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Binge eating and an increased role for palatability in determining food intake are abnormal adaptations in feeding behavior linked to eating disorders and body weight dysregulation. The present study tested the hypothesis that rats with limited access to highly preferred food would develop analogous opioid-dependent learned adaptations in feeding behavior, with associated changes in metabolism and anxiety-like behavior. For this purpose, adolescent female Wistar rats were daily food deprived (2 h) and then offered 10-min access to a feeder containing chow followed sequentially by 10-min access to a different feeder containing either chow (chow/chow; n =7) or a highly preferred, but macronutrient-comparable, sucrose-rich diet (chow/preferred; n =8). Chow/preferred-fed rats developed binge-like hyperphagia of preferred diet from the second feeder and anticipatory chow hypophagia from the first feeder with a time course suggesting associative learning. The feeding adaptations were dissociable in onset, across individuals, and in their dose–response to the opioid-receptor antagonist nalmefene, suggesting that they represent distinct palatability-motivated processes. Chow/preferred-fed rats showed increased anxiety-like behavior in relation to their propensity to binge as well as increased feed efficiency, body weight, and visceral adiposity. Chow/preferred-fed rats also had increased circulating leptin levels and decreased growth hormone and ‘active’ ghrelin levels. Thus, the short-term control of food intake in rats with restricted access to highly preferred foods comes to rely more on hedonic, rather than nutritional, properties of food, through associative learning mechanisms. Such rats show changes in ingestive, metabolic, endocrine, and anxiety-related measures, which resemble features of binge eating disorders or obesity.

The κ-opioid receptor (KOR) has recently emerged as an alternative therapeutic target for the development of pain medications, without deleterious side effects associated with the μ-opioid receptor (MOR). However, modulation of KOR is currently under investigation for the treatment of depression, mood disorders, psychiatric comorbidity, and specific drug addictions. However, KOR agonists also trigger adverse effects including sedation, dysphoria, and hallucinations. In this respect, there is currently much debate on alternative paradigms. Recent effort has been devoted in search of biased ligands capable of selectively activating favorable signaling over signaling associated with unwanted side effects. On the other hand, the use of partial agonists is expected to allow the analgesia to be produced at dosages lower than those required to produce the adverse effects. More empirically, the unwanted central effects can be also avoided by using peripherally restricted agonists. In this review, we discuss the more recent trends in the design of KOR-selective, biased or partial, and finally, peripherally acting agonists. Special emphasis is given on the discussion of the most recent approaches for controlling functional selectivity of KOR-specific ligands.

The administration of κ‐opioid receptor antagonists, nor‐binaltorphimine (norBNI) and 5′‐guanidinonaltrindole (GNTI) enhanced allodynia in rats and mice after sciatic nerve ligation. In order to understand the mechanism underlying this effect, we examined the possible involvement of the endogenous ligand of κ‐opioid receptor dynorphin. The experiments were carried out on male Wistar rats and on Albino‐Swiss mice. The rats had been implanted with a catheter 7 days earlier in the subarachnoid space of the spinal cord. Intrathecal (i.t.) administrations in mice were made by lumbar puncture. The animals were i.t. injected with norBNI, GNTI (κ‐opioid receptor antagonists), dynorphin A1–17 antiserum (DYN A/S), ketamine (NMDA receptor antagonist) and their combinations. The nociceptive sensitivity was assessed using the mechanical (von Frey) and therma allodynia tests on days 2–4 and 8–10 after the sciatic nerve ligation. Both antagonists, norBNI and GNTI, significantly enhanced mechanical and therma allodynia in rats and mice with neuropathic pain. The potentiation of allodynia after the administration of norBNI or GNTI was inhibited by earlier administration of DYN A/S or by ketamine. Our results suggest that allodynia is mediated through nonopioid effect of the endogenous opioid peptide, dynorphin. The nonopioid action is potentiated by the blockade of κ‐opioid receptors, and corresponding to the elevation of prodynorphin mRNA level in neuropathic pain. Furthermore, the potentiation of allodynia after the administration of the above drugs appears to be mediated through the activation of NMDA receptors directly by dynorphin. British Journal of Pharmacology (2003) 140, 538–546. doi:10.1038/sj.bjp.0705427

Background: HSK21542, a novel selective peripherally-restricted κ-opioid receptor agonist has been proven to be a safe and effective analgesic and antipruritic drug in both in vitro and in vivo studies. We aimed to evaluate its safety, pharmacokinetics and efficacy in hemodialysis patients over a 1-week treatment period, and to establish the optimal dosage for a further 12-week stage 2 trial. Methods: In this multiple ascending dose study, hemodialysis patients were randomly assigned to receive HSK21542 (0.05–0.80 μg/kg), or a placebo three times within 2.5 h at the end of each dialysis session for 1 week. Safety evaluations included reports of treatment-emergent adverse events (TEAEs); pharmacokinetics and efficacy outcomes were also assessed. Results: Among the 44 screened patients, 41 were enrolled and completed the trial. The overall incidence of TEAEs was higher in the HSK21542 group compared to the placebo group, with an incidence of 75.0%, 50.0%, 75.0%, and 88.9% in the range of 0.05–0.80 μg/kg. All TEAEs were grade 1 or 2 in severity. HSK21542 exhibited linear pharmacokinetics characteristics within the dose range 0.05–0.80 μg/kg, without drug accumulation after multiple-doses. Compared to the placebo, a significant decrease of the weekly mean Worst Itching Intensity Numerical Rating Scale was found in the HSK21542-0.30 μg/kg group ( p = 0.046), but without significant improvement in the Skindex-16 score. Conclusion: HSK21542 was well tolerated in the dose range 0.05–0.80 μg/kg in hemodialysis patients. HSK21542-0.3 μg/kg exhibited promising efficacy in patients with moderate to severe pruritus and warrants a further Stage 2 trial. Clinical Trial Registration: https://clinicaltrials.gov/ , identifier NCT04470154.

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.

Background We previously reported that ginsenoside Re (GRe) attenuated against methamphetamine (MA)-induced neurotoxicity via anti-inflammatory and antioxidant potentials. We also demonstrated that dynorphin possesses anti-inflammatory and antioxidant potentials against dopaminergic loss, and that balance between dynorphin and substance P is important for dopaminergic neuroprotection. Thus, we examined whether GRe positively affects interactive modulation between dynorphin and substance P against MA neurotoxicity in mice. Methods We examined changes in dynorphin peptide level, prodynorphin mRNA, and substance P mRNA, substance P-immunoreactivity, homeostasis in enzymatic antioxidant system, oxidative parameter, microglial activation, and pro-apoptotic parameter after a neurotoxic dose of MA to clarify the effects of GRe, prodynorphin knockout, pharmacological inhibition of κ-opioid receptor (i.e., nor-binaltorphimine), or neurokinin 1 (NK1) receptor (i.e., L-733,060) against MA insult in mice. Results GRe attenuated MA-induced decreases in dynorphin level, prodynorphin mRNA expression in the striatum of wild-type (WT) mice. Prodynorphin knockout potentiated MA-induced dopaminergic toxicity in mice. The imbalance of enzymatic antioxidant system, oxidative burdens, microgliosis, and pro-apoptotic changes led to the dopaminergic neurotoxicity. Neuroprotective effects of GRe were more pronounced in prodynorphin knockout than in WT mice. Nor-binaltorphimine, a κ-opioid receptor antagonist, counteracted against protective effects of GRe. In addition, we found that GRe significantly attenuated MA-induced increases in substance P-immunoreactivity and substance P mRNA expression in the substantia nigra. These increases were more evident in prodynorphin knockout than in WT mice. Although, we observed that substance P-immunoreactivity was co-localized in NeuN-immunreactive neurons, GFAP-immunoreactive astrocytes, and Iba-1-immunoreactive microglia. NK1 receptor antagonist L-733,060 or GRe selectively inhibited microgliosis induced by MA. Furthermore, L-733,060 did not show any additive effects against GRe-mediated protective activity (i.e., antioxidant, antimicroglial, and antiapoptotic effects), indicating that NK1 receptor is one of the molecular targets of GRe. Conclusions Our results suggest that GRe protects MA-induced dopaminergic neurotoxicity via upregulatgion of dynorphin-mediated κ-opioid receptor and downregulation of substance P-mediated NK1 R.

This systematic review examines chronic kidney disease-associated pruritus (CKD-aP) as a complex clinical manifestation in patients undergoing hemodialysis. Traditionally considered a secondary symptom of end-stage renal disease, emerging evidence now positions CKD-aP as a multidimensional disorder with substantial pathogenic influence on patient outcomes. Using the PRISMA 2020 methodology, we critically evaluated 54 peer-reviewed studies published between 2020 and 2025. Our synthesis highlights a convergence of five mechanistic frameworks underpinning CKD-aP: elevated levels of uremic toxins originating from gut microbial dysbiosis, immune activation driven by IL-31 and other pro-inflammatory cytokines, heightened peripheral and central neural sensitization, dysregulation of endogenous opioid receptor pathways favoring μ-receptor activation, and xerosis-related epidermal barrier dysfunction. These mechanisms contribute to a systemic cycle of microinflammation, pruritogenic signaling, and neural hyperexcitability. We also identified and compared validated assessment tools—including the NRS, VAS, Skindex-10, and the UP-Dial scale—that facilitate standardized quantification of disease burden. While available treatments such as gabapentinoids and phototherapy offer partial relief, targeted therapies—including κ-opioid receptor agonists—represent a major advancement, although long-term effectiveness and accessibility remain under investigation. Growing scientific consensus establishes CKD-aP as a priority therapeutic target in hemodialysis care, underscoring the need for integrated, mechanism-based management strategies to improve quality of life and clinical outcomes. This work represents a narrative systematic review, integrating evidence from mechanistic, translational, and clinical studies to critically examine the biological pathways underlying CKD-associated pruritus.

Chronic kidney disease-associated pruritus (CKD-aP) is a common and distressing symptom in hemodialysis patients. This Phase II trial evaluated the efficacy and safety of HSK21542, a selective kappa-opioid receptor agonist, in managing CKD-aP. Adult patients on hemodialysis with moderate to severe pruritus, were randomized 1:1:1 to placebo, or HSK21542 (0.3 μg/kg or 0.6 μg/kg) administered thrice weekly post-dialysis for 12 weeks. The primary endpoint was the change from baseline in the weekly mean of the worst itching intensity Numerical Rating Scale (WI-NRS) score at week 12. Secondary endpoints included quality-of-life assessments, safety evaluations, and pharmacokinetic properties. A total of 90 patients were enrolled. At week 12, mean changes in WI-NRS scores from baseline were -2.94 for the placebo group, -3.40 for the 0.3 μg/kg HSK21542 group, and -2.21 for the 0.6 μg/kg HSK21542 group. The percentages of patients who had a reduction of 3 points or above in their WI - NRS scores were 44.4% in the placebo group, 62.1% in the 0.3 μg/kg HSK21542 group, and 37.0% in the 0.6 μg/kg HSK21542 group. The 0.30 μg/kg HSK21542 group demonstrated more significant improvements in Skindex - 16 scores compared to the placebo. The 5-D Itch Scale scores also presented similar trends. Both the 0.3 μg/kg and 0.6 μg/kg doses of HSK21542 were well - tolerated, with no dose-dependent adverse effects. The 0.3 μg/kg dose of HSK21542 demonstrated superior efficacy and safety in reducing pruritus and improving quality of life in hemodialysis patients.

Major depressive disorder (MDD) is a highly prevalent psychiatric illness for which rapid-acting antidepressants such as ketamine provide only transient benefit. Because κ-opioid receptor (KOR) signaling contributes to stress-related dysphoria and impaired neuroplasticity, we examined whether KOR antagonism could prolong ketamine’s antidepressant-like effects in a mouse model of adolescent chronic unpredictable stress (CUS). Male C57BL/6J mice (n = 10 per group for behavioral analyses) were exposed to CUS during adolescence and developed persistent depression-like behavior in adulthood. Mice with depressive-like behavior received a single injection of ketamine, the selective KOR antagonist norbinaltorphimine (nBNI), or their combination. Behavioral testing showed that all treatments reduced immobility in the tail suspension test (TST) 24 h post-administration; however, only the combined ketamine/nBNI treatment maintained antidepressant-like effects one week post-treatment. Molecular analyses (n = 4–8 per group) were conducted at this single time point, one week post-treatment, to characterize region-specific signaling states in the prefrontal cortex, hippocampus, and striatum, focusing on ERK, AKT, JNK, mTOR, and BDNF pathways. These molecular findings represent correlates of sustained behavioral effects rather than evidence of causal mechanisms. Together, the data indicate that concurrent KOR antagonism is associated with prolonged antidepressant response to ketamine in stress-exposed male mice and with distinct region-dependent signaling profiles at one week post-treatment. Further studies are needed to establish mechanistic causality and confirm the possible applicability of these findings.

The dynorphin/κ-opioid receptor system has been implicated in the pathogenesis and pathophysiology of several psychiatric disorders. In the present review, we present evidence indicating a key role for this system in modulating neurotransmission in brain circuits that subserve mood, motivation, and cognitive function. We overview the pharmacology, signaling, post-translational, post-transcriptional, transcriptional, epigenetic and cis regulation of the dynorphin/κ-opioid receptor system, and critically review functional neuroanatomical, neurochemical, and pharmacological evidence, suggesting that alterations in this system may contribute to affective disorders, drug addiction, and schizophrenia. We also overview the dynorphin/κ-opioid receptor system in the genetics of psychiatric disorders and discuss implications of the reviewed material for therapeutics development.