Interaction of a Cannabinoid-2 Agonist With Tramadol on Nociceptive Thresholds and Immune Responses in a Rat Model of Incisional Pain.

The aim of this study was to elucidate the antinociceptive interaction between cannabinoids and tramadol and their impact on proinflammatory response, in terms of serum intereleukin-6 (IL-6) and interleukin-2 (IL-2) release, in a rat model of incisional pain. Prospective randomized trial assessing the individual or combined application of intraperitoneal tramadol (10 mg/kg) and the selective cannabinoid-2 (CB-2) agonist (R,S)-AM1241 (1 mg/kg) applied postsurgical stress stimulus. Pharmacological specificity was established by antagonizing tramadol with naloxone (0.3 mg/kg) and (R,S)-AM1241 with SR144528 (1 mg/kg). Thermal allodynia was assessed by hot plate test 30 (T30), 60 (T60), and 120 (T120) minutes after incision. Blood samples for plasma IL-6 and IL-2 level determination were obtained 2 hours after incision. Data from 42 rats were included in the final analyses. Significant augmentation of thermal threshold was observed at all time points, after administration of either tramadol or (R,S)-AM1241 compared with the control group (P = 0.004 and P = 0.015, respectively). The combination of (R,S)-AM1241 plus tramadol promoted the induced antinociception in an important manner compared with control (P = 0.002) and (R,S)-AM1241 (P = 0.022) groups. Although the antiallodynic effect produced by tramadol was partially reversed by naloxone 30 and 60 minutes after incision (P = 0.028 and P = 0.016, respectively), SR144528 blocked the effects of (R,S)-AM1241 administration in a significant manner (P = 0.001) at all time points. Similarly, naloxone plus SR144528 also blocked the effects of the combination of (R,S)-AM1241 with tramadol at all time points (P = 0.000). IL-6 level in (R,S)-AM1241 plus tramadol group was significantly attenuated compared with control group (P = 0.000). Nevertheless, IL-2 levels remained unchanged in all experimental groups. It seems that the concomitant administration of a selective CB-2 agonist with tramadol in incisional pain model may improve antinociceptive effects and immune responses of cannabinoids, but this effect does not seem to be superior to that of tramadol alone.

Nimesulide may be more efficient than allopurinol in protecting pancreas from acute ischemia/reperfusion injury in an animal model.

OBJECTIVE: To determine the influence of allopurinol and nimesulide in the protection of the pancreas from acute ischemia-reperfusion (I/R) injury. MATERIALS AND METHODS: A total of 30 rabbits were divided into 3 groups, group A: acute I/R only; group B: allopurinol (30 mg/kg) was administered intravenously 10 minutes before ischemia; group C: nimesulide (50 mg/kg) was given intraperitoneally 20 minutes before ischemia. Neopterin and superoxide dismutase (SOD) levels were examined. Pancreatic biopsies were obtained for electron microscopy study. RESULTS: The mean neopterin concentrations in group A are 3.56 ± 3.41, 7.74 ± 3.59, and 8.94 ± 2.86 ng/mL, respectively, in the stabilization, ischemia, and reperfusion phases; group B: 3.40 ± 3.03, 7.45 ± 8.89, and 10.64 ± 7.47 ng/mL; and group C: 3.41 ± 2.71, 5.67 ± 2.76, and 4.34 ± 2.87 ng/mL. The mean SOD concentrations in group A are 4.25 ± 1.79, 4.48 ± 1.60, and 5.57 ± 1.15 ng/mL; group B: 4.32 ± 0.81, 5.08 ± 1.10, and 4.45 ± 1.31 ng/mL; and group C: 4.10 ± 0.99, 5.23 ± 1.60, and 3.72 ± 1.30 ng/mL. Histopathology showed the least deterioration in group C. CONCLUSION: Nimesulide is more efficient than allopurinol in protecting pancreas from acute I/R injury.

Baroreceptors discharge due to bilateral aortic denervation evokes acute neuronal damage in rat brain.

Deep hypothermic circulatory arrest in cardiothoracic surgery evokes severe brain damages. On the other hand, blood pressure stimuli discontinuation to the brain has been found to induce alterations in neurotransmitter release, including glutamate, in numerous brain regions. Furthermore, it is well established that excessive glutamate release can induce neuronal injury, a process called excitotoxicity. Aim of the present study was the evaluation of possible acute neuronal damage after bilateral aortic denervation (bAD), imitating the baroreceptors discharge during circulatory arrest. Male, Wistar rats underwent either bAD or Sham operation under continuous hemodynamic monitoring. Two hours after completion of the procedure, rats were sacrificed and the brains were dissected and cut in specific levels corresponding to selective brain regions, based on either their participation in neuronal circuits, regulating blood pressure, or their vulnerability, after deep hypothermic circulatory arrest. Slices were stained and examined under light microscope using morphometric techniques. Increased number of necrotic neurons were found among bAD rats in amygdaloid complex (p=0.005), motor cortex (p=0.001), CA1 and CA3 (p=0.02 and 0.015) but not in posterior hypothalamic nucleus and Purkinje cell. Higher ratios of necrotic neurons were found in amygdaloid complex (p=0.002), motor layer (p=0.003 and p=0.000) and the hippocampal CA1 region (p=0.027) of bAD rats. The present study shows that baroreceptors discharge due to bAD may induce acute neuronal loss in brain regions involved in blood pressure regulation. Neuronal loss might be attributed to excitotoxic phenomena and it is following the same topographic distribution seen in deep hypothermic circulatory arrest, revealing a concurrent to hypoxia/ischemia mechanism of brain damage.

The efficacy of antithrombin administration in the acute phase of burn injury.

Severe burn injury is characterized by the activation of coagulation, decreased fibrinolytic activity and decreased natural anticoagulant activity. The aim of our study was to investigate the effect of antithrombin (AT) administration on coagulation status and on organ function in the early post-burn period. Thirty-one patients were admitted to the burn intensive care unit and were then randomised into two groups (AT-treated and non-AT-treated) for four consecutive days after thermal injury. The clinical data, coagulation and fibrinolysis parameters were compared and the adverse effects were monitored. Significant differences in the time course of coagulation markers (thrombin/AT complexes, tissue plasminogen activator, D-dimer) were observed between AT-treated and non-AT treated groups. According to the International Society on Thrombosis and Haemostasis criteria, disseminated intravascular coagulation (DIC) diagnosis was made in 28 of 31 patients. The presence of overt DIC was associated with mortality (p < 0.001). The Sequential Organ Failure Assessment (SOFA) score time trend differed significantly between the two investigation groups (decreased in the treated group and did not change in the non-AT-treated group). AT-treated patients had an absolute reduction in a 28-day mortality of 25% as compared to the non-AT-treated group (p = 0.004). No treatment related side effects were observed. Treatment with AT seems to affect the coagulation status and reduce multiple organ failure incidence and mortality in the early post-burn period.

Effects of pneumoperitoneum and LPS-induced endotoxemia on cerebral perfusion pressure in pigs.

Multitrauma patients commonly develop abdominal compartment syndrome, which is defined as the end result of sustained, uncorrected, intra-abdominal hypertension. We aimed to assess the effects of increased intra-abdominal pressure (IAP) upon intracranial pressure (ICP) and cerebral perfusion pressure (CPP) in the presence or absence of lipopolysacharide (LPS)-induced endotoxemia using an experimental porcine model of pneumoperitoneum. Experimental procedures were approved by the Animal Care Review Committee of the National Veterinary Institute. Sixteen female pigs weighing 20 to 25 kg, aged 3 to 4 months were used. The animal model of increased IAP employed in our studies was produced with intraperitoneal administration of helium at 25 mm Hg under general anesthesia. After induction of pneumoperitoneum, 16 animals were randomly divided into 2 groups of 8 pigs each. One group received LPS intravenously (endotoxin group) and the second group received saline (control group). ICP, CPP, and hemodynamic variables were continuously monitored and recorded. A significant reduction of the cardiac output and concurrent increases in systemic vascular resistance and central venous pressure were observed in both groups after induction of pneumoperitoneum. ICP increased whereas CPP decreased significantly compared with baseline values in both groups after elevation of IAP. After LPS administration (endotoxin group), the cardiac output and mean arterial pressure decreased significantly. The CPP decreased further in the endotoxin group after LPS administration, whereas ICP remained unchanged. IAP increases produce significant increases in the ICP and decreases in the CPP in this animal model. LPS-induced endotoxemia further decreased CPP.