use disorder (OUD) represent two interlinked challenges that may be addressed by targeting the NOP receptor system. In chronic pain, especially neuropathic and mixed pain conditions, NOP agonists have shown durable analgesic effects with lower risk of tolerance development. Their unique ability to modulate pain perception through both central and peripheral pathways enables them to offer relief where conventional therapies often fail. Importantly, bifunctional NOP/MOR ligands are being explored as transition therapies in OUD, aiming to provide effective pain control while mitigating withdrawal symptoms and reducing relapse risk [33]. These agents can deliver analgesia with a reduced euphoric profile, helping to decouple the analgesic and reinforcing effects of opioids. Additionally, the anxiolytic and mood-stabilizing properties of NOP-targeting agents may support broader recovery efforts in patients struggling with both chronic pain and substance dependence.

7. Challenges and Controversies

Despite the promising therapeutic potential of N/OFQ and its receptor (NOP), several challenges and controversies hinder its clinical integration. These challenges span from biological complexities to translational and regulatory hurdles.

7.1. Dose-Dependent and Context-Specific Signaling

One of the most significant issues is the dose-dependent and context-specific nature of NOP receptor signaling [21]. Unlike classical opioid agonists, NOP agonists can exhibit paradoxical effects depending on the site of action (spinal vs. supraspinal), dose, and physiological state of the patient. For instance, low doses of NOP agonists may be pronociceptive in certain supraspinal regions, whereas higher doses tend to be analgesic [7]. Similarly, in conditions of chronic pain or inflammation, NOP receptor expression and signaling may be altered, further complicating the predictability of drug effects [3]. These context-sensitive dynamics necessitate precise dosing strategies and may limit the applicability of NOP-targeting agents across diverse patient populations without personalized approaches.

7.2. Pharmacokinetic and Formulation Challenges

Developing effective NOP-targeting agents faces several additional hurdles, including chemical stability, efficient penetration of the blood–brain barrier (BBB), and formulation challenges [31,34]. Many NOP ligands, especially peptide-based compounds, suffer from enzymatic degradation and poor metabolic stability, limiting their bioavailability and therapeutic utility [34,42]. Achieving sufficient BBB penetration is critical for central nervous system effects but remains difficult due to molecular size, polarity, and active efflux mechanisms [47,48]. Formulation strategies must balance these pharmacokinetic considerations with patient compliance factors such as oral dosing feasibility and controlled release profiles [31,47]. Addressing these challenges is essential for translating promising preclinical compounds into clinically viable drugs [31,34].

7.3. Translational Gap Between Preclinical and Clinical Studies

Another major barrier lies in the translational gap between animal models and human clinical outcomes. Although preclinical studies have consistently demonstrated analgesic, anxiolytic, and sedative effects of NOP agonists and antagonists, these findings have not always translated robustly to clinical settings [4,31]. Differences in receptor distribution, behavioral paradigms, and metabolic profiles between species contribute to these discrepancies. Moreover, the complex interplay of the N/OFQ–NOP system with other neurotransmitter systems in humans remains incompletely understood, posing further challenges in predicting therapeutic outcomes.

7.4. Sex and Genetic Differences Impacting Treatment Outcomes

Sex and genetic differences significantly influence NOP receptor function and treatment outcomes, adding complexity to clinical translation [57,58]. Preclinical studies have shown that males and females may differ in NOP receptor expression levels, receptor density, and downstream signaling pathways, potentially leading to sex-specific variations in analgesic efficacy and side-effect profiles [57,58]. For example, female rodents have demonstrated altered nociceptive responses to NOP agonists compared with males, potentially due to hormonal modulation of receptor activity or interaction with estrogen and progesterone receptors [57,58]. Clinically, these differences may necessitate sex-specific dosing or drug selection to optimize therapeutic benefit and minimize adverse effects [57,58].

Genetic polymorphisms in the OPRL1 gene, which encodes the NOP receptor, have been identified and associated with variability in pain sensitivity, opioid response, and susceptibility to certain neuropsychiatric disorders [59,60]. Such genetic variants can alter receptor structure, ligand binding affinity, or signal transduction efficiency, thereby impacting individual responses to NOP-targeting drugs [59,60]. This genetic heterogeneity underscores the potential for pharmacogenomic approaches to identify patients who may benefit most from NOP-based therapies or who may be at increased risk for treatment failure or side effects [59,60].

Together, these sex- and genetics-driven differences highlight the need for personalized medicine strategies in the development and clinical use of NOP receptor modulators [57,58,59,60]. Incorporating sex as a biological variable in both preclinical and clinical research, alongside genetic screening, can improve the precision of dosing regimens and the prediction of therapeutic outcomes [57,58,59,60]. Such tailored approaches align with current trends in precision pain medicine and could enhance the safety and effectiveness of future NOP-targeted analgesics.

7.5. Regulatory and Approval Challenges

Finally, regulatory and formulation challenges add to the complexity of developing NOP-targeting drugs. The structural diversity and pharmacokinetic limitations of many early NOP ligands, such as poor oral bioavailability or rapid metabolism, have hindered their advancement [31,47,48]. Even promising agents like cebranopadol, which have reached late-stage trials, face scrutiny regarding long-term safety, abuse potential, and market positioning relative to existing opioids and non-opioid analgesics [46,47,48]. Additionally, the dual activity of bifunctional ligands may complicate regulatory approval, as they must be assessed for both opioid and non-opioid pharmacological profiles [49,51].

Furthermore, regulatory considerations encompass rigorous evaluation of abuse liability, especially given the opioid-like activity of many NOP-targeting compounds [6,31]. Agencies require extensive safety pharmacology, toxicology, and controlled substance assessments before approval [31,61]. This includes post-marketing surveillance to monitor potential misuse or adverse effects in broader populations [6]. Regulatory pathways for novel NOP agents may also face uncertainty due to the evolving understanding of the receptor’s pharmacology and the need to balance analgesic benefits against risks of dependence and side effects [31,61]. Collaborative efforts between drug developers and regulatory bodies are crucial to establish clear guidelines and streamline the approval process for these innovative therapeutics [31,61].

8. Conclusions

The N/OFQ–NOP system represents a compelling target in the pursuit of safer, more effective strategies for pain management and anesthesia. Preclinical and emerging clinical data highlight that NOP agonists and bifunctional MOP/NOP ligands can provide stronger anesthesia with reduced risk of respiratory depression, tolerance, and depend-ence. These agents show particular promise in perioperative care, procedural sedation, and chronic pain management, including in populations with opioid tolerance or sub-stance use disorders.

While challenges remain, such as dose variability and translational gaps, ongoing research and clinical trials are critical for optimizing NOP-targeted therapies and inte-grating them into modern pain management protocols. Clarifying the full therapeutic po-tential of the NOP system will require multi-center clinical trials, biomarker-guided stud-ies, and pharmacogenomic approaches that personalize treatment. Novel delivery tech-nologies may also improve central targeting while reducing peripheral adverse effects. Future efforts should focus on developing optimized NOP ligands, leveraging personalized approaches based on receptor expression and genetic variability, and integrating these agents into enhanced recovery and pain stewardship protocols. With a growing body of evidence and expanding clinical interest, nociceptin signaling stands at the forefront of next-generation analgesia and anesthesia.