China
Africa
Explore chapters and articles related to this topic
CNS Receptors for Opioids
Published in Edythe D. London, Imaging Drug Action in the Brain, 2017
Richard J. Knopp, Mary Hunt, James K. Wamsley, Henry I. Yamamura
Other recently described δ opioid ligands include the naltrexone derivative, naltrindole (Portoghese et al., 1988a and 1988b) and the peptide, deltorphin (Kreil et al., 1989). Naltrindole is a nonpeptide antagonist of the δ opioid receptor reported to have an approximately 100-fold selectivity for the δ relative to the μ opioid receptor. Naltrindole has a substantial affinity advantage over the established δ receptor antagonist, ICI 174,864 (Cotton et al., 1984) in that the Ki, value of naltrindole at the δ receptor (0.1 to 0.3 nM) is over 300-fold lower than that of ICI 174,864.
Antinociceptive potency of a fluorinated cyclopeptide Dmt-c[D-Lys-Phe-p-CF3-Phe-Asp]NH2
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Justyna Piekielna-Ciesielska, Adriano Mollica, Stefano Pieretti, Jakub Fichna, Agata Szymaszkiewicz, Marta Zielińska, Radzisław Kordek, Anna Janecka
Anti-nociception was studied in the hot-plate test in mice after i.c.v. or i.v. administration of peptides. The results obtained in the dose-response studies after i.c.v. administration are shown in Figure 1(A). Both tested compounds showed dose-dependent anti-nociceptive activity, significantly stronger than that of endomorphin-2 (EM-2). The ED50 values (jumping response) for C-36 and F-81 were 57.78 and 17.27 ng, respectively, indicating that F-81 was approximately threefold more potent than C-36 (Figure 1(A)). In order to investigate if these peptides are able to cross the BBB, peripheral i.v. administration of the peptides was performed, and the results are reported in Figure 1(B). After i.v. administration at the dose of 20 mg/kg, only a negligible anti-nociceptive activity was observed for both compounds (Figure 1(B)). To characterize the involvement of opioid receptors in the anti-nociceptive action of analog F-81, co-administration studies with opioid receptor antagonists were performed. The anti-nociceptive effect of F-81 (10 ng/animal, i.c.v.) was blocked by β-funaltrexamine (β-FNA, 1 µg/animal), showing the involvement of the mu opioid receptors. The delta-opioid receptor antagonist, naltrindole (NTL, 1 µg/animal), and kappa-opioid receptor antagonist, norbinaltorphimine (nor-BNI, 5 µg/animal, i.c.v.), did not modify the anti-nociceptive action of F-81 (Figure 1(C)). Even though F-81 and C-36 showed significant kappa-affinity, the obtained results are in agreement with a generally accepted fact that the anti-nociceptive effects are mainly mediated by the mu opioid receptor32,38.
Morphine reduces mouse microglial engulfment induced by lipopolysaccharide and interferon-γ via δ opioid receptor and p38 mitogen-activated protein kinase
Published in Neurological Research, 2018
Jung-Hee Ryu, Sang-Hwan Do, Sung-Hee Han, Zhiyi Zuo
Western blotting showed that the phosphorylated p38 MAPK (pp38 MAPK × 100/p38 MAPK) in microglial cells was up-regulated in LPS and IFN-γ group compared with control group (100% for control group vs. 777 [97] % for LPS and IFN-γ group, p < 0.001). This up-regulation was decreased in LPS and IFN-γ plus 1 μM morphine group (398 [102] %, p < 0.001, Figure 4). In addition, naltrindole (a selective δ opioid receptor antagonist, 10 μM) abolished morphine effect (566 [138] % for LPS and IFN-γ plus 1 μM morphine and naltridole group vs. 398 [102] % for LPS and IFN-γ plus 1 μM morphine group, p = 0.015, Figure 4).
Current strategies toward safer mu opioid receptor drugs for pain management
Published in Expert Opinion on Therapeutic Targets, 2019
Aliza T. Ehrlich, Brigitte L. Kieffer, Emmanuel Darcq
There is considerable biochemical and functional evidence for the existence of MOR and DOR heteromers with distinct pharmacology [62,63]. Furthermore, knock-in mice expressing MOR-mCherry and DOR-eGFP showed MOR/DOR co-localization in neurons from regions regulating pain, such as periaqueductal gray and pons [10]. Targeting MORs in heteromers to design safer painkillers, may thus be an approach that would take advantage of the restricted tissue distribution of heteromers and unique signaling properties of such complexes [64]. Several compounds selectively targeting MOR-DOR heteromers have been developed and produce analgesia with less tolerance [63]. Among them are, (i) CYM51010, a small molecule identified by ligand screening that produces an analgesic effect similar to morphine in mice [63], (ii) MDAN-21 a bivalent ligand in which a MOR agonist (oxymorphone) was linked to DOR antagonist (naltrindole) inducing thermal analgesia with lower dependence in rhesus monkeys [65] and eluxadoline (viberzi), a clinical orally active MOR agonist and DOR antagonist for the treatment of diarrhea-predominant irritable bowel syndrome [66,67]. However, recent in-vivo evidence also shows that, in fact, MOR and DOR co-expressed in the same neurons internalize and function independently [68] questioning the development of novel analgesics based on the concept of MOR-DOR heteromerization. Another well-documented heteromer consists of MOR in complex with metabotropic glutamate receptor 5 (mGluR5). A bivalent ligand, MMG22, has been developed to activate MOR-mGluR5 heteromers and produces potent reversal of tactile hypersensitivity [69] and reduces neuropathic pain [70] in rodents. Altogether, preclinical studies support the notion that MOR targeting in heteromers in-vivo is an option, but further mechanistic studies are required and clinical evaluation remains a far-reaching goal.