CNS Receptors for Opioids
Edythe D. London in Imaging Drug Action in the Brain, 2017
The distribution of δ opioid receptors in rat brain is illustrated in Plates 1 and 2*. The pseudocolor receptor density scale used extends from dark red (highest) to purple (lowest). The highest receptor densities labeled with [4’-125I-Phe4]DPDPE are in the olfactory bulb, neostriatum, and laminea I to III and V of the cerebral cortex. The lowest δ receptor densities are seen in the thalamic and medulla oblongata areas. These results are consistent with previous studies of δ opioid receptor distribution in the rat brain (Figure 4a). The ability of [4’-125I-Phe4]DPDPE to detect low receptor densities is best illustrated by the unambigious labeling observed in the cerebellum. Several receptor autoradiography studies using [3H]DPDPE (Gulya et al., 1986; Temple and Zukin, 1987; Blackburn et al., 1988; Sharif and Hughes, 1989) were unable to quantitate the presence of δ opioid receptors in the cerebellum. Thus, it can be concluded that [4’-125I-Phe4]DPDPE is a valuable new radioligand for the measurement of δ opioid receptors that is especially useful for the measurement of low δ receptor densities.
Miscellaneous Neuropeptides
Paul V. Malven in Mammalian Neuroendocrinology, 2019
A large body of knowledge about opioid receptors has developed in the years since their discovery (Goldstein and Naidu, 1989). Based on comparisons of activity in various bioassays and binding affinities for many synthetic opioid- related drugs, a number of subtypes of the opioid receptor have been identified. Some of these subtypes may represent altered forms of a single receptor, or they may be different molecules (Wollemann, 1990). The selectivity of each subtype for any given EOP or antagonist is never absolute, so that selectivity of binding always depends on dosage (Goldstein and Naidu, 1989). For example, naloxone can antagonize most subtypes if the dosage is sufficiently high. The three primary subtypes are known as mu, delta, and kappa, with an additional one called epsilon. In some of the early literature, there was another one called sigma, but that receptor is probably not opioid in nature. The mu subtype was named for the prototypic opioid drug, morphine, but an endogenous ligand specific for only mu opioid receptors has not been established. Subdivisions of the mu and kappa receptor subtypes, which will not be considered here, have also been characterized. The delta opioid receptor is preferentially selective for endogenous enkephalin-related EOP, although exogenous enkephalin-related compounds can be synthesized which react preferentially with mu receptors. Kappa opioid receptors react preferentially with endogenous dynorphin-related EOP. The epsilon opioid receptor is defined as being specific for β-endorphin, but there is some question about the separate existence of epsilon receptors because β-endorphin binds readily to both mu and delta receptors.
A narrative review of buprenorphine in adult cancer pain
Published in Expert Review of Clinical Pharmacology, 2020
Matthew Degnan, Shaker A. Mousa
Buprenorphine has biased signaling whereby it acts by multi-mechanisms as a partial agonist at the G-protein levels, as an agonist at the mu-opioid receptor, and as an antagonist at the kappa-opioid receptor [6]. This means that buprenorphine’s agonism at the mu-opioid receptor has limited effects after increasing past a certain dose [17]. It also has agonism at OLR-1 receptors, weak antagonism at the kappa-opioid receptor, and weak agonism at the delta-opioid receptor [6]. Buprenorphine is a unique opioid because it has a high affinity to the mu receptor and has slow dissociation kinetics. It has a long duration of action, with peak effects seen several hours after administration, though this is faster if given IV or SQ. Buprenorphine has a longer CNS residence time than does the mu-receptor and for that reason its plasma level does not correlate with analgesia. Both transdermal (TD) and SL buprenorphine have half-lives of over 24 hours in adults [18–21]. These qualities allow it to be used as a pharmacologic aid in treating opioid addiction, and as a unique option in treating pain.
What ketamine can teach us about the opioid system in depression?
Published in Expert Opinion on Drug Discovery, 2020
Laura Perez-Caballero, Victor Perez, Esther Berrocoso
Additionally, preclinical assays demonstrated that MOR and δ-opioid receptor activation and/or κ-opioid receptor blockade produces antidepressant-like effects in animal models of depression [24]. Accordingly, evidence has accumulated that severe and recurrent depression can be alleviated by multimodal opioid-based compounds [25]. However, the risk of abuse and dependence on these drugs has discouraged their use to treat depressed patients. Currently, buprenorphine offers the greatest promise as a drug to treat MDD. Buprenorphine is a partial MOR agonist and κ-opioid receptor antagonist, and it is an opioid medication commonly prescribed to treat opioid use disorder. However, it has also been seen to significantly dampen the symptoms of depression and suicidal ideation, either in monotherapy or as an add-on therapy [26]. Furthermore, recent clinical trials have shown that ALKS-5461, a combination of buprenorphine and samidorphan (a MOR antagonist), can significantly alleviate depressive symptoms, with no signs of tolerance during the treatment or withdrawal symptoms following discontinuation [27]. However, such therapy has failed to be approved by the FDA as an adjunctive treatment for MDD as additional clinical data is still required to confirm its efficacy.
Proenkephalin and risk of developing chronic kidney disease: the Prevention of Renal and Vascular End-stage Disease study
Published in Biomarkers, 2018
Lyanne M. Kieneker, Oliver Hartmann, Andreas Bergmann, Rudolf A. de Boer, Ron T. Gansevoort, Michel M. Joosten, Joachim Struck, Stephan J. L. Bakker
Due to the low molecular weight of pro-ENK (4586.60 g/mol), it is assumed to be freely filtered through the glomerulus and therefore the proposed association of enkephalins with renal disease therefore likely implies impaired clearance or increased production of enkephalins in renal disease. Genome-wide association analysis revealed genetic variation at the PENK locus that was associated with higher pro-ENK levels and with higher incidence in CKD, suggesting a causal relationship between pro-ENK and CKDeGFR (Schulz et al. 2017). Besides inflammation, various other physiological functions have been shown to be modulated by enkephalins, including processes of cell growth, differentiation, and apoptosis (Ovadia et al. 1996, McTavish et al. 2007, Denning et al. 2008, Awad et al. 2012). In an experimental study in conscious Sprague-Dawley rats, activation of the delta opioid system by infusion of a delta opioid receptor agonist evoked a profound diuretic and natriuretic response, which suggest significant changes in renal excretory function (Sezen et al. 1998). We could therefore speculate that an increment in pro-ENK concentrations could be a reflection of counteracting the decreasing functionality of the kidney by promoting kidney function. Further experimental studies blocking or stimulating the opioid receptors could demonstrate the potential role of pro-ENK in this relationship.
Related Knowledge Centers
- Enkephalin
- G Protein
- Ligand
- Neocortex
- Pain Management
- Hypoventilation
- Basal Ganglia
- Opioid Receptor
- G Protein-Coupled Receptor
- Gi Alpha Subunit