@article{PritchardFalkLarssonetal.2016,
  author    = {Pritchard, Rory A. and Falk, Lovissa and Larsson, Mathilda and Leinders, Mathias and Sorkin, Linda S.},
  title     = {Different phosphoinositide 3-kinase isoforms mediate carrageenan nociception and inflammation},
  series = {Pain},
  volume    = {157},
  journal   = {Pain},
  number    = {1},
  doi       = {10.1097/j.pain.0000000000000341},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150248},
  pages     = {137-146},
  year      = {2016},
  abstract  = {Phosphoinositide 3-kinases (PI3Ks) participate in signal transduction cascades that can directly activate and sensitize nociceptors and enhance pain transmission. They also play essential roles in chemotaxis and immune cell infiltration leading to inflammation. We wished to determine which PI3K isoforms were involved in each of these processes. Lightly anesthetized rats (isoflurane) were injected subcutaneously with carrageenan in their hind paws. This was preceded by a local injection of 1\% DMSO vehicle or an isoform-specific antagonist to PI3K-α (compound 15-e), -β (TGX221), -δ (Cal-101), or -γ (AS252424). We measured changes in the mechanical pain threshold and spinal c-Fos expression (4 hours after injection) as indices of nociception. Paw volume, plasma extravasation (Evans blue, 0.3 hours after injection), and neutrophil (myeloperoxidase; 1 hour after injection) and macrophage (CD11b+; 4 hour after injection) infiltration into paw tissue were the measured inflammation endpoints. Only PI3K-γ antagonist before treatment reduced the carrageenan-induced pain behavior and spinal expression of c-Fos (P ≤ 0.01). In contrast, pretreatment with PI3K-α, -δ, and-γ antagonists reduced early indices of inflammation. Plasma extravasation PI3K-α (P ≤ 0.05), -δ (P ≤ 0.05), and -γ (P ≤ 0.01), early (0-2 hour) edema -α (P ≤ 0.05), -δ (P ≤ 0.001), and -γ (P ≤ 0.05), and neutrophil infiltration (all P ≤ 0.001) were all reduced compared to vehicle pretreatment. Later (2-4 hour), edema and macrophage infiltration (P ≤ 0.05) were reduced by only the PI3K-δ and -γ isoform antagonists, with the PI3K-δ antagonist having a greater effect on edema. PI3K-β antagonism was ineffective in all paradigms. These data indicate that pain and clinical inflammation are pharmacologically separable and may help to explain clinical conditions in which inflammation naturally wanes or goes into remission, but pain continues unabated.},
  language  = {en}
}
@article{EnigkWagnerSamapatietal.2014,
  author    = {Enigk, Fabian and Wagner, Antje and Samapati, Rudi and Rittner, Heike and Brack, Alexander and Mousa, Shaaban A. and Sch{\"a}fer, Michael and Habazettl, Helmut and Sch{\"a}per, J{\"o}rn},
  title     = {Thoracic epidural anesthesia decreases endotoxin-induced endothelial injury},
  series = {BMC Anesthesiology},
  volume    = {14},
  journal   = {BMC Anesthesiology},
  number    = {23},
  doi       = {10.1186/1471-2253-14-23},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116787},
  year      = {2014},
  abstract  = {Background: The sympathetic nervous system is considered to modulate the endotoxin-induced activation of immune cells. Here we investigate whether thoracic epidural anesthesia with its regional symapathetic blocking effect alters endotoxin-induced leukocyte-endothelium activation and interaction with subsequent endothelial injury. Methods: Sprague Dawley rats were anesthetized, cannulated and hemodynamically monitored. E. coli lipopolysaccharide (Serotype 0127: B8, 1.5 mg x kg(-1) x h(-1)) or isotonic saline (controls) was infused for 300 minutes. An epidural catheter was inserted for continuous application of lidocaine or normal saline in endotoxemic animals and saline in controls. After 300 minutes we measured catecholamine and cytokine plasma concentrations, adhesion molecule expression, leukocyte adhesion, and intestinal tissue edema. Results: In endotoxemic animals with epidural saline, LPS significantly increased the interleukin-1 beta plasma concentration (48\%), the expression of endothelial adhesion molecules E-selectin (34\%) and ICAM-1 (42\%), and the number of adherent leukocytes (40\%) with an increase in intestinal myeloperoxidase activity (26\%) and tissue edema (75\%) when compared to healthy controls. In endotoxemic animals with epidural infusion of lidocaine the values were similar to those in control animals, while epinephrine plasma concentration was 32\% lower compared to endotoxemic animals with epidural saline. Conclusions: Thoracic epidural anesthesia attenuated the endotoxin-induced increase of IL-1 beta concentration, adhesion molecule expression and leukocyte-adhesion with subsequent endothelial injury. A potential mechanism is the reduction in the plasma concentration of epinephrine.},
  language  = {en}
}