http://www.back-in-business-physiotherapy.com/images/files/DescendingControl.pdf

Descending control of pain.

https://www.cell.com/cell/pdf/S0092-8674(00)81965-0.pdf

The Sleep Disorder Canine Narcolepsy Is Caused by a Mutation in the Hypocretin (Orexin) Receptor 2 Gene

http://yael-nissan.weebly.com/uploads/5/2/9/2/5292348/the_introduction_to_pain_an_integrative_review_-_millan.pdf

The induction of pain: an integrative review

Exogenous α-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death.

Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled µ-opioid receptor (µ-OR) in the central nervous system. Here we describe the 2.8 A crystal structure of the mouse µ-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the µ-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.

/pdf/crystal-structure-of-the-u-opioid-receptor-bound-to-a-3114f9v1hs.pdf

Crystal structure of the µ-opioid receptor bound to a morphinan antagonist

Peptides have been identified in mammalian brain that are considered to be endogenous agonists for the delta (enkephalins) and kappa (dynorphins) opiate receptors, but none has been found to have any preference for the mu receptor. Because morphine and other compounds that are clinically useful and open to abuse act primarily at the mu receptor, it could be important to identify endogenous peptides specific for this site. Here we report the discovery and isolation from brain of such a peptide, endomorphin-1 (Tyr-Pro-Trp-Phe-NH2), which has a high affinity (Ki = 360 pM) and selectivity (4,000- and 15,000-fold preference over the delta and kappa receptors) for the mu receptor. This peptide is more effective than the mu-selective analogue DAMGO in vitro and it produces potent and prolonged analgesia in mice. A second peptide, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), which differs by one amino acid, was also isolated. The new peptides have the highest specificity and affinity for the mu receptor of any endogenous substance so far described and they may be natural ligands for this receptor.

A potent and selective endogenous agonist for the mu-opiate receptor.

Glucagon-like peptide-1 (GLP-1) reduces insulin requirement in diabetes mellitus and promotes satiety. GLP-1 in the periphery (outside the CNS) has been shown to act on the brain to reduce food ingestion. As GLP-1 is readily degraded in blood, we focused on the interactions of [Ser 8 ]GLP-1, an analog with similar biological effects and greater stability, with the blood-brain barrier (BBB). The influx of radiolabeled [Ser 8 ]GLP-1 into brain has several distinctive characteristics: 1. A rapid influx rate of 8.867 ± 0.798 × 10 4 mL/g-min as measured by multiple-time regression analysis after iv injection in mice. 2. Lack of self-inhibition by excess doses of the unlabeled [Ser 8 ]GLP-1 either iv or by in situ brain perfusion, indicating the absence of a saturable transport system at the BBB. 3. Lack of modulation by short-term fasting and some other ingestive peptides that may interact with GLP-1, including leptin, glucagon, insulin, neuropeptide Y, and melanin-concentrating hormone. 4. No inhibition of influx by the selective GLP-1 receptor antagonist exendin(9–39), suggesting that the GLP-1 receptor is not involved in the rapid entry into brain. Similarly, there was no efflux system for [Ser 8 ]GLP-1 to exit the brain other than following the reabsorption of cerebrospinal fluid (CSF). The fast influx was not associated with high lipid solubility. Upon reaching the brain compartment, substantial amounts of [Ser 8 ]GLP-1 entered the brain parenchyma, but a large proportion was loosely associated with the vasculature at the BBB. Finally, the influx rate of [Ser 8 ]GLP-1 was compared with that of GLP-1 in a blood-free brain perfusion system; radiolabeled GLP-1 had a more rapid influx than its analog and neither peptide showed the self-inhibition indicative of a saturable transport system. Therefore, we conclude that [Ser 8 ]GLP-1 and the endogenous peptide GLP-1 can gain access to the brain from the periphery by simple diffusion and thus contribute to the regulation of feeding.

Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier.

We determined the ability of orexin A and orexin B, recently discovered endogenous appetite enhancers, to cross the blood-brain barrier (BBB) of mice. Multiple time-regression analysis showed that an i.v. bolus of 125I-orexin A rapidly entered the brain from the blood, with an influx rate (Ki = 2.5 +/- 0.3 x 10(-4) ml/g.min) many times faster than that of the 99mTc-albumin control. This relatively rapid rate of entry was not reduced by administration of excess orexin A (or leptin) or by fasting for 22 h, even when penetration into only the hypothalamus was measured. Lack of saturability also was shown by perfusion in blood-free buffer. HPLC revealed that most of the injected 125I-orexin A reached the brain as intact peptide. Capillary depletion studies showed that the administered peptide did not remain bound to the endothelial cells comprising the BBB but reached the brain parenchyma. Efflux of 125I-orexin A from the brain occurred at the same rate as 99mTc-albumin. The octanol/buffer partition coefficient of 0.232 showed that orexin A was highly lipophilic, whereas the value for orexin B was only 0.030. Orexin B, moreover, was rapidly degraded in blood, so no 125I-orexin B could be detected in intact form in brain when injected peripherally. Thus, although orexin B is rapidly metabolized in blood and has low lipophilicity, orexin A rapidly crosses the BBB from blood to reach brain tissue by the process of simple diffusion.

Orexin A but not orexin B rapidly enters brain from blood by simple diffusion.

HIV-1 induces the AIDS dementia complex and infects brain endothelial and glial cells. Because the endothelial cells comprising the blood-brain barrier (BBB) do not possess CD4 receptors or galactosylceramide binding sites, it is unclear how HIV-1 negotiates the BBB. Previous work has suggested that gp120, the glycoprotein viral coat of HIV-1, is capable of inducing adsorptive endocytosis. Glycoprotein lectins like wheatgerm agglutinin induce adsorptive endocytosis and greatly potentiate the uptake by and passage across mouse endothelial cells in vivo and in vitro. We show here that the wheatgerm agglutinin-induced binding of gp120 is dose-dependent and involves components of the cytoskeleton. The uptake is partially dependent on temperature and energy and is modestly enhanced by potassium depletion. Glycosylation of gp120 is critical for its uptake by adsorptive endocytosis since the non-glycosylated form of gp120 is unaffected by wheatgerm agglutinin. Evidence is presented for the existence of a coreceptor sensitive to protamine sulfate that is primarily involved in membrane fusion after 125I-gp120 has bound to the cell membrane and is probably activated after internalization. This coreceptor probably contains a negatively charged heparin sulfate group and could be a member of the chemokine receptor family.

Adsorptive endocytosis mediates the passage of HIV-1 across the blood-brain barrier: evidence for a post-internalization coreceptor

Systemic administration of luteinizing hormone-releasing hormone (LHRH) in rats has been found to influence behavior independently of pituitary or ovarian function. A previous study has shown that LHRH can cross the blood-brain barrier in one direction, but it was not known whether this was due to a saturable transport system. The rate of entry of 125I-labeled LHRH from blood to brain was determined by two different single-pass methods of carotid perfusion. The first, a multiple time point method, measures Ki from the slope of the linear regression when brain-to-blood ratios of radioiodinated LHRH are plotted against time. Saturable transport was determined by the difference between the Ki of rats perfused with 125I-LHRH (12.51 X 10(-3) mg.g-1.min-1) vs. rats perfused with 125I-LHRH and unlabeled LHRH (10 nmol/ml; 2.20 X 10(-3) ml.g-1.min-1). The inhibition by the unlabeled peptide was statistically significant (P less than 0.001). The second method, a single time point technique, measures the cerebrovascular permeability-surface area coefficient (PA). Saturable transport was determined in rats by the competition of unlabeled LHRH with 125I-LHRH. The PA value for 125I-LHRH (20.00 X 10(-3) ml.g-1.min-1) was significantly greater (P less than 0.05) than for 125I-LHRH with the addition of 10 nmol/ml unlabeled LHRH (4.14 X 10(-3) ml.g-1.min-1). Saturable transport of LHRH from brain to blood in mice was also determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Abba J. Kastin

Papers

A potent and selective endogenous agonist for the mu-opiate receptor.

Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier.

Orexin A but not orexin B rapidly enters brain from blood by simple diffusion.

Adsorptive endocytosis mediates the passage of HIV-1 across the blood-brain barrier: evidence for a post-internalization coreceptor

Bidirectional saturable transport of LHRH across the blood-brain barrier