Distribution Of Opioid Peptides Research Articles

Sex differences in the rodent hippocampal opioid system following stress and oxycodone associated learning processes

Over the past two decades, opioid abuse has risen especially among women. In both sexes hippocampal neural circuits involved in associative memory formation and encoding of motivational incentives are critically important in the transition from initial drug use to drug abuse/dependence. Opioid circuits, particularly the mossy fiber pathway, are crucial for associative memory processes important for addiction. Our anatomical studies, especially those utilizing electron microscopic immunocytochemistry, have provided unique insight into sex differences in the distribution of opioid peptides and receptors in specific hippocampal circuits and how these distributions are altered following stress and oxycodone-associative learning processes. Here we review the hippocampal opioid system in rodents with respect to ovarian hormones effects and baseline sex differences then sex differences following acute and chronic stress. Next, we review sex differences in the hippocampal opioid system in unstressed and chronically stressed rats following oxycodone conditioned place preference. We show that opioid peptides and receptors are distributed within hippocampal circuits in females with elevated estrogen states in a manner that would enhance sensitivity to endogenous and exogenous opioids. Moreover, chronic stress primes the opioid system in females in a manner that would promote opioid-associative learning processes. In contrast, chronic stress has limited effects on the opioid system in males and reduces its capacity to support opioid-mediated learning processes. Interestingly, acute stress appears to prime males for opioid associative learning. On a broader scale the findings highlighted in this review have important implications in understanding sex differences in opioid drug use and abuse.

Investigation of Mechanisms Underlying the Pharmacokinetics of Peptide Drugs and their Physiological Model Analysis.

In order to provide mechanistic insights into the pharmacokinetics of peptide drugs (including cytokines and growth factors), I investigated the mechanisms underlying the clearance and distribution of opioid peptides (β-endorphin, dynorphin, and dynorphin-like analgesic peptide), human insulin, and synthetic cyclopeptides (cyclosporine and PSC 833), by use of in vivo animals, perfused organs, and in vitro experimental systems. For opioid peptides, their tissue distribution was suggested to be governed by specific binding with K-type opioid receptors present in peripheral tissues including lung and liver, whereas for insulin the distribution and clearance were suggested to be governed by receptor binding and receptor-mediated endocytosis (RME), respectively, at the physiological concentration range in target organs. The “receptorrecycling” model, in which the internalized receptors are recycled back to the surface to be reutilized for subsequent binding, was developed to predict the hepatic handling of insulin in mice at low and high doses, and successfully incorporated in a physiologically-based pharmacokinetic model, together with transcapillary permeability and static receptor binding in extrahepatic tissues. For cyclopeptides, moreover, their brain penetration was shown to be modulated by P-glycoprotein-mediated efflux functioning at the blood-brain barrier. The kinetic RME analysis enables the prediction of not only the nonlinear target-mediated clearance and distribution of peptides, but also the down-regulation and subsequent recovery of surface receptors, which is useful for assessing the time-dependent changes of in vivo efficacy of peptide drugs. In conclusion, the therapeutic efficacy and protocols of peptide drugs should be assessed from its microscopic pharmacology based on the RME mechanisms, in conjunction with macroscopic pharmacokinetic modeling.

Distribution of opiate receptor subtypes and enkephalin and dynorphin immunoreactivity in the hippocampus of squirrel, guinea pig, rat, and hamster.

The distribution of enkephalin and dynorphin immunoreactivity in the hippocampus of four rodent species (gray squirrel, guinea pig, rat, and hamster) is compared with the pattern of opiate receptor subtypes (mu, delta, and kappa). The distribution of opioid peptides is fairly consistent in the anterior hippocampus of these four species. Intense immunoreactivity for dynorphin and enkephalin is found in the hilus of the dentate gyrus and in the mossy fiber system. Occasional immunoreactive processes are seen in the dentate molecular layer and scattered throughout the CA1 and CA3 fields. In the rat and hamster, an additional plexus of enkephalinergic fibers straddles both sides of the hippocampal fissure. Cells immunoreactive for both opioid peptides are located in and just superficial to the dentate granule cell layer. Opiate receptors are variably distributed in these rodent species. In the squirrel, guinea pig, and hamster, mu and kappa binding is dense in the stratum lucidum of CA3 and the molecular layer of the dentate gyrus. In the rat, dense mu and kappa binding is localized within and adjacent to the pyramidal and granule cell layers. Delta receptor patterns show additional species differences. In the rat, the delta distribution is similar to the mu and kappa patterns. In the other species, the delta binding pattern is generally the inverse of the mu/kappa pattern: most areas of the hippocampus are enriched in delta sites, whereas the stratum lucidum and the pyramidal cell layer are receptor-sparse. Thus, the stratum lucidum--site of dense terminations of mossy fibers containing opioid peptides--is characterized by selectively sparse delta receptors in four species and by selectively dense kappa receptors in three species. The three receptor subtypes, taken either individually or together and compared to the peptides, are more variably and more widely distributed throughout the hippocampus and fail to show a correspondence with opioid-peptide-containing terminals. The mismatches suggest that receptor locations and densities are organized without relation to the sites of relevant transmitter release.

Glucagon is an antagonist of morphine bradycardia and antinociception

Glucagon and its receptors have been identified within the mammalian brain, and their anatomical distribution correlates well with the distribution of opioid peptides and their receptors. To evaluate possible physiological interactions between these two peptidergic systems, we examined the Glucagon administered either intravenously (iv) (100–1000 μg/kg) effects of glucagon on two opioid responses - bradycardia and antinociception. or intracerebroventricularly (icv) (5 μg) significantly attenuated morphine-induced (200 μg/kg, iv) bradycardia without producing any alterations in cardiovascular parameters when given alone. Furthermore, glucagon did not antagonize the bradycardia produced by phenyldiguanide (10 μg/kg, iv), a non-opioid substance. Peripheral (1 mg/kg, iv) and central (5 μg, icv) glucagon pretreatment antagonized morphine-induced (7.5 mg/kg, intraperitoneal) antinociception by 67% and 86%, respectively, at 30 minutes (as determined by the hot plate test). Glucagon treatment alone at these doses did not alter baseline response latencies. In both cases, central injections of glucagon were more effective than iv injections in antagonizing morphine's effects. These findings demonstrate a central action for glucagon and provide the first evidence that this neuropeptide may function as an endogenous antagonist of opioid actions.

Immunohistochemical localization of enkephalinlike peptides during testicular development in rats.

The distribution of opioid peptides is of interest in the rat testes, because the presence of opiate binding sites strongly supports the hypothesis of paracrine function for these peptidergic factors. Testes of Wistar albino rats between birth and adult stage were examined immunocytochemically for enkephalins, dynorphin, and alpha neoendorphin. The presence of immunoreactive enkephalinlike substances was visualized in both interstitial tissue and seminiferous tubules, but no staining was observed for dynorphin or neoendorphin. In interstitial tissue the material stained in Leydig cells raised after birth, declined at day 12, and increased again between day 22 and day 35 of life. From day 35 till adult stage we observed again a slight decrease of immunostaining. In seminiferous tubules, intense immunostaining was observed in stem spermatogonia until day 7 of life. After this period the presence of immunoreactive enkephalinlike material was detected, mainly in some spermatogonia and peritubular primary spermatocytes. These data suggest a possible implication of enkephalinlike peptides in spermatogonesis.

Biosynthesis and distribution of opioid peptides.

Group III opioid peptides are derived from proenkephalin B. The processing of this precursor peptide is still only partly understood and we still do not know how many final products come from proenkephalin B and whether Leu-enkephalin is produced from Group III peptides. However, potent biologic activity of Group III opioid peptides and existence of opiate-receptors specific for these peptides (k receptors) strongly suggest that Group III opioid peptides are not precursors of Leu-enkephalin but bioactive substances per se. Further studies should clarify details of the processing of proenkephalin B.