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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
Naloxazone is a monomeric hydrazone derivative of naloxone, and naloxonazine is a dimeric azine derivative of naloxone. The ability of naloxazone to undergo spontaneous transformation to naloxonazine suggests that naloxonazine may be the active form of naloxazone (Hahn and Pasternak, 1982; Hahn et al., 1982). The ability of these naloxone derivatives to react covalently with opioid receptors cannot be readily demonstrated and is inferred by the inability of repeated washing to remove the ligand. Even if a covalent linkage is produced, it is unclear how stable it would be under in vivo or in vitro conditions. These considerations are important since it has been shown that unreacted (free) naloxonazine binds to μ opioid receptors (μ2 using Pasternak’s terminology) in the GPI (Gintzler and Pasternak, 1983). Crucizni et al. (1987) investigated the effect of naloxonazine treatment combined with extensive washing to remove unreacted ligand on opioid receptor binding and failed to observe a noncompetitive (i.e., irreversible) loss of high affinity binding sites. Instead, they observed that the naloxonazine treatment produced a reduction of the apparent binding affinity of the ligands tested (labeled and unlabeled DADLE and DAMGO) at all sites labeled with no significant change in the measured binding capacity. This is characteristic of reversible competitive interactions.
The effect of tramadol on blood glucose concentrations: a systematic review
Published in Expert Review of Clinical Pharmacology, 2020
Samaneh Nakhaee, Jeffrey Brent, Christopher Hoyte, Khadijeh Farrokhfall, Farshad M Shirazi, Masoumeh Askari, Omid Mehrpour
Several studies have provided potential explanations for tramadol-induced hypoglycemia. Exposure of neurons to tramadol activates the insulin signaling pathway, thereby increasing insulin receptor expression, and eventually causing higher glucose uptake [39]. Tramadol’s serotonergic effect is also a possible mediator of hypoglycemia. Serotonin causes an increase in insulin concentrations, the release of beta-endorphin, and, eventually, stimulation of glucose uptake by muscles [65,66]. Another mechanism for the hypoglycemic effects of tramadol similar to other opioids is the activation of peripheral opioid µ-receptors and modification of glucose metabolism associated gene expression which can increase glucose uptake in peripheral tissues and eventually lead to hypoglycemia [38,65,67]. Previous reports have suggested that the opioid receptor is the main target involved in the hypoglycemic effect of tramadol and emphasize the role of the µ-opioid receptor in glucose homeostasis [35]. Some studies have shown the resolution of blood glucose-lowering effects of tramadol after the administration of naloxone at sufficient doses [38]. Cheng et al. (2001) evaluated the impact of tramadol on the plasma glucose concentration among diabetic rats by STZ. This hypoglycemia was reversible when a sufficient dose of naloxonazine or naloxone administrated [38]. In a pancreatectomized rodent model, the administration of tramadol evoked a hypoglycemic response due to enhanced hepatic glucose use that was mediated by an insulin signaling pathway in the cerebral cortex and hypothalamus [39]. In both of these animal studies, the glucose-lowering impact of tramadol was reversible after the administration of naloxone, indicating that these effects were correlated to the μ-opioid receptors.