kappa-opioid receptors were visualized by light and electron microscopical immunohistochemistry in young rat and chick brains, using a monoclonal antibody KA8 (IgG1, kappa) raised against a kappa-opioid receptor preparation from frog brain, which recognizes selectively the kappa-type receptor with preference for the kappa-2 subtype. The most pronounced kappa-opioid receptor-like immunoreactivity was observed in the hypothalamic nuclei of the rat brain and in the chick optic tectum, in regions where the functional significance of kappa-opioid receptors is well documented. Both neurons and glia were stained, the former on both somata and dendrites. At the ultrastructural level, the receptor-like immunoreactivity was similar in both species. Immunoprecipitate decorated the inner surface of the plasma membrane of glial cells, neuronal somata and dendrites, in a discontinuous arrangement. In the cytoplasm, labelling was associated with ribosomes, polyribosomes and rough endoplasmic reticulum membranes but not with Golgi cisternae. In the neuropil, the immunoprecipitate was observed along the dendritic microtubules and was also associated with postsynaptic sites. Nuclei and axons were devoid of label and immunoreactivity was never visible presynaptically. Our findings indicate that the antibody used in the present study marks various forms of the kappa-opioid receptor protein including those synthesised in ribosomes, transported along dendritic microtubules and incorporated into postsynaptic and non-synaptic membranes. The antibody also recognizes glial opioid receptors. The observed subcellular distribution appears to be conserved in phylogenetically distant species.
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Drugs
January 2025
Palliative Medicine, Geisinger Medical Center, Danville, PA, USA.
Buprenorphine is an agonist at the mu opioid receptor (MOR) and antagonist at the kappa (KOR) and delta (DOR) receptors and a nociceptin receptor (NOR) ligand. Buprenorphine has a relatively low intrinsic efficacy for G-proteins and a long brain and MOR dwell time. Buprenorphine ceiling on respiratory depression has theoretically been related multiple factors such as low intrinsic efficacy at MOR, binding to six-transmembrane MOR and interactions in MOR/NOR heterodimers.
View Article and Find Full Text PDFLarge library docking of tangible molecules has revealed potent ligands across many targets. While make-on-demand libraries now exceed 75 billion enumerated molecules, their synthetic routes are dominated by a few reaction types, reducing diversity and inevitably leaving many interesting bioactive-like chemotypes unexplored. Here, we investigate the large-scale enumeration and targeted docking of isoquinuclidines.
View Article and Find Full Text PDFBioorg Med Chem Lett
January 2025
Contineum Therapeutics, 3565 General Atomics Court, Suite 200, San Diego, CA 92121, United States.
Novel kappa opioid receptor (KOR) agonists that preferentially activate G-protein signaling versus β-arrestin-2 recruitment are described. Starting from a literature-reported phenol-containing diphenethylamine KOR agonist, structure-activity relationship (SAR) studies revealed replacement of the phenol with various non-hydroxylated bicyclic heteroaromatics led to tertiary diarylethylamines which retained KOR agonist activity and improved metabolic stability in human liver microsomes. Further optimizations produced compound 39, a potent activator of G-protein signaling (GTPγS EC = 14 nM, 83 % E) that did not elicit a β-arrestin-2 recruitment functional response (E < 10 %).
View Article and Find Full Text PDFNeuropharmacology
January 2025
Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA. Electronic address:
Akuammicine (AKC), an indole alkaloid, is a kappa opioid receptor (KOR) full agonist with a moderate affinity. 10-Iodo-akuammicine (I-AKC) and 10-Bromo-akuammicine (Br-AKC) showed higher affinities for the KOR with K values of 2.4 and 5.
View Article and Find Full Text PDFNeurosci Biobehav Rev
January 2025
Department of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing, China; Beijing Life Science Academy, Beijing, China. Electronic address:
Nicotine, a neuroactive substance in tobacco products, has been widely studied for its effects on feeding and body weight, mostly focusing on the involvement of nervous system, metabolism, hormones, and gut microbiota. To elucidate the action mechanism of nicotine on feeding and body weight, especially the underlying neurobiological mechanisms, we reviewed the studies on nicotine's effects on feeding and body weight by the regulation of various nerve systems, energy expenditure, peripheral hormones, gut microbiota, etc. The role of neuronal signaling molecules such as AMP-activated protein kinase (AMPK) and kappa opioid receptor (κOR) were specialized in the nicotine-regulating energy expenditure.
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