Antiallodynic Effect of Intrathecal Korean Red Ginseng in Cisplatin-Induced Neuropathic Pain Rats.

BACKGROUND: Chemotherapy-induced neuropathic pain (CINP) is a serious side effect of chemotherapy. Korean Red Ginseng (KRG) is a popular herbal medicine in Asian countries. We examined the therapeutic potential of intrathecally administered KRG for CINP and clarified the mechanisms of action with regard to 5-hydroxytryptamine (5-HT)7 receptor at the spinal level. METHODS: CINP was evoked by intraperitoneal injection of cisplatin in male Sprague-Dawley rats. After examining the effects of intrathecally administered KRG on CINP, 5-HT receptor antagonist (dihydroergocristine [DHE]) was pretreated to determine the involvement of 5-HT receptor. In addition, intrathecal 5-HT7 receptor antagonist (SB269970) was administered to define the role of 5-HT7 receptor on the effect of KRG. 5-HT7 receptor mRNA expression levels and 5-HT concentrations were examined in the spinal cord. RESULTS: Intrathecally administered KRG produced a limited, but a dose-dependent, antiallodynic effect. Intrathecally administered DHE antagonized the antiallodynia caused by KRG. Furthermore, intrathecal SB269970 also reversed the effect of KRG. No changes in 5-HT7 receptor mRNA expression were seen in the dorsal horn of the spinal cord after cisplatin injection. After injecting cisplatin, 5-HT levels were decreased in the spinal cord, whereas those of 5-HT were increased by intrathecal KRG. CONCLUSIONS: Intrathecally administered KRG decreased CINP. In addition, spinal 5-HT7 receptors contributed to the antiallodynic effect of KRG.

The effects of BMS-470539 on lipopolysaccharide-induced acute lung injury.

BACKGROUND: Overactivation of inflammatory cells, including macrophages and neutrophils, is associated with acute lung injury. BMS-470539 is a selective agonist of melanocortin 1 receptor, which triggers the inhibition of proinflammatory responses, suppressing neutrophil infiltration and protecting tissue. This study evaluated the effects of BMS-470539 on lipopolysaccharide-induced acute lung injury in a mouse model. METHODS: Mice received a subcutaneous injection of saline or BMS-470539 (18.47 mg/kg) 1 hour before an intratracheal injection of saline or lipopolysaccharide (20 µg). Mice were sacrificed to analyze the severity of pulmonary edema (lung wet-to-dry weight [W/D] ratio) and inflammatory responses (level of leukocytes, polymorphonuclear neutrophils [PMNs] and tumor necrosis factor alpha [TNF-α] in bronchoalveolar lavage fluid [BALF]), and neutrophil infiltration (myeloperoxidase activity). TNF-α activation was also measured in neutrophils from bone marrow. Survival was investigated in a second-hit sepsis mouse model. RESULTS: BMS-470539 improved sepsis-induced pulmonary edema, as demonstrated by a decreased W/D ratio (5.76%±0.83% to 3.81%±0.86%, P<0.05). The inflammatory response also improved, as shown by decreased levels of leukocytes (551±116 to 357±86×10²/mm³, P<0.05), PMNs (51.52%±16.23% to 18.41%±7.25%, P<0.01), and TNF-α (550±338 to 128±52 pg/ml, P<0.01) in the BALF. BMS-470539 also improved the inflammatory response, as shown by TNF-α levels (850±158 to 423±59 pg/ml, P<0.01) in neutrophils. BMS-470539 downregulated neutrophil infiltration in the lung (myeloperoxidase: 654±98 to 218±89 U/g, P<0.001). Lastly, BMS improved the survival rate (0% to 70%, P<0.01) in a mice multiple organ failure model. CONCLUSIONS: BMS-470539 improved lipopolysaccharide-induced acute lung injury and mortality in mice by affecting the inflammatory response.

Antiallodynic Effects of Intrathecal Areca Nut for Spinal Nerve-Ligated and Chemotherapy-Induced Neuropathic Pain in Rats.

This study examined the effects of intrathecal areca nut on spinal nerve-ligated and chemotherapy-induced neuropathic pain (NP), and investigated the relevance of spinal 5-hydroxytryptamine (5-HT) and α2-adrenergic receptors to those effects. For drug administration, intrathecal catheters were inserted into the subarachnoid space of male Sprague-Dawley rats. NP was induced either by spinal nerve ligation (left spinal nerves L5 and L6) or by chemotherapeutic injection (intraperitoneal cisplatin, 2 mg/kg/day, once daily for 4 days). Paw withdrawal thresholds (PWT) were mechanically assessed using von Frey filaments. The involvement of 5-HT and α2-adrenergic receptors in antiallodynia was determined using antagonists with the following receptor specificities: nonselective 5-HT (dihydroergocristine), 5-HT7 (SB269970), nonselective α2-adrenoceptor (yohimbine), α-2A (BRL 44408), α-2B (ARC 239), and α-2C (JP 1302). Intrathecal areca nut significantly increased the PWT in both spinal nerve-ligated and chemotherapy-induced NP (‡ p < 0.001). Intrathecal dihydroergocristine, SB269970, yohimbine, BRL 44408, ARC 239, and JP 1302 significantly reversed the antiallodynic effects of areca nut in both NP states (‡ p < 0.001). Collectively, intrathecal areca nut suppressed mechanical allodynia induced by spinal nerve ligation and cisplatin injection. Furthermore, spinal 5-HT7 receptor and α2A, α2B, and α2C-adrenoceptors contributed to the antiallodynic effects of areca nut.

Cytotoxic activity and subset populations of peripheral blood natural killer cells in patients with chronic pain.

BACKGROUND: Chronic pain reportedly exerts complex effects on immune function. Natural killer (NK) cells are lymphocytes that play a critical role in cellular and innate immunity. This study examined changes in the subset populations and cytotoxic activity of peripheral blood NK cells in patients with chronic pain. METHODS: Thirty patients with chronic moderate-to-severe pain (group P) and age-matched pain-free subjects (group NoP) were enrolled. Peripheral whole blood was analyzed for the percentage and expression of NK cell surface markers (CD56 and CD16) by flow cytometry. Cytotoxic activity was assayed by evaluating CD69 expression on CD3-/CD56+NK cells. RESULTS: The percentage of NK cells among total lymphocytes was not significantly different between groups P and NoP (16.3 ± 9.3 vs. 20.2 ± 10.5%). Likewise, the percentages of two major NK cell subsets, CD56bright and CD56dim, were also not significantly different between the two groups. However, the percentage of CD56bright/CD16+ subset, was slightly but significantly increased in group P (1.0 ± 0.9%; P < 0.01) compared with group NoP (0.5 ± 0.6%). The cytotoxicity of NK cells was not different between the two groups, showing similar CD69 expression (P vs. NoP = 29.2 ± 15.2 vs. 32.0 ± 15.0%). These findings were not influenced by pain intensity, opioid use, or disease causing pain in group P. CONCLUSIONS: NK cell cytotoxic activity and major subset populations, with the exception of an increased percentage of the CD56bright/CD16+ subset, are not significantly altered in patients with chronic severe pain.

Background anaesthetic agents do not influence the impact of arginine vasopressin on haemodynamic states and cerebral oxygenation during shoulder surgery in the beach chair position: a prospective, single-blind study.

BACKGROUND: Administration of arginine vasopressin (AVP) is associated with reducing jugular venous (SjvO2) and regional cerebral (rScO2) oxygen saturation under propofol-remifentanil (P/R) anaesthesia. We determined whether background anaesthetics modulate the effect of AVP on cerebral oxygenation and haemodynamics. METHODS: We randomly allocated 60 adult patients scheduled for shoulder surgery in the beach chair position (BCP) into 4 groups, to receive either an intravenous bolus of saline (groups PR-S and SN-S) or 0.05 U/kg AVP (groups PR-AVP and SN-AVP) under P/R or sevoflurane-nitrous oxide (S/N) anaesthesia (n = 15 each). Haemodynamic variables, SjvO2 and rScO2 were measured. RESULTS: AVP significantly increased mean arterial blood pressure (MAP) and decreased rScO2 in either anaesthetic group. AVP also decreased SjvO2 in the P/R groups but not in the S/N groups. The AVP-treated groups showed higher MAP and cerebral desaturation (>20% rScO2 decrease from baseline), along with lower HR and rScO2 in the BCP than those in the saline-treated groups. In contrast, AVP did not affect SjvO2 values or the incidence of SjvO 2  < 50%. Baseline SjvO2 was lower and the magnitude of its reduction in the BCP was greater in the PR-AVP group than in the SN-AVP group, and the lowest SjvO2 values were 37 ± 6 and 57 ± 8%, respectively (P < 0.001). CONCLUSIONS: The choice of anaesthetic regimen did not affect cerebral oxygenation or haemodynamics of AVP in the BCP. However, the negative effect of AVP on cerebral oxygenation should be considered, especially under P/R anaesthesia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01687894 , registered on September 18, 2012.

Comparison of effects of intraoperative nefopam and ketamine infusion on managing postoperative pain after laparoscopic cholecystectomy administered remifentanil.

BACKGROUND: Although intraoperative opioids provide more comfortable anesthesia and reduce the use of postoperative analgesics, it may cause opioid induced hyperalgesia (OIH). OIH is an increased pain response to opioids and it may be associated with N-methyl-D-aspartate (NMDA) receptor. This study aimed to determine whether intraoperative nefopam or ketamine, known being related on NMDA receptor, affects postoperative pain and OIH after continuous infusion of intraoperative remifentanil. METHODS: Fifty-four patients undergoing laparoscopic cholecystectomy were randomized into three groups. In the nefopam group (N group), patients received nefopam 0.3 mg/kg at the induction of anesthesia followed by a continuous infusion of 0.065 mg/kg/h. In the ketamine group (K group), patients received ketamine 0.3 mg/kg at the induction of anesthesia followed by a continuous infusion of 3 µg/kg/min. The control group did not received any other agents except for the standard anesthetic regimen. Postoperative pain score, first time and number of demanding rescue analgesia, OIH and degrees of drowsiness/sedation scale were examined. RESULTS: Co-administrated nefopam or ketamine significantly reduced the total amount of intraoperative remifentanil and postoperative supplemental morphine. Nefopam group showed superior property over control and ketamine group in the postoperative VAS score and recovery index (alertness and respiratory drive), respectively. Nefopam group showed lower morphine consumption than ketamine group, but not significant. CONCLUSIONS: Both nefopam and ketamine infusion may be useful in managing in postoperative pain control under concomitant infusion of remifentanil. However, nefopam may be preferred to ketamine in terms of sedation.

Prognostic significance of Notch 3 gene expression in ovarian serous carcinoma.

The Notch signaling pathway is an important cell signaling system, which regulates cell differentiation, proliferation, and apoptosis, and is aberrantly activated in a wide range of cancer, including ovarian cancers. However, it remains unclear as to whether Notch signaling plays a role in the progression and prognosis of ovarian cancer. We examined the mRNA and protein expression of Notch 3, Jagged 1, and Jagged 2 in 98 ovarian epithelial tumors via real-time PCR and in 175 tumors with immunohistochemical analysis, and then correlated their expression levels with clinicopathological parameters and patient survival. In this study, we detected high levels of Notch3 mRNA and protein expression especially in serous ovarian carcinomas compared to their benign counterparts, accompanied by a positive correlation with the expressions of Jagged 1 and Jagged 2. High levels of Notch 3 mRNA expression (>2-fold than that of benign tumor) were noted in 63% of the serous carcinomas (mean level: 17-fold, P = 0.032). Additionally, Notch 3 protein overexpression was significantly associated with advanced stage (P = 0.0008), lymph node (P = 0.001), and distant metastasis (P = 0.003). Notably, high Notch 3 mRNA and protein expressions were correlated with chemoresistance (P = 0.033) and poor overall survival (P = 0.027, P = 0.042) in these patients. Our results indicate that the Notch 3 signaling pathway is involved in the tumor progression of ovarian serous carcinoma, and higher Notch 3 expression may be an independent poor prognostic factor in this subset of tumors.

Analgesic effect of intrathecal ginsenosides in a murine bone cancer pain.

BACKGROUND: Bone cancer pain has a disruptive effect on the cancer patient's quality of life. Although ginsenosides have been used as traditional medicine in Eastern Medicine, the effect on bone cancer pain has not been thoroughly studied. The aim of this study was to determine whether ginsenosides may alter the bone cancer pain at the spinal level. METHODS: NCTC 2472 tumor cells (2.5 × 10(5)) were injected into the femur of adult male C3H/HeJ mice to evoke bone tumor and bone cancer pain. To develop bone tumor, radiologic pictures were obtained. To assess pain, the withdrawal threshold was measured by applying a von Frey filament to the tumor cells inoculation site. The effect of intrathecal ginsenosides was investigated. Effect of ginsenosides (150, 500, 1,000 µg) was examined at 15, 30, 60, 90, 120 min after intrathecal delivery. RESULTS: The intrafemoral injection of NCTC 2472 tumor cells induced a radiological bone tumor. The withdrawal threshold with tumor development was significantly decreased compared to the sham animals. Intrathecal ginsenosides effectively increased the withdrawal threshold in the bone cancer site. CONCLUSIONS: NCTC 2472 tumor cells injection into the mice femur caused bone tumor and bone cancer pain. Intrathecal ginsenosides attenuated the bone cancer-related pain behavior. Therefore, spinal ginsenosides may be an alternative analgesic for treating bone cancer pain.