Lipid mediators regulating pain sensitivity

The papers in this symposium demonstrate that lipid molecules are ubiquitous messengers that participate in intracellular signaling, function in intercellular communication, and serve as neurotransmitters. This review examines the contribution of lipid messengers in regulating a specific physiological function, the transmission of noxious sensory information (pain) in the nervous system. Lipid molecules play major roles in the modulation of pain sensitivity. Six types of lipid molecules (prostanoids, phosphatidyl inositol bisphosphate, ceramide, lipoxygenase metabolites of arachidonic acid, fatty acyl dopamines, and acylethanolamides) have been shown to modulate systems important in the regulation of pain responses. These molecules exert their actions by interacting with varied receptor systems. Evidence for their participation in the regulation of pain responses comes from in vitro demonstrations of their interactions with signaling systems known to be important in the regulation of pain sensitivity and, in some cases, from demonstration of their ability to modulate pain sensitivity after in vivo administration. One of these classes of lipid mediators, the acylethanolamides, inhibits pain responses, while the others appear to enhance pain sensitivity. Given the rapid growth in our understanding of lipidomics, evident in the papers of this issue, it is virtually certain that additional lipid mediators will be identified as being central to the regulation of pain responses.     

Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT

Ghrelin is an acyl-peptide gastric hormone acting on the pituitary and hypothalamus to stimulate growth hormone (GH) release, adiposity, and appetite. Ghrelin endocrine activities are entirely dependent on its acylation and are mediated by GH secretagogue (GHS) receptor (GHSR)-1a, a G protein-coupled receptor mostly expressed in the pituitary and hypothalamus, previously identified as the receptor for a group of synthetic molecules featuring GH secretagogue (GHS) activity. Des-acyl ghrelin, which is far more abundant than ghrelin, does not bind GHSR-1a, is devoid of any endocrine activity, and its function is currently unknown. Ghrelin, which is expressed in heart, albeit at a much lower level than in the stomach, also exerts a cardio protective effect through an unknown mechanism, independent of GH release. Here we show that both ghrelin and des-acyl ghrelin inhibit apoptosis of primary adult and H9c2 cardiomyocytes and endothelial cells in vitro through activation of extracellular signal-regulated kinase-1/2 and Akt serine kinases. In addition, ghrelin and des-acyl ghrelin recognize common high affinity binding sites on H9c2 cardiomyocytes, which do not express GHSR-1a. Finally, both MK-0677 and hexarelin, a nonpeptidyl and a peptidyl synthetic GHS, respectively, recognize the common ghrelin and des-acyl ghrelin binding sites, inhibit cell death, and activate MAPK and Akt.These findings provide the first evidence that, independent of its acylation, ghrelin gene product may act as a survival factor directly on the cardiovascular system through binding to a novel, yet to be identified receptor, which is distinct from GHSR-1a.     

Structure and stereochemistry of dimeric proteracacinidins possessing the rare C-4(C) --> C-5(D) interflavanyl linkage

The rare series of (4-->5)-linked proteracacinidins is extended by identification of oritin-(4alpha-->5)-epioritin-4beta-ol, ent-epioritin-(4alpha-->5)-epioritin-4beta-ol, epioritin-(4beta-->5)-epioritin-4alpha-ol and ent-oritin-(4beta-->5)-epioritin-4alpha-ol from the heartwoods of Acacia galpinii and Acacia caffra.     

Sexual selection,germline mutation rate and sperm competition

Background  

An important component of sexual selection arises because females obtain viability benefits for their offspring from their mate choice. Females choosing extra-pair fertilization generally favor males with exaggerated secondary sexual characters, and extra-pair paternity increases the variance in male reproductive success. Furthermore, females are assumed to benefit from 'good genes' from extra-pair sires. How additive genetic variance in such viability genes is maintained despite strong directional selection remains an evolutionary enigma. We propose that sexual selection is associated with elevated mutation rates, changing the balance between mutation and selection, thereby increasing variance in fitness and hence the benefits to be obtained from good genes sexual selection. Two hypotheses may account for such elevated mutation: (1) Increased sperm production associated with sperm competition may increase mutation rate. (2) Mutator alleles increase mutation rates that are revealed by the expression of condition-dependent secondary sexual characters used by choosy females during their mate choice. M Petrie has independently developed the idea that mutator alleles may account for the maintenance of genetic variation in viability despite strong directional selection.     

Physicochemical prediction of a brain-blood distribution profile in polycyclic amines

Recent investigation into the pharmacological character of the pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecyl and related polycyclic amines has revealed interesting facts regarding their possible use as neuroprotective agents. At this stage however, a clear shortcoming in the quest for further development of this novel class of compounds is the lack of concrete data on their ability to cross the blood-brain barrier (BBB). Working towards the aim of predicting BBB permeability, a series of related N-substituted 8-amino-8,11-oxapentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecanes were synthesised. Compounds were characterised by both experimental and calculative methods, followed by biological assessment and statistical manipulation of the results obtained. In doing so, a simple biological model was established for the comparative evaluation of brain-blood distribution properties within the class. A highly sensitive ESI-MS.MS analytical procedure was developed for the detection of these compounds in biological tissues, indicating significant drug concentrations in the brain after intraperitoneal administration to C57Bl/6 mice. Stepwise multiple linear regression analysis of all data yielded two meaningful models (R(2)=0.9996 and R(2)=0.7749) depicting lipophilicity (log P(oct)), solvent accessible molecular volume (SV), molar refractivity (MR) and system energy as the prime determinants of the brain-blood profile for these amines. The inherently high lipophilicity potential within the series is attributed to strong hydrophobic influences dominating hydrogen bonding effects. A possible conformational and energy dependent preference at the site of permeation is also suggested. The proposed estimations allow for the expedient and reliable prediction of brain partitioning behaviour for related polycyclic amines, facilitating the early rejection of unsuitable candidates and enabling research to focus on neuroprotective activity.     

Phosphoinositide 3-kinase gamma controls autonomic regulation of the mouse heart through Gi-independent downregulation of cAMP level

Cardiac beta-adrenergic and the muscarinic receptors control contractility and heart rate by triggering multiple signaling events involving downstream targets like the phosphoinositide 3-kinase gamma (PI3Kgamma). We thus investigated whether the lack of PI3Kgamma could play a role in the autonomic regulation of the mouse heart. Contractility and ICaL of mutant cardiac preparations appeared increased in basal conditions and after beta-adrenergic stimulation. However, basal and beta-adrenergic stimulated heart rate were normal. Conversely, muscarinic inhibition of heart rate was reduced without alteration of the Gbetagamma-dependent stimulation of IK,ACh current. In addition, muscarinic-mediated anti-adrenergic effect on papillary muscle contractility and ICaL was significantly depressed. Consistently, cAMP level of PI3Kgamma-null ventricles was always higher than wild-type controls. Thus, PI3Kgamma controls the cardiac function by reducing cAMP concentration independently of Gi-mediated signaling.     

Neuropathic pain: the paradox of dynorphin

One of the curious but common consequences of opioid administration in the clinical setting is the induction, at sites uninvolved in the original presentation of discomfort, of pain itself. The induction of pain is also a reliable, measurable phenomenon in animals receiving continuous delivery of opioid. Such pain induction is associated with the expression of spinal dynorphin, a finding that is especially intriguing in light of dynorphin's ability to recapitulate many of the characteristics of chronic, neuropathic pain when administered intrathecally (i.e., into the spine). The effective treatment of chronic pain syndromes-and of tolerance to antinociceptive therapies-may thus rest on an understanding of the biological roles of dynorphin in neurotransmission.     

Sequencing three crocodilian genomes to illuminate the evolution of archosaurs and amniotes

The International Crocodilian Genomes Working Group (ICGWG) will sequence and assemble the American alligator (Alligator mississippiensis), saltwater crocodile (Crocodylus porosus) and Indian gharial (Gavialis gangeticus) genomes. The status of these projects and our planned analyses are described.     

Potential of South African entomopathogenic nematodes (Heterorhabditidae and Steinernematidae) for control of the citrus mealybug, Planococcus citri (Pseudococcidae)

Planococcus citri, the citrus mealybug, is the most important species of mealybug known to infest citrus in South Africa. Various laboratory bioassays were conducted to determine the potential of entomopathogenic nematodes to control P. citri. Adult female P. citri were screened for susceptibility to six indigenous nematode species. P. citri was found to be most susceptible to Steinernema yirgalemense and Heterorhabditis zealandica, causing 97% and 91% mortality, respectively. The development of nematodes after infecting adult female P. citri showed both H. zealandica and S. yirgalemense were able to complete their life cycles inside the host. Further bioassays illustrated a linear relationship between mealybug mortality and the concentration of nematodes applied, with the highest level of control using a concentration of 80 infective juveniles (IJs)/insect. As nematodes would be used as an above-ground application to control P. citri in citrus orchards, available water is a major limiting factor. Insecticidal activity proved to be dependent on the available surface moisture after nematode application. The water activity (a(w)) bioassay indicated that S. yirgalemense to be two times more tolerant to lower levels of free water, with a(w)(50)=0.96 and a(w)(90)=0.99, compared to H. zealandica with a(w)(50)=0.98 and a(w)90=1.0. After application, nematodes have a limited time frame in which to locate and infect hosts, as the level of available free water gradually decreases, as trees dry out. S. yirgalemense proved able to locate and infect P. citri quicker than H. zealandica. Nematode activity was not significantly affected when exposed to 15°C, 20°C and 25°C. IJs were able to infect P. citri at an exposure time as short as half an hour. Results also showed that the first 2-4h post application is the most decisive time for establishing successful infection of mealybugs. This is the first report on the potential use of nematodes for the control of P. citri.