Intrathecal resiniferatoxin elicits transient hemodynamic effects. In controls, a profound and sustained blockade of thermal stimuli is produced in a dose-dependent fashion. Similar administration in dogs with bone cancer produces a prolonged antinociceptive response.

A prospective study was undertaken to compare the analgesic effect of intra-articular bupivacaine, morphine, or saline in the 24-hour period following cranial cruciate ligament repair in dogs. Thirty-six clinical patients with ruptured cranial cruciate ligaments were randomly assigned to one of three groups. After surgical stabilization, and before skin closure, an intra-articular injection was given; group one (n = 12) received 0.5% bupivacaine HCl at 0.5 mL/kg, group two (n = 12) received morphine at 0.1 mg/kg diluted with saline to a volume of 0.5 mL/kg, and group three (n = 12) received saline at 0.5 mL/kg. Heart rate, respiratory rate, mean arterial blood pressure, cumulative pain score, visual analog pain score, and pain threshold test on both stifles were recorded preoperatively and at 0 to 6 and 24 hours postoperatively. Surgeons and pain scoring investigators were unaware of the intra-articular medication given. Supplemental analgesia, if needed, was provided in the postoperative period according to subjective assessment of patient discomfort. Postoperative pain scores were lowest in the bupivacaine group and highest in the saline group. Pain threshold, measured by applying calibrated loads to the knee, was higher postoperatively in the bupivacaine group than in the saline group. Dogs in the morphine and bupivacaine groups required less supplemental analgesia than dogs in the saline group. The local provision of analgesia reduces the need for systemic drugs with potential side effects. Both intra-articular morphine and intra-articular bupivacaine provided better postoperative analgesia than intra-articular saline, with intra-articular bupivacaine showing the greatest effect.

To identify molecular events occurring during the early response to hyperoxia, we measured changes over time in total lung gene expression in C57BL/6 mice during prolonged exposure to > 95% O2. Specifically, differential gene expression of > 8,734 sequence-verified murine complementary DNAs was analyzed after 0, 8, 24, and 48 h of O2 exposure, with additional genes of interest analyzed at 24 h. Of the 385 genes differentially expressed, hyperoxia increased expression of 175 genes (2.0%) and decreased expression of 210 genes (2.3%). The majority of "classic" antioxidant enzymes, including catalase, MnSOD, and Cu-Zn SOD, showed no change in expression during hyperoxia, with a number of other antioxidant enzymes, including glutathione peroxidase, glutathione-S-Transferase (GST) Pi1, GST mu2, and heme oxygenase-1 showing relatively moderate increases. The exception was the heavy metal-binding protein metallothionein, which increased expression over 7-fold after 48 h of O2. We found no change in the expression of a number of known proinflammatory genes after 24 or 48 h of hyperoxia. A large increase in p21 expression was demonstrated, suggesting overall inhibition of cell cycle progression. Increases of the antiapoptotic gene Bcl-XL were counterbalanced by similar increases of the proapoptotic gene BAX. New findings included significant increases in expression of cysteine-rich protein 61(cyr61) at 48 h, suggesting a potential role for this factor in angiogenesis or remodeling of the extra cellular matrix during recovery from hyperoxia. In addition, downregulation of thrombomodulin expression occurred by 24 h and was further decreased at 48 h. Given the importance of thrombomodulin/thrombin interaction in regulating protein C activity, decreases in thrombomodulin may contribute to activation of the coagulation and inflammatory cascades and development of lung injury with hyperoxia.

The objective of this study was to quantitatively assess changes in cell adhesion molecule (CAM) expression on the pulmonary endothelial surface during hyperoxia and to assess the functional significance of those changes on cellular trafficking and development of oxygen-induced lung injury. Mice were placed in >95% O(2) for 0-72 h, and pulmonary injury and neutrophil (PMN) sequestration were assessed. Specific pulmonary CAM expression was quantified with a dual-radiolabeled MAb technique. To test the role of CAMs in PMN trafficking during hyperoxia, blocking MAbs to murine P-selectin, ICAM-1, or platelet-endothelial cell adhesion molecule-1 (PECAM-1) were injected in wild-type mice. Mice genetically deficient in these CAMs and PMN-depleted mice were also evaluated. PMN sequestration occurred within 8 h of hyperoxia, although alveolar emigration occurred later (between 48 and 72 h), coincident with rapid escalation of the lung injury. Hyperoxia significantly increased pulmonary uptake of radiolabeled antibodies to P-selectin, ICAM-1, and PECAM-1, reflecting an increase in their level on pulmonary endothelium and possibly sequestered blood cells. Although both anti-PECAM-1 and anti-ICAM-1 antibodies suppressed PMN alveolar influx in wild-type mice, only mice genetically deficient in PECAM-1 showed PMN influx suppression. Neither CAM blockade, nor genetic deficiency, nor PMN depletion attenuated lung injury. We conclude that early pulmonary PMN retention during hyperoxia is not temporally associated with an increase in endothelial CAMs; however, subsequent PMN emigration into the alveolar space may be supported by PECAM-1 and ICAM-1. Blocking PMN recruitment did not prevent lung injury, supporting dissociation between PMN infiltration and lung injury during hyperoxia in mice.