Opioids are the most effective analgesics, with most clinically available opioids being agonists to the µ-opioid receptor (MOR). The MOR is also responsible for their unwanted effects, including reward and opioid misuse leading to the current public health crisis. The imperative need for safer, non-addictive pain therapies drives the search for novel leads and new treatment strategies. In this study, the recently discovered MOR/nociceptin (NOP) receptor peptide hybrid KGNOP1 (H-Dmt-D-Arg-Aba-β-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) was evaluated following subcutaneous administration in mouse models of acute (formalin test) and chronic inflammatory pain (Complete Freund’s adjuvant-induced paw hyperalgesia), liabilities of spontaneous locomotion, conditioned place preference, and the withdrawal syndrome. KGNOP1 demonstrated dose-dependent antinociceptive effects in the formalin test, and efficacy in attenuating thermal hyperalgesia with prolonged duration of action. Antinociceptive effects of KGNOP1 were reversed by naltrexone and SB-612111, indicating the involvement of both MOR and NOP receptor agonism. In comparison with morphine, KGNOP1 was more potent and effective in mouse models of inflammatory pain. Unlike morphine, KGNOP1 displayed reduced detrimental liabilities, as no locomotor impairment nor rewarding and withdrawal effects were observed. Docking of KGNOP1 to the MOR and NOP receptors and subsequent 3D interaction pattern analyses provided valuable insights into its binding mode. The mixed MOR/NOP receptor peptide KGNOP1 holds promise in the effort to develop new analgesics for the treatment of various pain states with fewer MOR-mediated side effects, particularly abuse and dependence liabilities.

The development of simple, versatile strategies for the synthesis of gold nanoparticles (AuNPs) on semiconducting transition metal dichalcogenides (TMDC) layers is of increasing scientific and technological interest in photocatalysis, optical sensing, and optoelectronics sectors, but challenges exist on the nucleation and hybridization of AuNPs with the TMDC basal plane. At present, the widely used aqueous solution approaches suffer from poor dispersion of produced hybrids as well as from limited growth and coverage of the AuNPs on the TMDC semiconducting plane, since Au nanoclusters nucleate preferentially at the electron rich defect edges, which act as reducing agents and not on the defect free basal plane. Here, we report for the first time, the controlled synthesis of AuNPs on the basal plane of semiconducting molybdenum disulfide nanosheets (2H-MoS2 NSs) via a N,N-dimethylformamide (DMF)-based hot-injection synthesis route. This organic solvent-based synthesis route eliminates problems of poor dispersion of AuNPs@2H-MoS2 NS hybrids, whereas at the same time maintains the semiconducting crystalline quality of the pristine 2H-MoS2 NSs. In addition, the study establishes the important role of trisodium citrate, on enhancing the nucleation and improving the hybridization of AuNPs on 2H-MoS2 NSs as evidenced by the induced p-type doping. This organic solvent synthesis approach can be adopted for other hybrid systems opening the way for controlled hybridization of semiconducting layers with metal nanoparticles. 4 MoS2 NSs of metallic phase (M-MoS2), produced by Li intercalation, where dominance of defects on the basal plane promoted the MoS2/ + redox reaction. 2-3 Nevertheless, many applications such as photocatalysis, optical sensing, and optoelectronics, favor the presence of a semiconducting-TMDC/metallic-NP interface to increase absorption, enhance photogeneration rate and/or achieve light induced charge separation. 15 As a result, the growth of AuNPs on semiconducting 2H-MoS2 is been sought. However, whereas the anchoring of AuNPs on M-MoS2 has been explored thoroughly, 2-3 strategies for synthesis of AuNPs on semiconducting 2H phase TMDCs (2H-TMDC), (AuNPs@2H-TMDC), are currently at incipient stages. 10, 16 To tackle this challenge, routes for producing solvent-dispersible hybrids, with a controlled nucleation and coverage of AuNPs on the 2H-TMDC basal plane are being avidly sought.Recently, the functionalization of 2H-TMDC, using chemical reactions of gold precursors in aqueous solution, has been explored. 16 However, the Au-nucleation was limited mainly at the electron rich edges, 16 due to the absence of highly energetic defects on the basal plane, whereas the efficient synthesis of hybrids was hindered by the poor dispersion of semiconducting 2H-MoS2 NSs in water. Lately, we reported the production of 2H-MoS2 NSs, via room temperature ionic liquid (RTIL) assisted grinding method combined with sequential centrifugation steps. 17 Such mechanically exfoliated 2H-MoS2 NSs retain their crystalline quality aft...

Mutations in the prodynorphin gene (PDYN) are associated with the development of spinocerebellar ataxia type 23 (SCA23). Pathogenic missense mutations are localized predominantly in the PDYN region coding for the dynorphin A (DynA) neuropeptide and lead to persistently elevated mutant peptide levels with neurotoxic properties. The main DynA target in the central nervous system is the kappa opioid receptor (KOR), a member of the G-protein coupled receptor family, which can elicit signaling cascades mediated by G-protein dissociation as well as β-arrestin recruitment. To date, a thorough analysis of the functional profile for the pathogenic SCA23 DynA mutants at KOR is still missing. To elucidate the role of DynA mutants, we used a combination of assays to investigate the differential activation of G-protein subunits and β-arrestin. In addition, we applied molecular modelling techniques to provide a rationale for the underlying mechanism. Our results demonstrate that DynA mutations, associated with a severe ataxic phenotype, decrease potency of KOR activation, both for G-protein dissociation as well as β-arrestin recruitment. Molecular modelling suggests that this loss of function is due to disruption of critical interactions between DynA and the receptor. In conclusion, this study advances our understanding of KOR signal transduction upon DynA wild type or mutant peptide binding.