Rs11726196 Single-Nucleotide Polymorphism of the Transient Receptor Potential Canonical 3 (TRPC3) Gene Is Associated with Chronic Pain.

Chronic pain is reportedly associated with the transient receptor potential canonical 3 (TRPC3) gene. The present study examined the genetic associations between the single-nucleotide polymorphisms (SNPs) of the TRPC3 gene and chronic pain. The genomic samples from 194 patients underwent linkage disequilibrium (LD) analyses of 29 SNPs within and around the vicinity of the TRPC3 gene. We examined the associations between the SNPs and the susceptibility to chronic pain by comparing the genotype distribution of 194 patients with 282 control subjects. All SNP genotype data were extracted from our previous whole-genome genotyping results. Twenty-nine SNPs were extracted, and a total of four LD blocks with 15 tag SNPs were observed within and around the TRPC3 gene. We further analyzed the associations between these tag SNPs and chronic pain. The rs11726196 SNP genotype distribution of patients was significantly different from the control subjects even after multiple-testing correction with the number of SNPs. The TT + TG genotype of rs11726196 is often carried by chronic pain patients, suggesting a causal role for the T allele. These results contribute to our understanding of the genetic risk factors for chronic pain.

Single-Nucleotide Polymorphisms of the PAR2 and IL-17A Genes Are Significantly Associated with Chronic Pain.

Patients with chronic pain are affected psychologically and socially. There are also individual differences in treatment efficacy. Insufficient research has been conducted on genetic polymorphisms that are related to individual differences in the susceptibility to chronic pain. Autoimmune disorders can lead to inflammation and chronic pain; therefore, we focused on the autoimmune-related protease-activated receptor 2 (PAR2/F2RL1) and interleukin 17A (IL-17A/IL17A) genes. PAR2 and IL-17A are associated with autoimmune diseases that lead to chronic pain, and PAR2 regulates T-helper (Th) cell activation and differentiation. We hypothesized that the PAR2 and IL-17A genes are associated with chronic pain. The present study used a case-control design to statistically examine associations between genetic polymorphisms and the vulnerability to chronic pain. The rs2243057 polymorphism of the PAR2 gene and rs3819025 polymorphism of the IL-17A gene were previously reported to be associated with pain- or autoimmune-related phenotypes. Thus, these polymorphisms were investigated in the present study. We found that both rs2243057 and rs3819025 were significantly associated with a susceptibility to chronic pain. The present findings revealed autoimmune-related genetic factors that are involved in individual differences in chronic pain, further aiding understanding of the pathomechanism that underlies chronic pain and possibly contributing to future personalized medicine.

Heparan sulfate 3-O-sulfotransferase 4 is genetically associated with herpes zoster and enhances varicella-zoster virus-mediated fusogenic activity.

Acute pain that is associated with herpes zoster (HZ) can become long-lasting neuropathic pain, known as chronic post-herpetic neuralgia (PHN), especially in the elderly. HZ is caused by the reactivation of latent varicella-zoster virus (VZV), whereas PHN is not attributed to ongoing viral replication. Although VZV infection reportedly induces neuronal cell fusion in humans, the pathogenesis of PHN is not fully understood. A genome-wide association study (GWAS) revealed significant associations between PHN and the rs12596324 single-nucleotide polymorphism (SNP) of the heparan sulfate 3-O-sulfotransferase 4 (HS3ST4) gene in a previous study. To further examine whether this SNP is associated with both PHN and VZV reactivation, associations between rs12596324 and a history of HZ were statistically analyzed using GWAS data. HZ was significantly associated with the rs12596324 SNP of HS3ST4, indicating that HS3ST4 is related to viral replication. We investigated the influence of HS3ST4 expression on VZV infection in cultured cells. Fusogenic activity after VZV infection was enhanced in cells with HS3ST4 expression by microscopy. To quantitatively evaluate the fusogenic activity, we applied cytotoxicity assay and revealed that HS3ST4 expression enhanced cytotoxicity after VZV infection. Expression of the VZV glycoproteins gB, gH, and gL significantly increased cytotoxicity in cells with HS3ST4 expression by cytotoxicity assay, consistent with the fusogenic activity as visualized by fluorescence microscopy. HS3ST4 had little influence on viral genome replication, revealed by quantitative real-time polymerase chain reaction. These results suggest that HS3ST4 enhances cytotoxicity including fusogenic activity in the presence of VZV glycoproteins without enhancing viral genome replication.

Genome-wide association study identifies candidate loci associated with chronic pain and postherpetic neuralgia.

BACKGROUND: Human twin studies and other studies have indicated that chronic pain has heritability that ranges from 30% to 70%. We aimed to identify potential genetic variants that contribute to the susceptibility to chronic pain and efficacy of administered drugs. We conducted genome-wide association studies (GWASs) using whole-genome genotyping arrays with more than 700,000 markers in 191 chronic pain patients and a subgroup of 89 patients with postherpetic neuralgia (PHN) in addition to 282 healthy control subjects in several genetic models, followed by additional gene-based and gene-set analyses of the same phenotypes. We also performed a GWAS for the efficacy of drugs for the treatment of pain. RESULTS: Although none of the single-nucleotide polymorphisms (SNPs) were found to be genome-wide significantly associated with chronic pain (p ≥ 1.858 × 10-7), the GWAS of PHN patients revealed that the rs4773840 SNP within the ABCC4 gene region was significantly associated with PHN in the trend model (nominal p = 1.638 × 10-7). In the additional gene-based analysis, one gene, PRKCQ, was significantly associated with chronic pain in the trend model (adjusted p = 0.03722). In the gene-set analysis, several gene sets were significantly associated with chronic pain and PHN. No SNPs were significantly associated with the efficacy of any of types of drugs in any of the genetic models. CONCLUSIONS: These results suggest that the PRKCQ gene and rs4773840 SNP within the ABCC4 gene region may be related to the susceptibility to chronic pain conditions and PHN, respectively.

Temperature-dependent inotropic and lusitropic indices based on half-logistic time constants for four segmental phases in isovolumic left ventricular pressure-time curve in excised, cross-circulated canine heart.

Varying temperature affects cardiac systolic and diastolic function and the left ventricular (LV) pressure-time curve (PTC) waveform that includes information about LV inotropism and lusitropism. Our proposed half-logistic (h-L) time constants obtained by fitting using h-L functions for four segmental phases (Phases I-IV) in the isovolumic LV PTC are more useful indices for estimating LV inotropism and lusitropism during contraction and relaxation periods than the mono-exponential (m-E) time constants at normal temperature. In this study, we investigated whether the superiority of the goodness of h-L fits remained even at hypothermia and hyperthermia. Phases I-IV in the isovolumic LV PTCs in eight excised, cross-circulated canine hearts at 33, 36, and 38 °C were analyzed using h-L and m-E functions and the least-squares method. The h-L and m-E time constants for Phases I-IV significantly shortened with increasing temperature. Curve fitting using h-L functions was significantly better than that using m-E functions for Phases I-IV at all temperatures. Therefore, the superiority of the goodness of h-L fit vs. m-E fit remained at all temperatures. As LV inotropic and lusitropic indices, temperature-dependent h-L time constants could be more useful than m-E time constants for Phases I-IV.

Half-Logistic Function Model for First Half of Descending Phase of Cardiomyocyte Cytoplasmic Ca(2+) Concentration ([Ca(2+)]i)-Time Curve (CaTCIII) in Isolated Aequorin-Injected Mouse Left Ventricular Papillary Muscle.

BACKGROUND: Myocardial contraction and relaxation are regulated by increases and decreases in cytoplasmic calcium concentration ([Ca(2+)]i). In previous studies, we found that a half-logistic (h-L) function, which represents a half-curve of a symmetrical sigmoid logistic function with a boundary at the inflection point, curve-fits the first half of the ascending phase and the second half of the descending phase of the [Ca(2+)]i transient curve better than a mono-exponential (m-E) function. In the present study, we investigated the potential application of an h-L function to analyse the first half of the descending phase of CaTC (CaTCIII). METHODS: The [Ca(2+)]i was measured using the Ca(2+)-sensitive aequorin, which was microinjected into 15 isolated mouse left ventricular (LV) papillary muscles. The observed CaTCIII data in the interval from the point corresponding to the peak [Ca(2+)]i to the point corresponding to dCa/dtmin was curve-fitted using the h-L and m-E function equations by the least-squares method. RESULTS: The mean correlation coefficient (r) values of the h-L and m-E function best curve-fits for 11 CaTCIIIs were 0.9986 and 0.9982, respectively. The Z transformation of h-L r (3.64 ± 0.45) was larger than that of m-E r (3.50 ± 0.33) (p < 0.05). CONCLUSIONS: The h-L function can evaluate most CaTCIIIs more accurately than the m-E function in isolated aequorin-injected mouse LV papillary muscle. The three calculated h-L parameters i.e., amplitude constant, time constant, and non-zero asymptote, are more reliable indices than m-E for evaluating the magnitude and time course of the change in the decrease in [Ca(2+)]i. KEY WORDS: Ca(2+) transient; Half-logistic amplitude constant; Half-logistic non-zero asymptote; Half-logistic time constant; Myocardial Ca(2+) handling.

[Transdermal Local Anesthetics].

Taking EMLA cream and Penles tape 18 mg as examples, this article describes the conditions for skin penetration of topical anesthetics, with their onset time of action, duration of effect and a precautions for their use. EMLA cream is a unique cream for topical anesthesia which is the eutectic mixture of lidocaine and propitocaine to increase skin penetration. The safety study demonstrated that blood concentrations of active ingredients of EMLA cream were below toxic levels. EMLA cream, with confirmed high skin penetrability and safety, should be used for pain reduction of various treatments for many diseases. Here in Japan, EMLA cream has indications not only for pain reduction of skin laser therapy but also for reduction of needle puncture pain. This means the use of topical anesthesia would be expanded to wider ranges of treatments.

[Device for quantitative analysis of perception and pain sensation].

The article describes an analysing device that measures the perception and intensity of pain quantitatively. While it is not necessarily true that psychological aspect is totally irrelevant to pain measurement, this device is remarkable in that it is capable of measuring the intensity of pain felt by the patient more objectively by using electric stimuli. The feature of this device is that it uses a non-pain heteresthesia for measuring the intensity of pain. The device is compact, light-weight, and portable. Unlike VAS that requires only a scale, the device requires a person to carry out the measurement. Nevertheless, as the National Health Insurance (NHI) coverage has been approved, introduction of the device may be facilitated in terms of budget for the purchase and labor. The device is useful to better understand not only the intensity of pain but also the pathological conditions, resulting in more appropriate treatment, by (1) comparing degree of pain or VAS values taken by a multicenter study with those of a patient; (2) using both degree of pain and VAS; and (3) multiple measurements of degree of pain and VAS in one case.

Intracellular Ca(2+) Transient Phase II Can be Assessed by Half-Logistic Function Model in Isolated Aequorin-Injected Mouse Left Ventricular Papillary Muscle.

BACKGROUND: Myocardial contraction and relaxation are regulated by increases and decreases in intracellular cytoplasmic calcium (Ca(2+)) concentration ([Ca(2+)]i). In previous studies, we found that a half-logistic (h-L) function, which represents a half-curve of a symmetrical sigmoid logistic function with a boundary at the inflection point, curve-fits the first half of the ascending phase (CaTI) and the second half of the descending phase of the [Ca(2+)]i transient curve (CaTIV) better than a mono-exponential (m-E) function. In the present study, we investigated the potential application of an h-L function to the analysis of the second half of the ascending phase of the [Ca(2+)]i transient curve (CaTII). METHODS: The [Ca(2+)]i transient was measured using the Ca(2+)-sensitive photoprotein aequorin, which was microinjected into 15 isolated left ventricular (LV) papillary muscles of mice. The observed CaTII data during the time duration from the point corresponding to the maximum of the first-order time derivative of Ca(2+) concentration (dCa/dtmax) to the point corresponding to the peak Ca(2+) concentration was curve-fitted by the least-squares method using the h-L and m-E function equations. RESULTS: The mean correlation coefficient (r) values of the h-L and m-E curve-fits for CaTII were 0.9996 and 0.9984, respectively. The Z transformation of h-L r was larger than that of m-E r (p < 0.0001). H-L residual mean square (RMS) was smaller than m-E RMS (p < 0.001). CONCLUSIONS: The h-L function tracks the magnitudes and time courses of CaTII more accurately than the m-E function in isolated aequorin-injected mouse LV papillary muscle. Compared with the m-E time constant, the h-L time constant of CaTII is a more reliable index for evaluating the time duration of the change in the increase in [Ca(2+)]i during the combination of the middle part of the contraction process and the early part of the relaxation process. CaTII can be assessed by the h-L function model in cardiac muscles. The h-L approach may provide a more useful model for studying each process in myocardial Ca(2+) handling. KEY WORDS: Calcium handling; Calcium transient; Curve-fit; Half-Logistic function; Time constant.

Pentazocine-induced antinociception is mediated mainly by µ-opioid receptors and compromised by κ-opioid receptors in mice.

Pentazocine is a widely used mixed agonist-antagonist opioid. Previous animal studies have demonstrated that pentazocine-induced antinociception displayed a ceiling effect characterized by biphasic dose response with a increasing and then descending analgesia like a bell-shaped curve. This study attempted to clarify the mechanisms underlying such dose-response relationships. ddY and C57BL/6J mice received subcutaneous injection of saline or pentazocine (3, 10, 30, 56, or 100 mg · kg(-1)), at 120 min after subcutaneous injection of saline, a µ-opioid receptor antagonist clocinnamox mesylate (C-CAM) (5 mg · kg(-1)), a κ-opioid receptor antagonist nor-binaltorphimine (nor-BNI) (10 mg · kg(-1)), or the combination of C-CAM and nor-BNI. The antinociceptive effects of pentazocine were evaluated using tail pressure, hot plate, tail flick, and acetic acid writhing tests. Without pretreatment with an opioid receptor antagonist, the antinociceptive effects of pentazocine exhibited biphasic bell-shaped dose-response curves peaking at 30 mg · kg(-1). C-CAM completely and partly antagonized the antinociception induced by pentazocine at low (3-30 mg · kg(-1)) and high (56-100 mg · kg(-1)) doses, respectively. nor-BNI enhanced the antinociception by pentazocine at high doses and turned the later descending portion of the biphasic dose-response curves into a sigmoid curve. The combination of C-CAM and nor-BNI completely abolished the antinociception by pentazocine at all doses. Our results suggest pentazocine produces antinociception primarily via activation of µ-opioid receptors, but at high doses, this µ-opioid receptor-mediated antinociception is antagonized by concomitant activation of κ-opioid receptors. This provides the first reasonable hypothesis to explain the ceiling effects of pentazocine analgesia characterized by a biphasic dose response.

Calcium-induced calcium release from the sarcoplasmic reticulum can be evaluated with a half-logistic function model in aequorin-injected cardiac muscles.

PURPOSE: Release of calcium (Ca(2+)) from the sarcoplasmic reticulum (SR) induced by Ca(2+) influx through voltage-dependent sarcolemmal L-type Ca(2+) channels (CICR) in cardiac muscle cells has been implicated as a potential target contributing to anesthetic-induced myocardial depression. In an earlier study, we found that (1) a half-logistic (h-L) function, which represents a half-curve of a sigmoid logistic function with a boundary at the inflection point, curve-fits the first half of the ascending phases of the isometric myocardial tension and isovolumic left ventricular (LV) pressure waveforms better than a mono-exponential (m-E) function and (2) the h-L time constants are useful as inotropic indices. We report here our investigation of the potential application of an h-L function to the analysis of the first half of the ascending phase of the Ca(2+) transient curve (faCaT) that precedes and initiates myocardial contraction and the increase in LV pressure. METHODS: Ca(2+) transients (CaT) were measured using the Ca(2+)-sensitive photoprotein aequorin, which was microinjected into seven isolated rabbit right ventricular and 15 isolated mouse LV papillary muscles. The faCaT data from the beginning of twitch stimulation to the maximum of the first-order time derivative of Ca(2+) concentration (dCa/dt(max)) was curve-fitted by the least-squares method using h-L and m-E function equations. RESULTS: The mean correlation coefficient (r) values of the h-L and m-E curve-fits for the faCaTs were 0.9740 and 0.9654 (P < 0.05) in the rabbit and 0.9895 and 0.9812 (P < 0.0001) in the mouse. CONCLUSION: The h-L curves tracked the amplitudes and time courses of the faCaTs in cardiac muscles more accurately than m-E functions. Based on this result, we suggest that the h-L time constant may be a more reliable index than the m-E time constant for evaluating the rate of CICR from the SR in myocardial Ca(2+) handling. The h-L approach may provide a more useful model for the study of CICR during the contraction process induced by anesthetic agents.

[Anesthetic management of a Jehovah's Witness for pancreaticoduodenectomy].

For religious reasons, Jehovah's Witnesses do not accept homologous blood transfusions. Instead, they request alternative medical care that does not involve such transfusions. A 58-year-old woman, a Jehovah's Witness, was scheduled for pancreaticoduodenectomy for pancreatic carcinoma under general and epidural anesthesia. She presented with hemoglobin (Hb) concentration of 10.3 g x dl(-1) and hematocrit (Ht) of 31.5% preoperatively. She was fully informed about the risk of cardiac arrest and postoperative complications without blood transfusion, and consented to the bloodless surgery with infusion of colloid solutions; albumin and hydroxyethylated starch, and intraoperative, salvaged, autologous blood transfusion. She submitted a signed letter, absolutely refusing homologous blood transfusion and releasing the hospital from any liability. The general anesthesia was induced using fentanyl, propofol, and vecuronium, and maintained with sevoflurane and vecuronium in combination with epidural anesthesia using lidocaine and fentanyl. An autologous blood transfusion device was prepared for use in the event of massive intraoperative hemorrhage. The pancreaticoduodenectomy and cholecystectomy were performed without the necessity of starting the intraoperative, salvaged, autotransfusion. The volume of intraoperative hemorrhage was 1,108 ml. Lactated Ringer's solution 3,300 ml, physiological saline 200 ml, and hydroxyethylated starch 500 ml were infused during the operation. Although her postoperative Hb and Ht dropped to 8.7 g x dl(-1) and 26.8%, respectively, no transfusion was performed. Anesthesiologists should respect the demands of Jehovah's Witnesses, and should attempt to manage surgery without transfusion.

[Predisposing factors and prevention of emergence agitation].

Agitation during the emergence from general anesthesia is a great post-operative problem that often injures the patients themselves and requires the medical staff to restrain and calm the patients. The predisposing factors for emergence agitation include anesthesia, operation, and patient. Sevoflurane anesthesia results in higher incidence of emergence agitation than halothane, because of the rapid emergence, and its effects on central nervous system inducing convulsion and post-operative behavioral changes. The otorhinolaryngologic and ophthalmologic surgeries, post-operative pain, young age, pre-operative anxiety, no past surgical history, and adjustment disorder of patients are risk factors for emergence agitation. The change from sevoflurane to propofol during anesthesia maintenance is a contributing factor to reduce incidence of emergence agitation. The medications including opioids, midazolam, alpha-2 agonists, ketamine, non-steroidal anti-inflammatory drugs, nitrous oxide, and propofol, and aggressive nerve block such as caudal epidural block for post-operative sedation and analgesia are effective to avoid incidence of emergence agitation. The calm emergence following general anesthesia would decrease the self-injuring behavior, and enhance the parent and caregiver satisfaction in general anesthesia and surgery.

[Tracheal intubation with Parker Flex-Tip tubes assisted by tube-guiding devices].

In tracheal intubation assisted by tube-guiding devices passing through the tube, such as fiberoptic scopes, bougies, tracheal tube exchange catheters, and light wands, passage of the tube-guiding device, by itself, is often easy. But advancing a tracheal tube with a conventional distal tip over these tube-guiding devices is frequently difficult or impossible, because its rigid, side-beveled tip frequently catches on anatomical features of the airway. A novel tracheal tube, the Parker Flex-Tip tube (Parker Medical, Colorado, USA) has a centered, curved, tapered and flexible distal tip that passes through the airway faster and easier than conventional tracheal tubes. As it is advanced along a tube-guiding device, the tip of the Parker tube travels along the midline of the airway, without the gap that usually exists between the distal edge of a conventional tracheal tube and the tube-guiding device. The gapless, midline travel of the Parker tube leads to a greater incidence of first-attempt intubation success with tube-guiding devices, because there is less risk of tube tip hang-ups on the arytenoids and the vocal cords. Clinically, use of the Parker tube is helpful for oral and nasal intubations, especially in patients with difficult airways.

Ageing, obesity, dyslipidaemia, and hospital-room hypertension are clinical risk factors relating to pre-anaesthesia.

BACKGROUND: Pre-anaesthesia hypertension (PAH) occurs when the blood pressure (BP) in patients before surgery, in the operating room, before anaesthesia induction, temporally elevates regardless of normal ambulatory recorded BP or self-measured BP at home. PAH might be caused by anxiety and mental stress about the anaesthesia and surgery. We know that most of the patients with sustained hypertension (SH) are elders, males, obese subjects, and dyslipidaemic subjects. Furthermore, most of the patients with white coat hypertension, which is caused by mental stress about the medical environment of an outpatient, clinic, and hospital ward, are elders, females, and non-smokers. In the present study, we investigated some relevant clinical characteristics influencing PAH. METHODS: Sampling data on patients more than 20 years old, who underwent consecutive operations under general, intrathecal, or epidural anaesthesia were retrospectively collected from hospital records and anaesthesia records. Hospital-room hypertension (HH) was defined as systolic BP (sBP) greater than or equal to 140 mm Hg in the hospital room before anaesthesia and surgery. Operating-room hypertension (OH) was defined as sBP greater than or equal to 140 mm Hg in the operating room before anaesthesia induction. RESULTS: 112 and 119 patients belonged to the OH and operating-room normotension (ON) groups, respectively. The OH group members were significantly older than the ON group members. Body mass index in the OH group was significantly greater than in the ON group. The proportions of males, dyslipidaemic subjects, and non-smokers in the OH group were significantly higher than in the ON group. In the logistic regression analysis, age, body mass, dyslipidaemia, and HH were selected as significant factors that contribute independently to OH (odds ratios; 1.045, 1.031, 2.912, and 4.354, respectively). CONCLUSIONS: The clinical characteristics of the patients with OH are: elders, obese subjects, dyslipidaemic subjects, and hospital-room hypertensive subjects. Ageing, obesity, dyslipidaemia, and HH are clinical risk factors relating to PAH.

[Anesthetic management for lymphaticovenular anastomosis in a lower leg of a patient with Klippel-Trenaunay-Weber syndrome].

A 39-year-old woman was diagnosed in infancy as suffering from Klippel-Trenaunay-Weber syndrome, affecting both her lower limbs. She had undergone, for several times, gastroepiploic transplantation at 18 years of age. She was scheduled for lymphaticovenular anastomosis of the right limb. Preoperatively, computed tomography showed no thrombosis in her lower limbs. We gave only general anesthesia, because of her strong anxiety, and concern of hemangioma and blood vessel malformation in epidural space. General anesthesia was induced with thiopental, fentanyl, and vecuronium, and maintained with nitrous oxide, oxygen and sevoflurane. Tourniquet had been used for only 30 minutes considering the risk of occurring deep vein thrombosis. Surgery was successfully finished in eight hours and thirty minutes. Using tourniquet increases the risk of deep vein thrombosis and pulmonary embolism. We should use tourniquet as briefly as possible to avoid the occurrence of pulmonary embolism. We recommend avoidance of epidural analgesia, as the patient may have hemangioma and arteriovenous malformation in epidural space, and we should evaluate them by magnetic resonance imaging before anesthesia.

The comparison of effects of processed Aconiti tuber, U50488H and MK-801 on the antinociceptive tolerance to morphine.

In the previous studies, we demonstrated that an oriental herbal medicine, processed Aconiti tuber (PAT), at subanalgesic doses could inhibit or reverse the antinociceptive tolerance to morphine. In the present study, we compared the effect of PAT, trans-(+/-)-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidin)cyclohexyl)-benzeneacetamide methane sulfonate hydrate (U50488H), a selective kappa opioid receptor (KOR) agonist, and (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine-maleate (MK-801), a N-methyl-D-aspartate (NMDA) receptor antagonist, on the antinociceptive tolerance to morphine in the same experimental condition. Mice received subcutaneous morphine (10 mg/kg), and oral PAT at a subanalgesic dose (0.3 g/kg for mechanical or 1.0 g/kg for thermal test), or intraperitoneal U50488H at a subanalgesic dose (3 mg/kg), or MK-801 at a subanalgesic dose (0.1 mg/kg) once daily for 14 days. The mechanical nociceptive threshold was measured before, and at 60 min by tail pressure testing, and thermal nociceptive latency was measured before, and at 30 min by hot plate testing, after daily morphine injections. PAT and U50488H could not only inhibit the development of morphine tolerance but also reverse the already-developed morphine tolerance, while MK-801 could only inhibit the development of morphine tolerance but not reverse the already-developed morphine tolerance, in both mechanical and thermal nociceptive tests. These data suggested that PAT, an indirect-acting KOR agonist, share the common pharmacological property of KOR agonists on morphine tolerance, and that PAT may be superior to some NMDA receptor antagonists which do not reverse already-developed morphine tolerance.

High doses of processed Aconiti tuber inhibit the acute but potentiate the chronic antinociception of morphine.

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-naïve 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-naïve 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.

[Right median nerve injury following laparoscopic sigmoidectomy].

Brachial plexus injury has often occurred secondary to malposition of the patient during general anesthesia. We have experienced median nerve injury following laparoscopic sigmoidectomy. A 61-year-old man with diabetes and hypertension received laparoscopic sigmoidectomy under general and epidural anesthesia. Tracheal intubation was easy without excessive retroflextion of his neck after anesthesia induction with fentanyl, propofol, and vecuronium. Both his upper arms were abducted to 80 degrees and his elbows were extended on a padded arm board. The shoulder braces were placed over both his acromioclavicular joints. His head remained in neutral position. Anesthesia was maintained with air, oxygen, sevoflurane, fentanyl, and vecuronium using mepivacaine via epidural catheter. During surgical procedures, he was in a combined lithotomy and head down position at maximum of 20 degrees. The operative table was tilted to the right at maximum of 20 degrees. The operation was finished successfully in 2 hours and 40 minutes without a special event. Postoperatively, he complained of numbness of the first, second, and third digits, and the radial side of fourth digit in his right hand. The redness on both his shoulders was observed. Muscle weakness and motor disturbance were not observed. Orthopedic surgeon diagnosed him as right median nerve injury. His symptoms improved gradually by physical training and disappeared one week after the operation. We suspect that his right median nerve injury was caused by compression and stretching of the brachial plexus in head down position, right lateral tilt table, use of shoulder brace, laparoscopy, abduction of the upper arm, and extension of the elbow. In laparoscopic operation in head down position, we should avoid using the shoulder brace to minimize the risk of brachial plexus injury. The arms should be approximated to the sides as nearly as possible and the elbows should be gently flexed to unload the median nerve and relieve tension on the brachial plexus.

[Novel assessment of intracellular calcium transient decay in cardiac muscle by curve-fitting with half-logistic function].

A decrease in intracellular calcium (Ca2+) concentration in the cardiac muscle is one of the important factors to induce myocardial relaxation. A mono-exponential (m-E) function has been used for assessing myocardial relaxation curve of isometric tension and intracellular calcium transient (CaT) decay, and the m-E time constants for the relaxation curve of isometric tension (F tau E) and CaT decay (Ca tau E) have been recognised as lusitropic indices. However, we found that a half-logistic (h-L) function fits the relaxation curve of isometric tension much more precisely than the conventional m-E function in the ferret right ventricular (RV) papillary muscle. Moreover, we demonstrated that the goodness of the h-L fits for CaT decays was superior to the goodness of the m-E fits in the rabbit RV and murine left ventricular papillary muscles. The changes in the h-L time constants for the relaxation curves of isometric tension (F tau L) and CaT decays (Ca tau L) with the different onsets were significantly smaller than the changes in F tau E and Ca tau E, respectively. The differences in the h-L non-zero asymptotes for the relaxation curves of isometric tension and CaT decays with the different onsets were smaller than the changes in the m-E non-zero asymptotes. The h-L function model characterises the amplitudes and time courses of the relaxation curve of isometric tension and CaT decay more precisely than the m-E function model, and thus F tau L and Ca tau L serve as more novel and reliable lusitropic indices. Simultaneous analysis of myocardial relaxation curve of isometric tension and CaT decay using h-L functions can become a useful method for assessment of myocardial calcium handling.