Li-Hua Hang

The ED50 and ED95 of ketamine for prevention of postoperative hyperalgesia after remifentanil- based anaesthesia in patients undergoing laparoscopic cholecystectomy

OBJECTIVE Various research programmes have shown that intraoperative infusion of remifentanil has been associated with postoperative hyperalgesia. Previous studies have demonstrated that low-dose ketamine can inhibit central sensitisation and prevent opioid-induced hyperalgesia (OIH). However, the optimal ketamine dose to prevent OIH has not been determined. In the present study we aimed to determine the ED50 and ED95 of ketamine for prevention of postoperative hyperalgesia after remifentanil-based anaesthesia in patients undergoing laparoscopic cholecystectomy. METHODS Fifty-four patients undergoing laparoscopic cholecystectomy were randomised into two groups: group C and group K. Group K was given ketamine before skin incision. An equal volume of normal saline was given to the patients in group C. Pain was assessed using visual analog scale (VAS) at 10 min after tracheal extubation. The ED50 and ED95 were determined by modified up-and-down method and the incidences of adverse effects were recorded. RESULTS The incidences of adverse effects were similar in the two groups and the VAS score was significantly lower in group K than in group C. The ED50 and ED95 of ketamine for prevention of postoperative hyperalgesia were 0.24 mg/kg (95%CI, 0.20~0.30 mg/kg) and 0.33 mg/kg (95%CI, 0.28~0.62 mg/kg) respectively. CONCLUSIONS The ED50 and ED95 of ketamine for prevention of postoperative hyperalgesia after remifentanil-based anaesthesia in patients undergoing laparoscopic cholecystectomy were 0.24 mg/kg and 0.33 mg/kg respectively.

Involvement of Spinal CC Chemokine Ligand 5 in the Development of Bone Cancer Pain in Rats

In this study, we aimed to investigate the role of spinal CC chemokine ligand 5 (CCL5) in the development of bone cancer pain (BCP). A BCP model was established by inoculation of Walker 256 cells into the intramedullary space of rat tibia. The levels of spinal CCL5 mRNA and protein expression significantly and time dependently increased in BCP rats compared with sham rats. On day 15 after inoculation, intrathecal administration of anti‐CCL5 neutralizing antibody (4 μg) significantly attenuated the established mechanical hyperalgesia in the Walker 256 cells‐injected rats, and the effect was abolished by intrathecal pre‐treatment with recombinant rat CCL5 (0.2 μg). These results suggest that the spinal CCL5 may be involved in the development of BCP. The findings of this study may provide an evidence for developing novel analgesic agents to treat BCP.

Connexin 43 Mediates CXCL12 Production from Spinal Dorsal Horn to Maintain Bone Cancer Pain in Rats

Tumor metastasis to bone can subsequently lead to bone cancer pain (BCP). Currently, BCP is difficult to conquer due to a poor understanding of the potential mechanisms. Several studies have indicated that astrocyte-specific connexin 43 (Cx43) was involved in the neuropathic pain, and Cx43 induced the release of chemokine CXCL12 in bone marrow stromal cells. However, whether spinal Cx43 mediates the production of CXCL12 to participate in the maintenance of BCP is still unknown. Here we showed that Walker 256 tumor cells inoculation into the tibia induced a significant mechanical allodynia, which was accompanied by upregulation of spinal p-Cx43 and CXCL12 expression levels from day 6 to day 18 after inoculation. Spinal Cx43 was mainly expressed in astrocytes, and intrathecal 43Gap26 (a selective Cx43 blocker) markedly attenuated mechanical allodynia as well as reduced p-Cx43 and CXCL12 expression at day 18 after inoculation. Pre-intrathecal administration of CXCL12 almost abolished the attenuated mechanical allodynia by 43Gap26. Furthermore, intrathecal injection of anti-CXCL12 neutralizing antibody could ameliorate mechanical allodynia with concomitant inhibition of upregulation of CXCL12 expression, but not influence on p-Cx43 expression. Our results indicate that Cx43 mediates CXCL12 production from spinal dorsal horn in astrocytes to maintain bone cancer pain in rats. These findings may improve our understanding of the underlying mechanisms of BCP and provide a novel target for the treatment of BCP.

Involvement of Spinal Bv8/Prokineticin 2 in a Rat Model of Cancer‐Induced Bone Pain

Cancer‐induced bone pain (CIBP) is seriously disruptive to the quality of life in cancer patients, and present therapies are limited. The Bv8/prokineticin 2, a new family of chemokines, has been demonstrated to be involved in inflammatory and neuropathic pain. However, whether it is involved in CIBP remains unclear. This study was designed to examine whether spinal Bv8 was involved in the development of CIBP in rats. A rat CIBP model was constructed by injecting Walker 256 carcinoma cells into the medullary cavity of rat tibia. Tibia inoculation with Walker 256 tumour cells resulted in the development of mechanical hyperalgesia. Compared with sham rats, spinal Bv8 mRNA and protein levels were markedly and time‐dependently increased in CIBP rats. Intrathecal administration of Bv8 neutralizing antibody (5 ng) could markedly attenuate pain behaviour as well as up‐regulation of spinal TNF‐α expression at day 18 after inoculation. Intrathecal pre‐treatment with synthetic Bv8 (50 pg) almost completely abolished these effects. These data suggested that spinal Bv8/prokineticin 2 participated in the development of CIBP. Targeting of spinal Bv8 might be a promising strategy for the management of cancer‐induced bone pain.

Evidence for involvement of spinal RANTES in the antinociceptive effects of triptolide, a diterpene triepoxide, in a rat model of bone cancer pain.

It has been shown that triptolide has beneficial effects in the treatment of neuropathic pain, but its effects on bone cancer pain (BCP) remain unclear. In this study, we aimed to explore the potential role of spinal regulated activation of normal T cell expressed and secreted (RANTES) in the antinociceptive effects of triptolide on BCP. A BCP model was induced by injecting Walker 256 mammary gland carcinoma cells into the intramedullary space of rat tibia. Intrathecal administration of triptolide (0.5, 1, 2 μg) could dose‐dependently alleviate mechanical hyperalgesia and spontaneous pain. In addition, there were also concomitant decreases in RANTES mRNA and protein expression levels in spinal dorsal horn. These results suggest that the antinociceptive effects of triptolide are related with inhibition of spinal RANTES expression in BCP rats. The findings of this study may provide a promising drug for the treatment of BCP.

Spinal RhoA/Rho Kinase Signalling Pathway may Participate in the Development of Bone Cancer Pain

It has been shown that activation of spinal RhoA/Rho kinase (ROCK) signalling pathway facilitates nociception in neuropathic and inflammatory pain, but its effects on bone cancer pain (BCP) have not previously been studied. This study was designed to examine the potential role of the spinal RhoA/ROCK signalling pathway in the development of BCP. A model for bone cancer was induced by injecting Walker 256 cells into the tibia of rats. On days 6, 9 and 15 after inoculation, the expression of spinal RhoA and ROCK2 protein levels was higher in the Walker 256 cells injected rats compared to the sham rats. On day 9, intrathecal injection of C3 exoenzyme (a RhoA inhibitor, 10 pg) significantly attenuated BCP behaviour as well as up‐regulation of spinal RhoA and ROCK2 protein levels. These effects were completely abolished by intrathecal pretreatment with U‐46619 (a RhoA agonist, 1.5 pg). These results suggest that the spinal RhoA/ROCK signalling pathway may be involved in the development of BCP. The findings of this study may lead to novel therapeutic strategies for prevention and/or treatment of BCP.

Involvement of Spinal CCR5/PKCγ Signaling Pathway in the Maintenance of Cancer-Induced Bone Pain

Cancer-induced bone pain (CIBP) is a challenging medical problem that considerably influences cancer patients’ quality of life. Currently, few treatments have been developed to conquer CIBP because of a poor understanding of the potential mechanisms. Our previous work has proved that spinal RANTES (a major ligand for CCR5) was involved in the maintenance of CIBP. In this study, we attempted to investigate whether spinal CCR5 and its downstream PKCγ pathway is involved in the maintenance of CIBP. Inoculation of Walker 256 cells into the tibia could induce a marked mechanical allodynia with concomitant upregulation of spinal CCR5 and p-PKCγ expression from day 6 to day 15 after inoculation. Spinal CCR5 was prominently expressed in microglia, and mechanical allodynia was attenuated by intrathecal injection of DAPTA (a specific antagonist of CCR5) with downregulation of spinal CCR5 and p-PKCγ expression levels at day 15 in inoculated rats. Pre-intrathecal injection of RANTES could reverse the anti-allodynia effects of DAPTA. Intrathecal administration of GF109203X (an inhibitor of PKC) could alleviate mechanical allodynia as well as decrease of spinal p-PKCγ expression level, but no influence on spinal CCR5 level. Our findings suggest that CCR5/PKCγ signaling pathway in microglia may contribute to the maintenance of CIBP in rats.

SPINAL α-AMINO-3-HYDROXY-5-METHYL-4-ISOXAZOLEPROPIONIC ACID RECEPTORS MAY MEDIATE THE ANALGESIC EFFECTS OF EMULSIFIED HALOGENATED ANAESTHETICS

1 The present study was designed to investigate the relationship between spinal cord α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors and the analgesic effects of emulsified halogenated anaesthetics. 2 After having established the mouse model of analgesia by intraperitoneal or subcutaneous injections of appropriate doses of emulsified enflurane, isoflurane or sevoflurane, we injected different doses of AMPA intrathecally and observed effects on the pain threshold using the hot‐plate and acetic acid‐induced writhing tests. 3 The results showed that intrathecal injection of AMPA (0.25, 0.5 and 1.0 ng) did not affect the pain threshold on the hot‐plate test or the writhing times in conscious mice. In contrast, AMPA (0.25, 0.5 and 1.0 ng intrathecally) significantly and dose‐dependently decreased the pain threshold on the hot‐plate test and increased the writhing times in mice treated with emulsified anaesthetics. 4 These results suggest that spinal AMPA receptors may be important targets for the analgesic effects of emulsified enflurane, isoflurane and sevoflurane.

Effects of dexmedetomidine on performance of bispectral index as an indicator of loss of consciousness during propofol administration

OBJECTIVE The performance of bispectral index (BIS) for the measurement of the sedative depth when dexmedetomidine is administered in propofol anaesthesia and sedation has not yet been established. This study evaluated the effects of adjunctive dexmedetomidine on the accuracy of BIS to predict loss of consciousness (LOC) and BIS values predicting LOC during propofol administration. METHODS In this randomised, double-blind and placebo-controlled trial, 225 patients scheduled for general anaesthesia were assigned to one of three groups. Dexmedetomidine 0.5 and 1.0 µg kg-1 were intravenously infused for 15 minutes in the dexmedetomidine 0.5 and 1.0 µg kg-1 groups, and saline was infused in the control group. Propofol was administered as an effect-site target-controlled infusion after completion of dexmedetomidine infusion. Patients in each group were allocated to five subgroups in which the concentration of propofol was set at 0, 1, 2, 3 and 4 μg ml-1, respectively. Three minutes after propofol administration, the BIS values and Observers Assessment of Alertness/Sedation (OAA/S) scores were recorded. RESULTS There were no significant differences in the prediction probability of BIS for detecting LOC in the three groups. At the time of LOC, BIS50 values were 71.1 and 71.4 in the dexmedetomidine 0.5 and 1.0 µg kg-1 groups, respectively, which were significantly larger than the BIS50 of 63.2 in the control group. CONCLUSIONS The ability of BIS to predict LOC is not influenced by dexmedetomidine during propofol administration, but BIS values are enhanced at the time of LOC.

Involvement of kainate receptors in the analgesic but not hypnotic effects induced by inhalation anesthetics.

In the present study, the role of kainate (KA) receptors in hypnosis and analgesia induced by emulsified inhalation anesthetics was investigated. A mouse model of hypnosis and analgesia was established by an intraperitoneal injection of emulsified enflurane, isoflurane or sevoflurane. We intracerebroventricularly (icv) or intrathecally (it) administered KA, a KA receptor agonist to mice. The effects of the KA on the sleep time were observed using a hypnosis test, and the tail-withdrawal latency was analyzed using the tail-withdrawal test. In the hypnosis test, KA (2.5, 5 or 10 ng; icv administered) treatment had no distinctive effects on the sleep time of mice treated with emulsified inhalation anesthetics. In the tail-withdrawal test, KA (0.2, 0.4 or 0.8 ng; it administered) treatment significantly and dose-dependently decreased the tail-withdrawal latency of mice treated with emulsified anesthetics. These results suggested that KA receptors may modulate the analgesic but not hypnotic effects induced by emulsified enflurane, isoflurane or sevoflurane.