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Miscellaneous Neuropeptides
Published in Paul V. Malven, 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.
Opioids and the Nucleus of the Tractus Solitarius: Effects on Cardiovascular and Baroreflex Function
Published in I. Robin A. Barraco, Nucleus of the Solitary Tract, 2019
Several reports have indicated that intraventricular or intracisternal administration of various opioid agonists attenuates reflex-mediated bradycardia provoked by increasing arterial pressure.19-21 Similar results have been obtained when reductions in sympathetic nerve activity have been measured in response to electrical stimulation of the aortic depressor nerve.22,23 These inhibitory effects on baroreflex function have most often been attributed to activation of the mu type of opioid receptor because agonists relatively selective for other receptor types (e.g., delta, kappa, or sigma) either had little or no effect on baroreflexes, were less potent than mu receptor agonists, or their effects were reversed by low doses of naloxone known to be selective for mu receptors vs. other opioid receptor types.21-24 However, as with generalized changes in arterial pressure and heart rate produced by central opioid administration, consistent effects on baroreflex function have not always been observed. In contrast to the often observed attenuation in reflex function outlined above, Matsumura et al.25 reported that intracisternal administration of [d-Ala2,MePhe4,Gly-ol5] enkephalin (a mu receptor-selective opioid agonist) enhanced rather than reduced baroreflex sensitivity in conscious rabbits when changes in renal sympathetic nerve activity provoked by alterations in arterial pressure were measured. Additionally, injections of kappa or delta opioid receptor agonists into the cisterna magna of anesthetized rabbits have been reported to increase the sensitivity of baroreflex control of heart rate in response to a rise in arterial pressure, while reducing reflex sensitivity when arterial pressure was lowered.19 Further research will be required to elucidate the reason(s) for these inconsistencies.
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.
Pharmacogenetic analysis of opioid dependence treatment dose and dropout rate
Published in The American Journal of Drug and Alcohol Abuse, 2018
Richard C. Crist, James Li, Glenn A. Doyle, Alex Gilbert, Bryan M. Dechairo, Wade H. Berrettini
In contrast to pharmacokinetics, pharmacodynamics is a broader category covering genes that may affect medication response. A small number of pharmacodynamic variants have been identified in opioid-dependence treatment. Variants in ARRB2 and DRD2 were found to be associated with methadone response in a European cohort (21). Since ARRB2 regulates internalization of the mu-opioid receptor, the primary target of methadone, and dopamine is released downstream of opioid signaling, both genes are logical pharmacogenetic candidates for the medication (22). Polymorphisms in intron 1 of OPRD1 have also been linked to treatment outcome on methadone and buprenorphine (2,4). The biological mechanisms underlying these effects are less clear since the classical targets of these medications are the mu- and kappa-opioid receptors rather than the delta-opioid receptor, although mu-delta receptor dimers may be involved (23). A common non-synonymous variant in OPRM1 (rs1799971) is another likely candidate for pharmacodynamics effects on opioid-dependence treatment, although a previous study found no association (24). Additional candidates are functional variants in genes connected to depression/anxiety (e.g., COMT, SLC6A4, HTR2A) or attention deficit hyperactivity disorder (ADHD) (e.g., ADRA2A). These psychiatric disorders been shown to negatively affect opioid-dependence treatment outcomes (3,6,25). To date, no pharmacogenetic findings in opioid-dependence treatment have been successfully replicated and the US Food and Drug Administration has not approved any pharmacogenetic tests for selecting an opioid-dependence medication.
Systematic review of sex-based differences in opioid-based effects
Published in International Review of Psychiatry, 2018
Andrew S. Huhn, Meredith S. Berry, Kelly E. Dunn
Three additional studies used immunoreactivity to examine sex-based differences in opioid receptor or peptide density as a function of sex. Quantitative immunoperoxidase light microscopy evaluation of delta opioid receptor expression in hippocampal sections of adult male and normal cycling female rats revealed that, relative to males, females exhibited reduced delta opioid receptor immunoreactivity in the granule cell layer of the dentate gyrus, suggesting lower receptor density (Williams, Torres-Reveron, Chapleau, & Milner, 2011). Females in proestrus (high oestrogen) displayed the lowest level of delta opioid receptor immunoreactivity in the CA1 pyramidal cell layer of all groups. Immunoreactivity has also been used to analyze hippocampal sections of adult male and proestrus female rats, to assess whether corticotropin-releasing factor (CRF) receptors were colocalized with delta-opioid receptors in pyramidal cell dendrites (Williams, Akama, Knudsen, McEwen, & Milner, 2011). Results showed that females in proestrus and males expressed similar levels of CRF receptor immunoreactivity per dendrite, although proestrus females also expressed increased dual-labelled dendritic profiles and membrane density of CRF and delta-opioid receptor immunoreactivity relative to males. This suggests that interactions between the opioid and stress systems may differ between males and females as a function of ovarian hormones. Finally, a quantitative immunocytochemistry study reported that, relative to males, female brains demonstrated higher levels of dynorphin and enkephalin immunoreactivity in the CA3a in CA3b sections of the hippocampus, respectively (Van Kempen et al., 2013).