Tissue-specific study across the stem reveals the chemistry and transcriptome dynamics of birch bark.

Tree bark is a highly specialized array of tissues that plays important roles in plant protection and development. Bark tissues develop from two lateral meristems; the phellogen (cork cambium) produces the outermost stem-environment barrier called the periderm, while the vascular cambium contributes with phloem tissues. Although bark is diverse in terms of tissues, functions and species, it remains understudied at higher resolution. We dissected the stem of silver birch (Betula pendula) into eight major tissue types, and characterized these by a combined transcriptomics and metabolomics approach. We further analyzed the varying bark types within the Betulaceae family. The two meristems had a distinct contribution to the stem transcriptomic landscape. Furthermore, inter- and intraspecies analyses illustrated the unique molecular profile of the phellem. We identified multiple tissue-specific metabolic pathways, such as the mevalonate/betulin biosynthesis pathway, that displayed differential evolution within the Betulaceae. A detailed analysis of suberin and betulin biosynthesis pathways identified a set of underlying regulators and highlighted the important role of local, small-scale gene duplication events in the evolution of metabolic pathways. This work reveals the transcriptome and metabolic diversity among bark tissues and provides insights to its development and evolution, as well as its biotechnological applications.

The binding of synthetic retinoids to lipocalin beta-lactoglobulins.

The binding of therapeutically relevant synthetic retinoid derivatives to bovine and reindeer beta-lactoglobulin (betaLG) is demonstrated using fluorescence quenching and ultrafiltration/HPLC methods. Furthermore, synthesis of methyl (E)-3-[4-[(E)-2-(2,6,6-trimethylcyclohex-1-enyl)vinyl]phenyl]-acrylate 4 and (E)-3-[4-[(E)-2-(2,6,6-trimethylcyclohex-1-enyl)vinyl]phenyl]acrylic acid 5 is described. All studied compounds bind to both betaLG homologues with nanomolar K(d) values, and the interaction diminishes the pH-dependent aggregation of retinoids. Thus, betaLG may show benefits in improving the bioavailability of retinoid derivatives.

Pharmacological characterization of noroxymorphone as a new opioid for spinal analgesia.

BACKGROUND: Noroxymorphone is one of the major metabolites of oxycodone. Although oxycodone is commonly used in the treatment of acute and chronic pain, little is known about the antinociceptive effects of noroxymorphone. We present an in vivo pharmacological characterization of noroxymorphone in rats. METHODS: The antinociceptive properties of noroxymorphone were studied with thermal and mechanical models of nociception in rats. RESULTS: Intrathecal noroxymorphone (1 and 5 microg/10 microL) induced a significantly longer lasting antinociceptive effect compared with oxycodone (200 microg/10 microL) and morphine (1 and 5 microg/10 microL). Pretreatment with subcutaneous naloxone (1 mg/kg) 15 min before intrathecal drug administration significantly decreased the antinociceptive effect of both noroxymorphone and morphine, indicating an opioid receptor-mediated antinociceptive effect. In the hotplate, paw pressure, and tail flick tests, subcutaneous noroxymorphone was inactive in doses of 5, 10, and 25 mg/kg. Also, no effect on motor function was observed in the rotarod test with doses studied. No antihyperalgesic effect was observed in the carrageenan model for inflammation in rats with subcutaneous noroxymorphone 25 mg/kg. CONCLUSIONS: The results of this study indicate that noroxymorphone is a potent mu-opioid receptor agonist when administered intrathecally. The lack of systemic efficacy may indicate reduced ability of noroxymorphone to penetrate the blood-brain barrier due to its low calculated logD value (log octanol/water partition coefficient). Thus, noroxymorphone should have a negligible role in analgesia after systemic administration of oxycodone. Because of its spinal efficacy and long duration of effect, noroxymorphone is an interesting opioid for spinal analgesia with a low potential for abuse. Its safety for spinal administration should be assessed before clinical use.

Antinociception by spinal and systemic oxycodone: why does the route make a difference? In vitro and in vivo studies in rats.

BACKGROUND: The pharmacology of oxycodone is poorly understood despite its growing clinical use. The discrepancy between its good clinical effectiveness after systemic administration and the loss of potency after spinal administration led the authors to study the pharmacodynamic effects of oxycodone and its metabolites using in vivo and in vitro models in rats. METHODS: Male Sprague-Dawley rats were used in hot-plate, tail-flick, and paw-pressure tests to study the antinociceptive properties of morphine, oxycodone, and its metabolites oxymorphone and noroxycodone. Mu-opioid receptor agonist-stimulated GTPgamma[S] autoradiography was used to study G-protein activation induced by morphine, oxycodone, and oxymorphone in the rat brain and spinal cord. Spontaneous locomotor activity was measured to assess possible sedation or motor dysfunction. Naloxone and the selective kappa-opioid receptor antagonist nor-binaltorphimine were used to study the opioid receptor selectivity of the drugs. RESULTS: Oxycodone showed lower efficacy and potency to stimulate GTPgamma[S] binding in the spinal cord and periaqueductal gray compared with morphine and oxymorphone. This could relate to the fact that oxycodone produced only weak naloxone-reversible antinociception after intrathecal administration. It also suggests that the metabolites may have a role in oxycodone-induced analgesia in rats. Intrathecal oxymorphone produced strong long-lasting antinociception, whereas noroxycodone produced antinociception with very high doses only. Subcutaneous administration of oxycodone and oxymorphone produced thermal and mechanical antinociception that was reversed by naloxone but not by nor-binaltorphimine. Oxymorphone was more potent than oxycodone, particularly in the hot-plate and paw-pressure tests. CONCLUSIONS: The low intrathecal potency of oxycodone in rats seems be related to its low efficacy and potency to stimulate mu-opioid receptor activation in the spinal cord.