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Patients with chronic pain develop peripheral neuropathy and experience sleep disturbance. Yokukansan is used to treat insomnia and control neuropathic pain. We studied if Yokukansan affects neuropathic pain and sleep disturbance using a rat model of chronic constriction injury (CCI). Male Wistar rats (4-week age) were divided into the following groups (n = 7, per group): CCI rats fed normal chow (CCI-0); CCI rats fed powdered chow mixed with 1% Yokukansan (CCI-1); CCI rats fed powdered chow mixed with 3% Yokukansan (CCI-3); and sham-operated control rats fed normal chow (SHAM). We examined sleep duration and quality using electroencephalograms and assessed pain using the von Frey and Hargreaves tests. Results were analyzed by one-way analysis of variance and Bonferroni post hoc tests. The CCI-0 group exhibited an increased wake period, decreased non-rapid eye movement (REM) sleep time, and no change in REM sleep time in comparison to the SHAM group. The CCI-1 group exhibited a decreased wake period, increased non-REM sleep time, and no change in REM sleep time compared to the CCI-0 group. The CCI-3 group exhibited increased non-REM sleep time but no changes in wake and REM sleep times compared to the CCI-1 group. The von Frey and Hargreaves test findings revealed an increase in the pain threshold in the CCI-1 group compared to the CCI-0 group. There was no difference in pain threshold between the CCI-1 and CCI-3 groups. In our rat model of CCI, sleep disturbance was reflected. Yokukansan inhibited CCI-induced sleep disturbance.

Although local anesthesia is commonly applied for pain relief, there are several issues such as its short duration of action and low effectiveness at the areas of inflammation due to the acidic pH. The presence of excessive amount of reactive oxygen species (ROS) is known to induce inflammation and aggravate pain. To resolve these issues, we developed a redox-active injectable gel (RIG) with ROS-scavenging activity. RIG was prepared by mixing polyamine-b-poly(ethylene glycol)-b-polyamine with nitroxide radical moieties as side chains on the polyamine segments (PMNT-b-PEG-b-PMNT) with a polyanion, which formed a flower-type micelle via electrostatic complexation. Lidocaine could be stably incorporated in its core. When the temperature of the solution was increased to 37 °C, the PIC-type flower micelle transformed to gel. The continuous release of lidocaine from the gel was observed for more than three days, without remarkable initial burst, which is probably owing to the stable entrapment of lidocaine in the PIC core of the gel. We evaluated the analgesic effect of RIG in carrageenan-induced arthritis mouse model. Results showed that lidocaine-loaded RIG has stronger and longer analgesic effect when administered in inflamed areas. In contrast, while the use of non-complexed lidocaine did not show analgesic effect one day after its administration. Note that no effect was observed when PIC-type flower micelle without ROS-scavenging ability was used. These findings suggest that local anesthetic-loaded RIG can effectively reduce the number of injection times and limit the side effects associated with the use of anti-inflammatory drugs for postoperative pain management. Statement of Significance 1. We have been working on nanomaterials, which effectively eliminate ROS, avoiding dysfunction of mitochondria in healthy cells. 2. We designed redox injectable gel using polyion complexed flower type micelle, which can eliminates ROS locally. 3. We could prepare local anesthesia-loaded redox injectable gel (lido@RIG). 4. Drug release could be extended by local administration of lido@RIG. 5. Deprotonation of lidocaine improved anesthetic effect because ROS were eliminated locally by RIG. 6. Local inflammation could be also suppressed by lido@RIG.

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Objective Although glucose-insulin-potassium (GIK) therapy ought to be beneficial for ischemic heart disease in general, variable outcomes in many clinical trials of GIK in acute coronary syndrome (ACS) had a controversial impact. This study was designed to examine whether “insulin resistance” is involved in ACS and to clarify other potential intrinsic compensatory mechanisms for GIK tolerance through highly statistical procedure. Methods and results We compared the degree of insulin resistance during ACS attack and remission phase after treatment in individual patients (n = 104). During ACS, homeostasis model assessment of insulin resistance (HOMA-IR) values were significantly increased (P

Previously, we found that processed Aconiti tuber (PAT) could inhibit morphine tolerance in mice. In the present study, we investigated mechanisms underlying this effect. Mice received subcutaneous (s.c.) morphine (10 mg/kg) and oral PAT at a subanalgesic dose (0.3 g/kg), once a day for 12 days. Additional PAT-treated groups received morphine and PAT, at 120 min after pretreatment with s.c. clocinnamox mesylate (C-CAM) (0.5 mg/kg), or nor-binaltorphimine (nor-BNI) (5 mg/kg). The antinociceptive effect was assessed with the tail pressure test, at 60 min after the daily s.c. morphine injections were given. In the placebo-treated group, repeated morphine injections caused morphine tolerance, and morphine antinociception was abolished by day 6, whereas in PAT-treated groups, significant antinociception was maintained until day 12, suggesting that PAT inhibited morphine tolerance, thereby sustaining morphine antinociception. C-CAM, a selective mu-opioid receptor (MOR) antagonist, blocked morphine antinociception whereas nor-BNI, a selective kappa-opioid receptor (KOR) antagonist, did not. However, both C-CAM and nor-BNI could block the antinociception maintained by the morphine–PAT combination. Results of the study suggested that chronic treatment with PAT at a subanalgesic dose maintained MOR-mediated morphine antinociception by attenuating development of morphine tolerance, and that this tolerance-attenuating effect of PAT was mediated by KOR.

Processed Aconiti tuber (PAT) is a herbal medicine that has been widely used as an analgesic since ancient times. We investigated effects of subanalgesic doses of PAT on morphine tolerance in mice. Mice received subcutaneous morphine (10 mg/kg) and oral PAT at subanalgesic doses (0.1 or 0.3 g/kg), once a day for 7 days. Mechanical nociceptive thresholds were measured using the tail pressure test, at 60 min after the daily s.c. morphine injections. In the placebo-treated group, repeated administration of s.c. morphine resulted in development of analgesic tolerance. In the PAT-treated groups, oral PAT attenuated morphine tolerance, dose-dependently. The main ingredient alkaloid of PAT causing its tolerance-attenuating activity was mesaconitine, but other ingredient alkaloids, such as aconitine and hypaconitine, also contributed to this activity. In addition, repeated treatment with PAT could reverse already-developed morphine tolerance. Subanalgesic doses of oral PAT thus can attenuate and reverse morphine tolerance in mice.

Background Lines of evidence have indicated that cyclooxygenase 2 plays a role in the pathophysiology of neuropathic pain. However, the site and mechanism of its action are still unclear. Spinal glia has also been reported to mediate pathologic pain states. The authors evaluated the effect of continuous intrathecal or systemic cyclooxygenase-2 inhibitor on the development and maintenance of neuropathic pain and glial activation in a spinal nerve ligation model of rats. Methods Continuous intrathecal infusion of meloxicam (32 or 320 mug . kg . day) or saline was started immediately after L5-L6 spinal nerve ligation. Mechanical allodynia and thermal hyperalgesia were evaluated on days 4 and 7 postoperatively. Spinal astrocytic activation was evaluated with glial fibrially acidic protein immunoreactivity on day 7. In other groups of rats, continuous intrathecal meloxicam was started 7 days after spinal nerve ligation, and effects on established neuropathic pain and glial activation were evaluated. Last, effects of continuous systemic meloxicam (16 mg . kg . day) on existing neuropathic pain and glial activation were examined. Results Intrathecal meloxicam prevented the development of mechanical allodynia and thermal hyperalgesia induced by spinal nerve ligation. It also inhibited spinal glial activation responses. In contrast, when started 7 days after the nerve ligation, intrathecal meloxicam did not reverse established neuropathic pain and glial activation. Systemic meloxicam started 7 days after ligation partially reversed neuropathic behaviors but not glial activation. Conclusions Spinal cyclooxygenase 2 mediates the development but not the maintenance of neuropathic pain and glial activation in rats. Peripheral cyclooxygenase 2 plays a part in the maintenance of neuropathic pain.

Background Children frequently suffer transient cerebral ischaemia during cardiac surgery. We measured cerebral ischaemia in children during cardiac surgery by combining two methods of monitoring. Methods We studied 65 children aged between 5 months and 17 yr having surgery to correct non-cyanotic heart disease using hypothermic cardiopulmonary bypass (CPB). During surgery, we measured the Bispectral Index (BIS) and regional cerebral haemoglobin oxygen saturation (SrO2) with near-infrared spectroscopy (NIRS). Cerebral ischaemia was diagnosed if both SrO2 and BIS decreased abruptly when acute hypotension occurred. In each patient, the relationship between SrO2 and arterial blood pressure (AP) was indicated by a plot of mean SrO2 against simultaneous mean AP. Results We noted 72 episodes of cerebral ischaemia in 38 patients. Sixty-three ischaemic events were during CPB. Cerebral ischaemia was less frequent in older patients. Cerebral ischaemia was more common and more frequent in children under 4 yr old. Haematocrit during CPB was lower and SrO2 was more dependent on AP in children under 4 yr. Conclusions Children less than 4 yr of age are more likely to have cerebral ischaemia caused by hypotension during cardiac surgery. Ineffective cerebral autoregulation and haemodilution during CPB may be responsible.

Objectives Malondialdehyde-modified low-density lipoprotein (MDA-LDL) level is a marker of oxidative stress and is linked to progression of arteriosclerosis; however, the clinical factors affecting the oxidised LDL level have not been elucidated. We investigate various factors to identify correlation with MDA-LDL level in high-risk patients requiring catheter intervention. Setting Secondary care (cardiology), single-centre study. Participants 600 patients who were admitted to our hospital and underwent cardiac catheterisation. Primary and secondary outcome measures Blood samples were obtained to measure lipid profiles and MDA-LDL level. Results With regard to smoking status, MDA-LDL level was significantly higher in ex-smokers/current smokers compared with non-smokers. Of note, there was no improvement of MDA-LDL level even in patients who had quit smoking. Multiple regression analysis showed that MDA-LDL level was positively correlated with LDL-cholesterol (LDL-C) level, Brinkman index and male gender. The correlation between smoking status and either MDA-LDL or LDL-C level was investigated in two groups: namely, patients with and patients without statin treatment. In the non-statin group, MDA-LDL level and MDA-LDL/LDL-C ratio were significantly higher in ex-smokers/current smokers compared with non-smokers, while no significant correlation was observed between smoking status and LDL-C level. In contrast, in the statin group, there were no significant correlations between smoking status and any of the cholesterol parameters. Conclusions We found that MDA-LDL level was affected by multiple factors, such as smoking status, LDL-C level and male gender. The present findings give additional evidence that smoking should be prohibited from a MDA-LDL standpoint. Furthermore, statin therapy might have a beneficial effect on the reduction of MDA-LDL level.

Background A major effect of general anesthesia is lack of response in the presence of a noxious stimulus. Anesthetic depression of spinal sensory neuronal responses to noxious stimuli is likely to contribute to that essential general anesthetic action. The authors tested the hypothesis that gamma-aminobutyric acid receptor type A (GABA(A)) and strychnine-sensitive glycine receptor systems mediate halothane depression of spinal sensory neuronal responses to noxious stimuli. Methods Extracellular activity of single spinal dorsal horn wide dynamic range (WDR) neurons was recorded in decerebrate, spinal cord transected rats. Neuronal responses to noxious (thermal and mechanical) and nonnoxious stimuli were examined in the drug-free state. Subsequently, cumulative doses (0.1-2.0 mg/kg) of bicuculline (GABA(A) antagonist) or strychnine (glycine antagonist) were administered intravenously in the absence or presence of 1 minimum alveolar concentration (MAC) of halothane. Results Halothane, 1.1%, depressed the response of WDR neurons to both forms of noxious stimuli. Antagonists, by themselves, had no effect on noxiously evoked activity. However, bicuculline and strychnine (maximum cumulative dose, 2.0 mg/kg) partially but significantly reversed the halothane depression of noxiously evoked activity. Similar results were seen with most, but not all, forms of nonnoxiously evoked activity. In the absence of halothane, strychnine significantly increased neuronal responses to low threshold receptive field brushing. Conclusion Halothane depression of spinal WDR neuronal responses to noxious and most nonnoxious stimuli is mediated, in part, by GABA(A) and strychnine-sensitive glycine systems. A spinal source of glycine tonically inhibits some forms of low threshold input to WDR neurons.

The purpose of this study was to assess the effect of local spinal cord cooling on spinal dorsal-horn neuronal activity, with special emphasis on the role of endogenous opioid.Decerebrate, spinal-cord-transected cats ( n= 30) were subjected to local spinal-cord irrigation, using 0.9 N saline solution (15 degrees C; n= 15, and 35 degrees C; n= 15) for 90 min. The extracellular, single-cell activity of spinal dorsal-horn neurons responding to noxious stimulation was recorded. Sixty-one minutes after induction of local spinal-cord irrigation, naloxone (0.1 mg.kg(-1)) was administered intravenously. Local spinal-cord blood flow was measured using the hydrogen clearance technique.Local spinal cord cooling produced significant suppression of both spontaneous and evoked activity (33.1 +/- 7.7% and 31.4 +/- 5.5%, respectively; mean +/- SE). Naloxone reversed this suppression immediately. Local spinal-cord blood flow was significantly reduced during spinal-cord cooling, but naloxone did not change local spinal-cord blood flow.The results demonstrate that endogenous opioids may play an important role in dorsal-horn neuronal suppression induced by local spinal-cord cooling.

We investigated the anesthetic management of patients with congenital insensitivity to pain and anhidrosis (CIPA) in Japan. CIPA is a rare inherited disease characterized by a lack of pain sensation and thermoregulation. Although lacking pain sensation, some patients do have tactile hyperesthesia. Thus, anesthetics are a necessity during operations. We also determined that because patients with CIPA have problems with thermoregulation, temperature management is a concern during the perioperative period and sufficient sedation is necessary to avoid accidental fractures. Additionally, it was found that the use of muscle relaxants does not present a problem, malignant hyperthermia is not associated with CIPA, and that the possibility of abnormalities in the autonomic nervous system must be taken into consideration. Therefore, patients with CIPA can be safely managed with anesthesia.We investigated the anesthetic management of patients with congenital insensitivity to pain and anhidrosis. We clarified the following three important points: anesthesia is necessary, temperature management must be maintained, and there must be sufficient perioperative sedation in the anesthetic management of patients with congenital insensitivity to pain and anhidrosis.

OBJECTIVE: Although the plasma B-type natriuretic peptide (BNP) level is a marker of heart failure, it is unclear whether BNP per se plays a pivotal role for pathogenic mechanisms underlying the development of ischemic heart disease (IHD). In this study, we retrospectively examined the plasma BNP levels in stable patients with IHD and compared to stable patients with cardiovascular diseases other than IHD. METHODS: The study population was 2088 patients (1698 males and 390 females) who were admitted to our hospital due to IHD (n = 1,661) and non-IHD (n = 427) and underwent cardiac catheterization. Measurements of the hemodynamic parameters and blood sampling were performed. RESULTS: The plasma BNP levels were significantly lower in the IHD group than in the non-IHD group (p

Both aldosterone and Akt signaling play pivotal roles in the pathogenesis of heart failure. However, little is known about the correlation between them. We herein investigated whether aldosterone interacts with Akt signaling in a coordinated manner in cardiomyocytes. Neonatal rat cardiomyocytes were stimulated with aldosterone for either a short (10-min) or long (24-h) time. The phosphorylation of Akt and its downstream effector, GSK3β, were transiently increased after short-term stimulation, which was blocked by either PI3K or Na + /H + exchanger inhibitors, but not by the mineralocorticoid receptor antagonist, eplerenone. Long-term stimulation also significantly increased Akt-GSK3β phosphorylation and this effect was reduced by eplerenone. Thus, these results suggest that aldosterone activates Akt signaling via a biphasic reaction that occurs through different cascades. To understand the significance of the rapid action of aldosterone, cardiomyocytes were exposed to hydrogen peroxide for from 10 to 60 min. A short-term aldosterone stimulation (for up to 30 min) significantly protected cardiomyocytes from oxidative stress-induced cellular damage. Eplerenone did not abrogate this beneficial effect, while a PI3K inhibitor did. Therefore, during the early phase, aldosterone has favorable effects on cardiomyocytes, partly by acute activation of a mineralocorticoid receptor-independent cascade through the Na + /H + exchanger, PI3K, and Akt. In contrast, its persistent activity produces pathological effects partly by chronic Akt activation in a mineralocorticoid receptor-dependent manner.

Plasma B-type natriuretic peptide (BNP) is finely regulated by the cardiac function and several extracardiac factors. Therefore, the relationship between the plasma BNP levels and the severity of heart failure sometimes seems inconsistent. The purpose of the present study was to investigate the plasma BNP levels in patients with cardiac tamponade and their changes after pericardial drainage. This study included 14 patients with cardiac tamponade who underwent pericardiocentesis. The cardiac tamponade was due to malignant diseases in 13 patients and uremia in 1 patient. The plasma BNP levels were measured before and 24–48 h after drainage. Although the patients reported severe symptoms of heart failure, their plasma BNP levels were only 71.2 ± 11.1 pg/ml before drainage. After appropriate drainage, the plasma BNP levels increased to 186.0 ± 22.5 pg/ml, which was significantly higher than that before drainage (P = 0.0002). In patients with cardiac tamponade, the plasma BNP levels were low, probably because of impaired ventricular stretching, and the levels significantly increased in response to the primary condition after drainage. This study demonstrates an additional condition that affects the relationship between the plasma BNP levels and cardiac function. If inconsistency is seen in the relationship between the plasma BNP levels and clinical signs of heart failure, the presence of cardiac tamponade should therefore be considered.

Background: Obesity has recently been shown to have a favorable effect on the prognosis of patients with congestive heart failure (CHF), but only a few such studies are available in Japan. The purpose of the present study was to investigate whether the obesity paradox is still present after adjusting for CHF characteristics. Methods and Results: A total of 219 patients hospitalized with CHF were reviewed, and the impact of body mass index (BMI) on prognosis was examined. Patients were divided into 4 groups according to BMI quartiles. The endpoint was defined as all-cause death or unplanned CHF hospitalization. According to univariate analysis, a higher BMI was associated with better outcomes. High-BMI patients were younger, likely to be male, and had a higher prevalence of hypertension and diabetes. The plasma B-type natriuretic peptide (BNP) levels and blood urea nitrogen (BUN) levels were lower, while the serum hemoglobin and sodium levels were higher in high-BMI patients. The prevalence of atrial fibrillation was lower in high-BMI patients. Predictors for all-cause death or CHF hospitalization based on univariate analysis were age, prior CHF hospitalization, estimated glomerular filtration rate, plasma BNP levels, BUN levels, and serum hemoglobin and sodium levels. According to multivariate analysis, a high BMI was still associated with better outcomes. Conclusions: High BMI was associated with better clinical outcomes in Japanese CHF patients. (Circ J 2012; 76: 145-151)

The ability to assess pain intensity is essential for both clinical trials and effective cancer pain management, although cancer pain assessment is complicated by a number of other bodily and mental symptoms such as fatigue and depression, all affecting quality of life. Several pain assessment tools have been shown to be reliable and reasonably valid in assessing cancer pain. Pain intensity scales are classified as self-report or observational and unidimensional or multidimensional. They include the numeric rating scales (e. g., 0 to 10), visual analogue scales (e. g., a 10-cm line with anchors such as "no pain" on the left and "severe pain" on the right; the patient indicates the place on the line that best represents the intensity of pain) or a verbal descriptor scales (e. g., "no pain", "mild pain", "moderate pain", "severe pain"). A variety of scales use drawings of faces (from smiling to distressed) for children or patients with cognitive impairment or dementia. The healthcare providers should use tools valid for the patient's age and cognitive abilities, with additional attention to the language needs of the patient.

Neural blockades are considered an alternative to pharmacotherapy for neuropathic pain although these blockades elicit limited effects. We encountered a patient with postbrachial plexus avulsion injury pain, which was refractory to conventional treatments but disappeared temporarily with the administration of the local anesthetic lidocaine around the left mandibular molar tooth during dental treatments. This analgesic effect on neuropathic pain by oral local anesthesia was reproducible. Under conditions of neuropathic pain, cerebral somatotopic reorganization in the sensorimotor cortices of the brain has been observed. Either expansion or shrinkage of the somatotopic representation of a deafferentated body part correlates with the degree of neuropathic pain. In our case, administration of an oral local anesthetic shrank the somatotopic representation of the mouth, which is next to the upper limb representation and thereby expanded the upper limb representation in a normal manner. Consequently, oral local anesthesia improved the pain in the upper limb. This case suggests that pain alleviation through neural plasticity within the brain is related to neural blockade.

Photolysis of cis,trans-1,2,3-trichloro-1,2,3-tris(tri-tert-butylsilyl)cyclotrigermane and trans-1,2-dichloro-3-methyl-1,2,3-tris(tri-tert-butylsilyl)cyclotrigermane in the presence of triethylsilane yielded products arising from a germylgermylene, which is formed by the 1,2-chlorine migration on digermenes.

This study evaluated the relationship between the severity of coronary artery disease (CAD) and traditional coronary risk factors, metabolic syndrome, and chronic kidney disease (CKD). Three hundred and forty-three patients (35–90 years of age) with initial diagnosis of CAD were separated into two groups: 165 patients with single-vessel coronary artery disease (SVD group) and 178 patients with multivessel coronary artery disease (MVD group). We compared the risk factors for CAD between the two groups. An adjusted multivariate analysis showed that only CKD was associated with MVD (odds ratio, 2.85; 95% confidence interval [CI], 1.76–4.63; P = 0.00002). Next, the relationship between the severity of CAD, CKD, and the incidence of subsequent major adverse cardiac event (MACE) was investigated in 338 patients during the patient follow-up. The risk of MACE was approximately threefold higher in the group with MVD and CKD stage of 3 or greater than in the group with SVD but without CKD stage of 3 or greater (adjusted hazard ratio, 3.40; 95% CI, 1.26–9.17; P = 0.016). A statistical analysis also suggested that having MVD and advanced CKD was a more powerful risk factor for MACE. The comparison of risk factors between patients with SVD and patients with MVD revealed that CKD was the most important risk factor for MVD. In addition, having MVD and advanced CKD together was a crucial risk factor for subsequent MACE. To reduce the progression of CAD and to improve the prognosis of patients with MVD, the renal status should therefore be carefully assessed during treatment for CAD.

Aim of the study In this study, we investigated the effects of processed Aconiti tuber (PAT), an oriental herbal medicine, at analgesic doses on acute morphine antinociception in morphine-naive mice and morphine tolerance in morphine-tolerant mice. Materials and Methods In acute experiments, mice received subcutaneous (s.c.) morphine (2, 5, or 10 mg/kg) and oral distilled water or PAT (0.3, 1.0, or 3.0 g/kg). The mechanical nociceptive threshold (MNT) and thermal nociceptive latency (TNL) were measured with the tail pressure test and tail flick test, respectively, before, and at 30, 60, 90, and 120 min after s.c. morphine injection. In chronic experiments, mice received s.c. morphine (10 mg/kg) and oral distilled water or PAT (0.3, 1.0, or 3.0 g/kg) once daily for 11 days. MNT was measured before, and at 60 min after, and TNL was measured before, and at 30 min after, daily morphine injections on days 1–11. Results PAT at analgesic doses inhibited the acute antinociceptive effect of morphine dose-dependently in morphine-naive mice. In contrast, PAT at analgesic doses potentiated the chronic antinociceptive effect of morphine dose-dependently by inhibiting the development of morphine tolerance dose-dependently. These effects of PAT on acute and chronic morphine antinociception were mediated through activation of kappa-opioid receptors. Conclusions These results indicated that chronic co-administration of PAT at analgesic doses with morphine could provide better-maintained morphine analgesia in a long-term morphine treatment after initial inhibition of acute morphine antinociception for a brief period of time.

Background Clonidine can effectively reduce pain and/or hypersensitivity. However, the antihypersensitivity effects of clonidine topically applied in cream (CC) have not been investigated. The authors evaluated effects of topical application of CC on pain behaviors and spinal Fos-like immunoreactivity in rats with hypersensitivity. Methods Clonidine (30, 100, and 300 microg/g) was prepared in a cream base. In rat models of neuropathic pain, inflammatory pain, and postoperative pain, the authors evaluated effects of CC (0.1 g), topically applied onto the plantar surface of the injured or uninjured paw, on thermal hyperalgesia and mechanical allodynia to von Frey filaments. The authors also evaluated effects of CC on lumbar spinal Fos-like immunoreactivity. Results In neuropathic rats, CC applied onto the injured paw reduced thermal hyperalgesia and mechanical allodynia dose dependently, whereas CC applied onto the uninjured paw had no effect. The antihypersensitivity effects of CC were antagonized by intraperitoneal yohimbine (10 mg/kg). Further, CC reduced Fos-like immunoreactivity in neuropathic rats. In contrast, CC in a single dose had no effects on hyperalgesia, allodynia, or Fos-like immunoreactivity in rats with inflammatory or postoperative pain. In rats with postoperative pain, CC repeatedly applied for 6 days reduced thermal hyperalgesia, but not mechanical allodynia, in the postoperative days, whereas it had no effects on hyperalgesia or allodynia in those with inflammatory pain. Conclusions Topical CC in concentrations examined significantly reduced hypersensitivity and lumbar spinal Fos-like immunoreactivity in rats with neuropathic pain, probably through activation of peripherally located alpha2 adrenoceptors. However, CC was only partially effective and totally ineffective in rats with postoperative pain and inflammatory pain, respectively.

The effect of linear polarized light irradiation around the lumbar sympathetic ganglion area upon the skin temperature of legs may be similar to that of irradiation of near stellate ganglion area upon arms.Linear polarized light irradiation was induced with SUPER LIZER (Tokyo Iken, Tokyo, Japan). The C probe of SUPER LIZER was placed on the left side of the supine at the level of L2.Seven-minute irradiation around the lumbar sympathetic ganglion area increased significantly the skin temperature of the irradiated side leg.These results suggest that linear polarized light irradiation around the lumbar sympathetic ganglion area might be useful and beneficial for clinical application.

In the previous studies, we demonstrated that an oriental herbal medicine processed Aconiti tuber (PAT) at subanalgesic doses could inhibit the development of mechanical antinociceptive tolerance to morphine using the tail pressure test. In the present study, we evaluated whether PAT could inhibit thermal antinociceptive tolerance to morphine using the high temperature (55 degrees C) hot plate test. Mice received subcutaneous morphine (10mg/kg), and oral PAT at doses that did not inhibit the hot plate response (0.3, 0.5, 1.0, and 2.0 g/kg), once daily for 14 days. The thermal nociceptive latency was measured at 30 min after daily morphine injections. Compared with placebo, oral PAT partially and dose-dependently inhibited the development of morphine tolerance in morphine-naive mice, and reversed already-developed morphine tolerance in morphine-tolerant mice. These data suggested that PAT at subanalgesic doses could dose-dependently inhibit and reverse thermal antinociceptive tolerance to morphine.

Drug challenge test (DCT) is performed to evaluate chronic pain pharmacologically and determine its medical treatment. One test drug is administered in one day for DCT and characterization of the test drug. Four patients developed side effects of the test drugs for DCT in whom other drug tests were postponed or canceled. A 58-year-old man with multiple arthritis of rheumatic arthritis and fibromyalgia had headache, nausea, and vomiting all day after ketamine test. A 76-year-old man with chronic general pain and failed back surgery syndrome had vomiting and abdominal discomfort two hours after morphine test and had redness and itching on his bilateral forearms the following day. A 78-year-old man with chronic lumbar and right lower limb pain due to L 4-5 lumbar disc herniation and postherpetic neuralgia felt dizzy, fell down and bruised on his lower back and left knee twelve hours after morphine test. A 32-year-old woman with chronic pelvic pain had skin eruption on her thigh the day after phentolamine test. Although the amount of the test drug in DCT is small and its half-life is short, long-term side effects might occur. We should decrease the amounts or frequencies of ketamine and morphine, and administer them taking long intervals before other tests.

Objective: No systematic study has been conducted to investigate effects of deep hypothermic circulatory arrest (DHCA) on electroencephalographic bispectral index (BIS) and suppression ratio (SR). Thus, the effects of DHCA were evaluated on BIS and SR. Design: A prospective clinical study. Setting: University hospital (single institute). Participants: Twenty consecutive patients undergoing thoracic aortic surgery using DHCA under narcotics-sevoflurane anesthesia. Interventions: BIS and SR were monitored during cardiopulmonary bypass, simultaneously with nasopharyngeal temperature (NPT). Measurements and Main Results: BIS decreased to 0 with induction of deep hypothermia and rose again with rewarming, although rates of BIS changes in response to cooling and rewarming varied widely among patients. Typically, BIS decreased slowly until NPT reached 26°C during cooling and then it began to decrease rapidly and reached 0 at 17°C, in inverse proportion to SR, which increased rapidly with deep hypothermia and reached 100% at 17°C. When SR was 50% or more, BIS was determined by SR according to the expression: BIS = 50 − SR/2. With rewarming, BIS rose again and returned to precooling baseline levels. Time to the beginning of the BIS recovery significantly correlated with duration of DHCA. Conclusions: With induction of deep hypothermia, BIS decreased in a biphasic manner to 0 at rates varying among patients. With rewarming, BIS rose again at rates extremely widely varying among patients. The rate of BIS recovery was related to duration of DHCA. BIS may be capable of conveniently tracing suppression and recovery of a part of cerebral electrical activity before, during, and after DHCA.

Neuropathic pain is often refractory to conventional pain therapies and thus requires exploration of effective drugs. We evaluated if processed Aconiti tuber (PAT), a traditional oriental herbal medicine that has been used as an analgesic, relieves neuropathic pain in the rat chronic constriction injury (CCI) model. Ten to 14 days after CCI in the right hind paw, six groups of rats received oral placebo, or PAT at 0.5, 1, 2, 3, or 5 g/kg. Additional groups received oral PAT, 2 g/kg, after pretreatment with intraperitoneal naloxone; intraperitoneal nor-binaltorphimine (norBNI); or intrathecal norBNI. As indicators of mechanical allodynia and thermal hyperalgesia, the pressure threshold of paw withdrawal (PWT) in response to linearly increasing pressure, and latency to paw withdrawal (PWL) in response to radiant heat, were measured before and after drug administration. Oral PAT dose-dependently increased PWT and PWL, which had been decreased due to CCI. The increases in PWT and PWL by oral PAT were inhibited by intraperitoneal and intrathecal norBNI: a selective kappa-opioid receptor antagonist, but not by intraperitoneal naloxone. These results indicate that oral PAT can alleviate mechanical allodynia and thermal hyperalgesia, dose-dependently, via spinal kappa-opioid receptor mechanisms in a rat CCI neuropathic pain model.

Background Basic data are lacking regarding the efficacy and mechanisms of action of corticosteroids in neuropathic pain. Because recent studies indicate that spinal glial activation mediates the pathologic pain states, the authors sought to determine the effects of systemic and intrathecal methylprednisolone on the development and maintenance of neuropathic pain and spinal glial activation in a rat model. Methods Rats were anesthetized, and L5 and L6 spinal nerves were tightly ligated. Then, continuous infusion of systemic (4 mg x kg(-1) x day(-1)) or intrathecal (80 microg x kg(-1) x day(-1)) methylprednisolone or saline was started. Mechanical allodynia and thermal hyperalgesia were evaluated on days 4 and 7 postoperatively with von Frey and Hargreaves tests, respectively. Spinal astrocytic activation was evaluated with glial fibrillary acidic protein immunoreactivity on day 7. In other groups of rats, continuous 3-day treatment with intrathecal methylprednisolone or saline was started 7 days after spinal nerve ligation, when neuropathic pain had already developed. Behavioral tests and immunostaining were performed up to 3 weeks after the treatment. Results Spinal nerve ligation induced mechanical allodynia and thermal hyperalgesia on days 4 and 7 postoperatively. Glial fibrillary acidic protein immunoreactivity was remarkably enhanced on day 7. Both systemic and intrathecal methylprednisolone inhibited the development of neuropathic pain states and glial activation. Three-day treatment with intrathecal methylprednisolone reversed existing neuropathic pain state and glial activation up to 3 weeks after the treatment. Conclusion : Systemic and intrathecal methylprednisolone inhibited spinal glial activation and the development and maintenance of a neuropathic pain state in a rat model of spinal nerve ligation.

UNLABELLED Inhaled anesthetics depress the response of spinal dorsal horn low-threshold (LT) neurons to peripheral receptive field stimulation. Part of that depression may be mediated by anesthetic interactions with gamma-aminobutyric acid type A (GABA(A)) and strychnine-sensitive glycine inhibitory neurotransmitter systems. In this electrophysiological study, we attempted to antagonize halothane depression of LT neurons by administering bicuculline (a competitive GABA(A) antagonist) and/or strychnine (a competitive glycine antagonist) systemically, alone or in combination, to decerebrate, spinal cord-transected rats. We observed that both bicuculline and strychnine, alone or in combination, significantly but only partially reversed halothane depression of LT neuronal responses to receptive field stimulation. The inability of bicuculline and strychnine, alone or in combination, to completely reverse halothane depression suggests that although GABA(A) and glycine systems are involved in the observed halothane depression, additional mechanisms of action are also required for halothane depression of LT spinal sensory neurons. IMPLICATIONS The results of this study support the hypothesis that halothane depression of spinal sensory neurons is mediated, but not completely, by the anesthetic effects on gamma-aminobutyric acid type A and strychnine-sensitive glycine neurotransmitter systems.

Management of cesarean section with spinal anesthesia is often accompanied with intraoperative nausea and pain. In a randomized controlled study, we explored the effect of intrathecal fentanyl on the characteristics of subarachnoid block in patients undergoing cesarean section.Twenty-four healthy parturients scheduled for elective Cesarean section were allocated to receive either fentanyl 0.3 ml (15 micrograms) or 0.9% saline 0.3 ml added to 0.5% hyperbaric bupivacaine 2.0 ml given intrathecally in the right decubitus position (n = 12 in each group). Level of sensory blockade was evaluated with cold test and intraoperative use of antiemetics and analgesics was recorded.The maximum level of sensory blockade was significantly higher in the fentanyl group as compared with the control group (P = 0.019). Use of intraoperative antiemetics was significantly less often in the fentanyl group (P = 0.007). The required amount of intraoperative analgesics was smaller in the fentanyl group, although the difference was not significant (P = 0.11). No remarkable side effects, such as respiratory depression and hypoxia were observed. Apgar scores in the newborn were similar.Addition of intrathecal fentanyl to hyperbaric bupivacaine in parturients undergoing cesarean section improved quality of anesthesia without producing significant side effects.

This report describes a case of two-yr-old female with severe clinical Reye syndrome (Stage III and over), who was treated with not only conventional therapies but also mild hypothermia therapy. She presented acute episodes of tonic convulsion, hepatic dysfunction and intracranial hypertension. The first treatment consisted of the administration of anticonvulsant and mannitol, which were not effective to control intracranial pressure. Therefore, we induced mild hypothermia to rectal temperature of 33-34 degrees C for ten days to control intracranial hypertension as well as barbiturate therapy and hyperventilation under mechanical ventilation. Although she had hypokalemia, atelectasis of the right upper lung lobe and thrombocytopenia as the side effects during this therapy, we effectively controlled ICP. Glucose fluid therapy is recommended for Reye syndrome. We especially should pay attention to hypokalemia because of hyperventilation, absorption of potassium with insulin and transudation of potassium from the intestine. We determined the initiation and weaning of mild hypothermia therapy by findings of MRI as well as intracranial pressure. MRI findings will contribute to the determination of initiation and weaning of mild hypothermia therapy. Mild hypothermia therapy should be considered in patients with severe clinical Reye syndrome if conventional supportive therapies are not effective.

We report here an efficient means of epidural catheter placement through atlanto-occipital membrane in rats.Male SD rats (n = 84) were divided into lumbar (n = 48) and cervical (n = 36) groups. Under sterile technique, PVC V-1 tubing was inserted and advanced caudally targeted to the C 4 or L 4 level. Analgesic efficacy and duration were measured by injecting increments of 2% lidocaine until a maximum paw withdrawal latency time from a radiant heat thermal stimulator. Rats (n = 6 each day) were sacrificed and an autopsy was performed to observe both the laterality of the catheter tip and the proliferation of fibrous tissue around the catheter.The volume of lidocaine and its duration was 52 +/- 17 microliters and 27 +/- 13 min (mean +/- SD) in lumbar, 30 +/- 10 microliters and 26 +/- 9 min in cervical group. In lumbar group, two catheters penetrated the dura. The remaining catheters were confirmed to be in the epidural space within L 4 +/- 1 or C 4 +/- 2 segment. Lumbar catheter tips were almost equally distributed between the center, left and right, while cervical catheter tips were distributed between left and center portion of the epidural space. The severity of tissue proliferation was time dependent. The proliferation of fibrotic tissue seemed more rapid in cervical than lumbar group.Although this approach for epidural catheter placement is efficient and produces excellent drug effects on day 3 after implantation, as reported by others, rapid development of fibrous tissue around the catheter quickly limits the usefulness of the epidural catheter.

Photolysis of cis,trans-1,2,3-trichloro-1,2,3-tris(tri-tert-butylsilyl)cyclotrigermane and trans-1,2-dichloro-3-methyl-1,2,3-tris(tri-tert-butylsilyl)cyclotrigermane in the presence of triethylsilane yielded products arising from a germylgermylene, which is formed by the 1,2-chlorine migration on digermenes.

The effects of intravenously (i.v.) administered midazolam on noxiously evoked activity of spinal wide dynamic range (WDR) neurons were investigated in decerebrate, spinal-cord-transected cats. Extracellular, single-unit recordings were measured during stimulation by pinching the receptive field on the hind paw and the effect of midazolam at doses of 0.25, 0.5, 1, 2, and 4 mg/kg were measured. Two series of experiments were performed to characterize the analgesic effects of midazolam. In the first, dose-response experiments (n = 59) demonstrated a dose-dependent suppression of the noxiously evoked activity of spinal WDR neurons after midazolam administration. This effect of midazolam was maximal at a dose of 1 mg/kg i.v.. The second series of experiments (n = 14) demonstrated that a benzodiazepine antagonist, flumazenil (n = 8), promptly reversed the effect of midazolam, while an opioid antagonist, naloxone (n = 6), had no effect on the effect of midazolam. The present study demonstrates that i.v. administered midazolam suppresses noxiously evoked activity of spinal WDR neurons that is reversible by a benzodiazepine antagonist. This is consistent with an analgesic action of midazolam.

Background Although a decrease in serum potassium level has been suggested to be a fairly common observation in acute coronary syndrome (ACS), there have so far been no definitive reports directly demonstrating the transient potassium decrease (the potassium dip) during ischemic attack of ACS compared to stable phase in individual patients. To understand the pathophysiological significance of the potassium dip, we examined the changes in serum potassium level throughout ischemic attack and evaluated the clinical factors affecting it. Methods The degree of the potassium dip during ischemic attack (as indicated by ΔK, ΔK = K at discharge − K on admission) was examined in 311 consecutive patients with ACS who required urgent hospitalization in our institution. Results Serum potassium level during ischemic attack was significantly decreased compared to that during stable phase (P Conclusions We have clearly demonstrated that there is a transient decrease in serum potassium level during ischemic attack of ACS compared to stable phase. The degree of the potassium dip was tightly correlated with glucose level, which overwhelmed the diabetic condition, and it also indicates the disease severity. The present study therefore promotes awareness of the significance of monitoring potassium level in parallel with glucose level in patients with ACS.