Antidepressants inhibit Nav1.3, Nav1.7, and Nav1.8 neuronal voltage-gated sodium channels more potently than Nav1.2 and Nav1.6 channels expressed in Xenopus oocytes.

Tricyclic antidepressants (TCAs) and duloxetine are used to treat neuropathic pain. However, the mechanisms underlying their analgesic effects remain unclear. Although many investigators have shown inhibitory effects of antidepressants on voltage-gated sodium channels (Nav) as a possible mechanism of analgesia, to our knowledge, no one has compared effects on the diverse variety of sodium channel α subunits. We investigated the effects of antidepressants on sodium currents in Xenopus oocytes expressing Nav1.2, Nav1.3, Nav1.6, Nav1.7, and Nav1.8 with a ß1 subunit by using whole-cell, two-electrode, voltage clamp techniques. We also studied the role of the ß3 subunit on the effect of antidepressants on Nav1.3. All antidepressants inhibited sodium currents in an inactivated state induced by all five α subunits with ß1. The inhibitory effects were more potent for Nav1.3, Nav1.7, and Nav1.8, which are distributed in dorsal root ganglia, than Nav1.2 and Nav1.6, which are distributed primarily in the central nervous system. The effect of amitriptyline on Nav1.7 with ß1 was most potent with a half-maximal inhibitory concentration (IC50) 4.6 µmol/L. IC50 for amitriptyline on Nav1.3 coexpressed with ß1 was lowered from 8.4 to 4.5 µmol/L by coexpression with ß3. Antidepressants predominantly inhibited the sodium channels expressed in dorsal root ganglia, and amitriptyline has the most potent inhibitory effect. This is the first evidence, to our knowledge, showing the diverse effects of antidepressants on various α subunits. Moreover, the ß3 subunit appears important for inhibition of Nav1.3. These findings may aid better understanding of the mechanisms underlying the pain relieving effects of antidepressants.

Sevoflurane-associated torsade de pointes in a patient with congenital long QT syndrome genotype 2.

Although patients with congenital long QT syndrome (c-LQTS) are considered to be at high risk for anesthesia, few reports describe c-LQTS genotype-specific considerations for anesthesia. We describe a case of torsade de pointes (TdP) caused by sevoflurane in a patient with c-LQTS genotype 2 (LQT2). A 39-year-old woman diagnosed with c-LQTS was scheduled for an elective therapeutic abortion. Immediately after starting the operation, the patient developed TdP. Since pulseless ventricular tachycardia was sustained despite intravenous injection of lidocaine, defibrillation was performed. Analysis of the electrocardiogram revealed that the corrected QT interval before anesthesia was 530 ms and 2.0% sevoflurane markedly prolonged the corrected QT interval to 693 ms. Postoperative studies revealed a mutation in the KCNH2 gene. Anesthesiologists should note that patients with LQT2 could be more susceptible to volatile anesthetics than are those with other major genotypes. Genotype-specific management of anesthesia may reduce the risk of developing TdP during the perioperative period.

[Drug Therapy for Shock-Resistant Ventricular Fibrillation: Comparison of Nifekalant and Amiodarone].

Early direct current (DC) shock is the most important therapy for ventricular fibrillation. Following the increased availability of automated external defibrillators (AED), the survival rate of cardiopulmonary arrest patients with ventricular fibrillation has improved. Although patients with shock-resistant ventricular fibrillation require additional antiarrhythmic drug therapy, the optimal protocol has not been established. Nifekalant is a pure potassium channel blocker with a pyrimidinedione structure. Nifekalant was approved in Japan for the treatment of life-threatening ventricular tachyarrhythmias in 1999, and is widely used as a class III antiarrhythmic intravenous drug. Intravenous amiodarone was approved in Japan in 2007, and exhibits various effects on ion channels, receptors, sympathetic activity, and thyroid function. Nifekalant and amiodarone also exhibit many pharmacological and pharmacodynamic differences. As nifekalant has no negative inotropic effect and a rapid action and clearance with a short half-life, it has some advantages over amiodarone for use in cardiopulmonary resuscitation. Indeed, data from clinical and animal studies suggest that nifekalant is superior to amiodarone for resuscitation of cardiopulmonary arrest resulting from shock-resistant ventricular fibrillation. A 300-mg bolus intravenous injection of amiodarone is considered an overdose for resuscitation of shock-resistant ventricular fibrillation. Further clinical studies are required to evaluate the effects of nifekalant compared with amiodarone, and to determine the optimal dose of amiodaone, for resuscitation of shock-resistant ventricular fibrillation.

[A Case of Hypoglossal Nerve Palsy after Cervical Spine Surgery].

A 46-year-old woman with cervical disc herniation underwent C4-6 laminoplasty and C4-5 foraminotomy under general anesthesia. The patient complained of the tongue deviation toward the right after surgery. She underwent several examinations and was diag- nosed as right hypoglossal nerve palsy caused by peripheral nerve disorder. It was considered that the main damage was the external branch of hypoglossal nerve which was likely to occur as a complication of compression because of the location. The cause of hypoglossal nerve palsy was assumed to be possibly direct compression of the hypoglossal nerve by the tracheal tube. In prone position surgery, it is important to take care of pressure to the tongue because the intraoral space tends to be reduced by edema of the face and neck.

[Anesthetic management of a Dialysis Patient with Chronic Inflammatory Demyelinating Polyneuropathy].

We report the successful management of anesthesia in a 46-year-old male dialysis patient with chronic inflammatory demyelinating polyneuropathy (CIDP). He underwent an osteosynthesis of the ankle joint using general anesthesia combined with epidural anesthesia. The anesthetic concerns in patients with CIDP are the possibility of postoperative respiratory dysfunction due to anesthetics or muscle relaxants and that of postoperative neurological deterioration due to spinal or epidural anesthesia. In this case, sevoflurane (1.5-2%) did not cause respiratory dysfunction postoperatively and muscle relaxant effect of rocuronium was effectively reversed by sugammadex. Epidural anesthesia using ropivacaine (0.2-0.375%) and fentanyl did not worsen the neurological symptoms of CIDP post-operatively.

[Measurement of the Minimum Pressure in the Bronchial Cuff during One-lung Ventilation Using a Capnometer].

BACKGROUND: It is recommended to avoid overinflation of the bronchial cuff, leading to ischemic pressure damages to the respiratory mucosa and bronchial rupture. We investigated the minimum bronchial cuff pressure of 35 Fr double lumen tubes (DLTs) during one lung ventilation using a capnometer. METHODS: We studied 50 patients who were scheduled to undergo thoracic surgery. General anesthesia was induced and the patients were intubated with 35 Fr left DLT. With a fiberoptic bronchoscope, the DLT was positioned appropriately. The bronchial cuff was inflated first with air 3-3.5 ml. Lung isolation was confirmed by auscultation. Measurements were performed with the patient in the lateral position. Ventilating one lung isolatedly for 5 minutes, we confirmed non ventilated condition with a capnometer displaying flat line. The bronchial cuff was deflated 0.5-ml steps just before displaying the respiratory pattern by the capnogram. The bronchial cuff pressure and volume were recorded at this point RESULTS: The minimum pressures of bronchial cuff (volume) for one lung ventilation are for male 5.46 ± 0.6 cmH2O (2.33?0.1 ml) and for female 1.5?0.5 cmH20 (1.09 ± 0.3 ml). These values are smaller than the recommended value (< 25 cmH2O). There was no case in which the collapse of the operated lung was insufficient. CONCLUSIONS: In this study, the bronchial pressure higher than 12 cmH2O was not necessary for one lung ventilation. If high intracuff pressure is necessary to seal the bronchus, there are possibilities of the incompatibility of the size of DLT and the herniation of the bronchial cuff to the proximal side. The method of confirmation of OLV using a capnometer can display the non ventilated condition on the monitor objectively. We can thus decrease troubles during operations.

Ikarisoside A inhibits acetylcholine-induced catecholamine secretion and synthesis by suppressing nicotinic acetylcholine receptor-ion channels in cultured bovine adrenal medullary cells.

Ikarisoside A is a natural flavonol glycoside derived from plants of the genus Epimedium, which have been used in Traditional Chinese Medicine as tonics, antirheumatics, and aphrodisiacs. Here, we report the effects of ikarisoside A and three other flavonol glycosides on catecholamine secretion and synthesis in cultured bovine adrenal medullary cells. We found that ikarisoside A (1-100 µM), but not icariin, epimedin C, or epimedoside A, concentration-dependently inhibited the secretion of catecholamines induced by acetylcholine, a physiological secretagogue and agonist of nicotinic acetylcholine receptors. Ikarisoside A had little effect on catecholamine secretion induced by veratridine and 56 mM K(+). Ikarisoside A (1-100 µM) also inhibited (22)Na(+) influx and (45)Ca(2+) influx induced by acetylcholine in a concentration-dependent manner similar to that of catecholamine secretion. In Xenopus oocytes expressing α3ß4 nicotinic acetylcholine receptors, ikarisoside A (0.1-100 µM) directly inhibited the current evoked by acetylcholine. It also suppressed (14)C-catecholamine synthesis and tyrosine hydroxylase activity induced by acetylcholine at 1-100 µM and 10-100 µM, respectively. The present findings suggest that ikarisoside A inhibits acetylcholine-induced catecholamine secretion and synthesis by suppression of nicotinic acetylcholine receptor-ion channels in bovine adrenal medullary cells.

Lidocaine preferentially inhibits the function of purinergic P2X7 receptors expressed in Xenopus oocytes.

BACKGROUND: Lidocaine has been widely used to relieve acute pain and chronic refractory pain effectively by both systemic and local administration. Numerous studies reported that lidocaine affects several pain signaling pathways as well as voltage-gated sodium channels, suggesting the existence of multiple mechanisms underlying pain relief by lidocaine. Some extracellular adenosine triphosphate (ATP) receptor subunits are thought to play a role in chronic pain mechanisms, but there have been few studies on the effects of lidocaine on ATP receptors. We studied the effects of lidocaine on purinergic P2X3, P2X4, and P2X7 receptors to explore the mechanisms underlying pain-relieving effects of lidocaine. METHODS: We investigated the effects of lidocaine on ATP-induced currents in ATP receptor subunits, P2X3, P2X4, and P2X7 expressed in Xenopus oocytes, by using whole-cell, two-electrode, voltage-clamp techniques. RESULTS: Lidocaine inhibited ATP-induced currents in P2X7, but not in P2X3 or P2X4 subunits, in a concentration-dependent manner. The half maximal inhibitory concentration for lidocaine inhibition was 282 ± 45 µmol/L. By contrast, mepivacaine, ropivacaine, and bupivacaine exerted only limited effects on the P2X7 receptor. Lidocaine inhibited the ATP concentration-response curve for the P2X7 receptor via noncompetitive inhibition. Intracellular and extracellular N-(2,6-dimethylphenylcarbamoylmethyl) triethylammonium bromide (QX-314) and benzocaine suppressed ATP-induced currents in the P2X7 receptor in a concentration-dependent manner. In addition, repetitive ATP treatments at 5-minute intervals in the continuous presence of lidocaine revealed that lidocaine inhibition was use-dependent. Finally, the selective P2X7 receptor antagonists Brilliant Blue G and AZ11645373 did not affect the inhibitory actions of lidocaine on the P2X7 receptor. CONCLUSIONS: Lidocaine selectively inhibited the function of the P2X7 receptor expressed in Xenopus oocytes. This effect may be caused by acting on sites in the ion channel pore both extracellularly and intracellularly. These results help to understand the mechanisms underlying the analgesic effects of lidocaine when it is administered locally at least.

Antinociceptive effect of intracerebroventricular administration of glycine transporter-2 inhibitor ALX1393 in rat models of inflammatory and neuropathic pain.

Glycinergic transmission has an important role in regulating nociception in the spinal cord. The glycine transporter-2 (GlyT2) is localized at presynaptic terminals of glycinergic neurons and eliminates glycine from the synaptic cleft to terminate glycinergic transmission. Systemic and intrathecal administration of GlyT2 inhibitors alleviate various types of pain. Although the GlyT2s and glycine receptors are widely distributed in the central nervous system, little is known about the role of glycinergic transmission in pain perception at supraspinal regions. The present study examined the antinociceptive effect of intracerebroventricular (i.c.v.) administration of the selective GlyT2 inhibitor ALX1393 on inflammatory and neuropathic pain in experimental models. For i.c.v. administration, a guide cannula was implanted into the right lateral ventricle of male Sprague-Dawley rats. Normal rats were used to assess inflammatory nociception using the formalin test and motor function using the rotarod test. Chronic constriction injury (CCI) to the sciatic nerve was induced in the rats. The CCI rats were then used to assess mechanical, cold, and thermal hyperalgesia using the electronic von Frey test, cold plate test, and the plantar test, respectively. ALX1393 (25, 50, and 100 µg) was administered i.c.v. to examine its effects on supraspinal antinociception. Supraspinal ALX1393 in normal rats suppressed the late-phase response in the formalin test but did not affect motor performance. In the CCI rats, ALX1393 inhibited mechanical and cold hyperalgesia in a dose-dependent manner. The antihyperalgesic effects of ALX1393 (100 µg) were reversed completely by i.c.v. pretreatment with a glycine receptor antagonist strychnine (10 µg). These results suggest that GlyT2 contributes to nociceptive transmission at supraspinal level and that the selective GlyT2 inhibitor is a promising candidate for the treatment of inflammatory and neuropathic pain without causing motor dysfunction.

[A Case of General Anesthesia in a Patient with Spinal and Bulbar Muscular Atrophy].

We report a successful management of anesthesia in a 55-year-old male patient with spinal and bulbar muscular atrophy (SBMA). His respiratory and swallowing functions were preserved preoperatively. He underwent an osteosynthesis for a femoral neck fracture under general anesthesia using nondepolarizing muscle relaxant. The anesthetic concerns in patients with SBMA are the possibility of postoperative respiratory dysfunction due to anesthetics or muscle relaxants and that of postoperative neurological deterioration due to spinal or epidural anesthesia. In this case, the effect of an intubating dose of rocuronium (0.5 mg · kg(-1)) was markedly prolonged, but it was completely reversed by sugammadex (2 mg · kg(-1)). Postoperative course was uneventful and clinical symptoms of SBMA did not become exacerbated.

Depressed production of beta-defensins from mouse splenic dendritic cells following thermal injury and its influence on susceptibility to infection.

PURPOSE: Beta-defensins (BDs) and dendritic cells (DC) have been described as major effectors on host antimicrobial innate immunities. In the present study, the ability of DC to produce BDs was explored using DC from normal mice and full-thickness (FT)-burned mice. METHODS: DCs were isolated from spleens of mice, and 1 × 10(6) cells/ml of them were cultured with LPS or SAC. Culture fluids harvested 24 h after cultivation were assayed for BD1 and BD3 and antibacterial activity (colony-counting, Pseudomonas aeruginosa). Also, DCs were tested for BD mRNAs by RT-PCR. RESULTS: Sixty-five percent of the bacterial killing activity was shown by the culture fluids of splenic DC from normal mice, while only 15 % killing activity was shown by the culture fluids of splenic DC from FT-burned mice. X-irradiated NOD SCID IL-2rγ(null) mice inoculated with splenic DC from FT-burned mice showed increased susceptibility to P. aeruginosa infection compared to those from normal mice. Mice splenic DC expressed BD1 mRNA constitutively and expressed BD3 mRNA after stimulation. These BDs were produced by mice splenic DC. As compared with DC from normal mice, DC from FT-burned mice produced decreased amounts of BD1 and BD3 in their culture fluids. CONCLUSIONS: These results indicate that (1) DC from spleens of mice have an ability to produce BDs, and (2) the production of BDs by DC is influenced strongly by thermally injured stress. Since FT-burned mice are susceptible to P. aeruginosa infection, BDs produced by DC may play an important role on the host's antibacterial resistance.

Analysis of G-protein-activated inward rectifying K(+) (GIRK) channel currents upon GABAB receptor activation in rat supraoptic neurons.

While magnocellular neurons in the supraoptic nucleus (SON) possess rich Gi/o-mediated mechanisms, molecular and cellular properties of G-protein-activated inwardly rectifying K(+) (GIRK) channels have been controversial. Here, properties of GIRK channels are examined by RT-PCR and whole-cell patch-clamp techniques in rat SON neurons. Patch clamp experiments showed that the selective GABAB agonist, baclofen, enhanced currents in a high K(+) condition. The baclofen-enhanced currents exhibited evident inward rectification and were blocked by the selective GABAB antagonist, CGP55845A, the IRK channel blocker, Ba(2+), and the selective GIRK channel blocker, tertiapin, indicating that baclofen activates GIRK channels via GABAB receptors. The GIRK currents were abolished by N-ethylmaleimide pretreatment, and prolonged by GTPγS inclusion in the patch pipette, suggesting that Gi/o proteins are involved. RT-PCR analysis revealed mRNAs for all four GIRK 1-4 channels and for both GABABR1 and GABABR2 receptors in rat SON. However, the concentration-dependency of the baclofen-induced activation of GIRK currents had an EC50 of 110 µM, which is about 100 times higher than that of baclofen-induced inhibition of voltage-dependent Ca(2+) channels. Moreover, baclofen caused no significant changes in the membrane potential and the firing rate. These results suggest that although GIRK channels can be activated by GABAB receptors via the Gi/o pathway, this occurs at high agonist concentrations, and thus may not be a physiological mechanism regulating the function of SON neurons. This property that the membrane potential receives little influence from GIRK currents seems to be uncommon for CNS neurons possessing rich Gi/o-coupled receptors, and could be a special feature of rat SON neurons.

Effects of intrathecal and intracerebroventricular administration of luteolin in a rat neuropathic pain model.

Luteolin, a major component of flavones, is known to have various physiological properties. Although luteolin reportedly has an antinociceptive effect on acute and inflammatory pain, little is known about its effect on neuropathic pain. The aim of the present study was to determine whether luteolin could ameliorate hyperalgesia in the central nervous system using a neuropathic pain model. Chronic constriction injury to the sciatic nerve was induced in male Sprague-Dawley rats. Luteolin (0.1-1.5 mg) was administered intrathecally or intracerebroventricularly to examine the central effects on mechanical, thermal, and cold hyperalgesia using the electronic von Frey test, plantar test, and cold plate test, respectively. A rotarod test was also performed to assess motor function in normal rats. Spinally applied luteolin dose-dependently attenuated mechanical and cold hyperalgesia, but it had no effect on thermal hyperalgesia. At the highest dose, luteolin affected motor performance. The spinal action of luteolin on mechanical hyperalgesia was inhibited by intrathecal pretreatment with the γ-aminobutyric acidA (GABAA) receptor antagonist bicuculline and µ-opioid receptor antagonist naloxone, but not by intrathecal pretreatment with either the benzodiazepine receptor antagonist flumazenil or glycine receptor antagonist strychnine. Supraspinal application of luteolin had no antihyperalgesic effects in any test. These findings suggest that luteolin ameliorates mechanical and cold hyperalgesia at least in part by activating GABAA receptors in a flumazenil-insensitive manner and µ-opioid receptors in the spinal cord, but that the supraspinal regions are unlikely to contribute to the antihyperalgesic action of luteolin. Luteolin could be a candidate therapeutic agent for neuropathic pain.

[Case of sudden asystole during direct laryngoscopy].

A 78-year-old man, weighing 74 kg and 172 cm in height suddenly developed asystole during direct laryngoscopy. His heart started beating soon after chest compressions. Direct larygoscopy can stimulate the vagal nerve of the larynx. Although a gradual decrease in heart rate ordinarily occurs prior to asystole, few reports describe the sudden asystole during direct laryngoscopy. Intravenous injection of atropine could avoid the adverse event. Anesthesiologists should pay attention to the occurence of asystole and prepare for resuscitation.

[A case of prolongation of rocuronium neuromuscular blockade in a pregnant patient receiving magnesium].

A 35-year-old pregnant female with systemic lupus erythematosus and lupus nephritis underwent emergency cesarean section at 24 weeks of gestation under general anesthesia. The patient had received magnesium sulfate with a diagnosis of pregnancy-induced hypertension since 20 weeks of gestation. Anesthesia was induced with thiopental 3.5 mg x kg(-1) and tracheal intubation was facilitated by administration of rocuronium 1.0 mg x kg(-1). No additional rocuronium was needed during operation. After operation, no twitch was noted on the ulnar nerve TOF monitor. The TOF returned to 4/4 at postoperative 11 hours and the patient was extubated uneventfully. When rocuronium is used to facilitate general endotracheal anesthesia in a patient for emergency cesarean delivery, it is important to recognize that magnesium may prolong neuromuscular block significantly.

Neurosteroids allopregnanolone sulfate and pregnanolone sulfate have diverse effect on the α subunit of the neuronal voltage-gated sodium channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8 expressed in xenopus oocytes.

BACKGROUND: The neurosteroids allopregnanolone and pregnanolone are potent positive modulators of γ-aminobutyric acid type A receptors. Antinociceptive effects of allopregnanolone have attracted much attention because recent reports have indicated the potential of allopregnanolone as a therapeutic agent for refractory pain. However, the analgesic mechanisms of allopregnanolone are still unclear. Voltage-gated sodium channels (Nav) are thought to play important roles in inflammatory and neuropathic pain, but there have been few investigations on the effects of allopregnanolone on sodium channels. METHODS: Using voltage-clamp techniques, the effects of allopregnanolone sulfate (APAS) and pregnanolone sulfate (PAS) on sodium current were examined in Xenopus oocytes expressing Nav1.2, Nav1.6, Nav1.7, and Nav1.8 α subunits. RESULTS: APAS suppressed sodium currents of Nav1.2, Nav1.6, and Nav1.7 at a holding potential causing half-maximal current in a concentration-dependent manner, whereas it markedly enhanced sodium current of Nav1.8 at a holding potential causing maximal current. Half-maximal inhibitory concentration values for Nav1.2, Nav1.6, and Nav1.7 were 12 ± 4 (n = 6), 41 ± 2 (n = 7), and 131 ± 15 (n = 5) µmol/l (mean ± SEM), respectively. The effects of PAS were lower than those of APAS. From gating analysis, two compounds increased inactivation of all α subunits, while they showed different actions on activation of each α subunit. Moreover, two compounds showed a use-dependent block on Nav1.2, Nav1.6, and Nav1.7. CONCLUSION: APAS and PAS have diverse effects on sodium currents in oocytes expressing four α subunits. APAS inhibited the sodium currents of Nav1.2 most strongly.

Thrombomodulin improved liver injury, coagulopathy, and mortality in an experimental heatstroke model in mice.

BACKGROUND: Heatstroke is a life-threatening illness and causes high mortality due to multiple organ injuries. Thrombomodulin (TM) is an endothelial anticoagulant cofactor that plays an important role in the regulation of intravascular coagulation. In this study, we investigated the effect of TM on the inflammatory process, liver function, coagulation status, and mortality in experimental heatstroke. METHODS: Male C3H/HeN (8-10 weeks) mice were randomly assigned to the TM-treated group (TG-Pre) or nontreated heatstroke group (HS). In group TG-Pre, mice were treated with recombinant soluble TM (1 mg/kg, intraperitoneally) before heat exposure. In some experiments, recombinant soluble TM was administrated during heat exposure (TG-Delay). Heatstroke was induced by exposure to ambient temperature of 38°C for 4 hours. After heat exposure, the levels of tumor necrosis factor-α, interleukin-6, and plasma high-mobility group box 1 (HMGB1), liver function, plasma aspartate aminotransferase and alanine aminotransferase concentrations, and immunohistochemical and histopathological characteristics of the livers were determined. The coagulation status, plasma protein C levels, and thrombin-antithrombin complex levels were also measured. RESULTS: In group HS, plasma cytokines and HMGB1 concentrations increased after heat exposure. Plasma aspartate aminotransferase and alanine aminotransferase concentrations increased after heat exposure. In group HS livers, strong and extensive immunostaining for HMGB1 was observed. In addition, there was extensive hepatocellular necrosis and collapse of nuclei observed. In group HS, plasma protein C levels were suppressed and plasma thrombin-antithrombin complex levels increased. In group TG-Pre, plasma cytokines and HMGB1 concentrations were suppressed after heat exposure compared with group HS. Liver injury, coagulopathy, and mortality also improved in group TG-Pre. Furthermore, recombinant soluble TM treatment decreased mortality even with delayed treatment. CONCLUSIONS: This study demonstrated that recombinant soluble TM suppressed plasma cytokines and HMGB1 concentrations after heat exposure. Recombinant soluble TM also improved liver injury and coagulopathy. Recombinant soluble TM treatment improved mortality even with delayed treatment. Recombinant soluble TM may be a beneficial treatment for heatstroke patients.

The endocannabinoid anandamide inhibits voltage-gated sodium channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8 in Xenopus oocytes.

BACKGROUND: Anandamide is an endocannabinoid that regulates multiple physiological functions by pharmacological actions, in a manner similar to marijuana. Recently, much attention has been paid to the analgesic effect of endocannabinoids in terms of identifying new pharmacotherapies for refractory pain management, but the mechanisms of the analgesic effects of anandamide are still obscure. Voltage-gated sodium channels are believed to play important roles in inflammatory and neuropathic pain. We investigated the effects of anandamide on 4 neuronal sodium channel α subunits, Nav1.2, Nav1.6, Nav1.7, and Nav1.8, to explore the mechanisms underlying the antinociceptive effects of anandamide. METHODS: We studied the effects of anandamide on Nav1.2, Nav1.6, Nav1.7, and Nav1.8 α subunits with ß1 subunits by using whole-cell, 2-electrode, voltage-clamp techniques in Xenopus oocytes. RESULTS: Anandamide inhibited sodium currents of all subunits at a holding potential causing half-maximal current (V1/2) in a concentration-dependent manner. The half-maximal inhibitory concentration values for Nav1.2, Nav1.6, Nav1.7, and Nav1.8 were 17, 12, 27, and 40 µmol/L, respectively, indicating an inhibitory effect on Nav1.6, which showed the highest potency. Anandamide raised the depolarizing shift of the activation curve as well as the hyperpolarizing shift of the inactivation curve in all α subunits, suggesting that sodium current inhibition was due to decreased activation and increased inactivation. Moreover, anandamide showed a use-dependent block in Nav1.2, Nav1.6, and Nav1.7 but not Nav1.8. CONCLUSION: Anandamide inhibited the function of α subunits in neuronal sodium channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8. These results help clarify the mechanisms of the analgesic effects of anandamide.

Comparison of nifekalant and amiodarone for resuscitation of out-of-hospital cardiopulmonary arrest resulting from shock-resistant ventricular fibrillation.

PURPOSE: Nifekalant is a pure potassium channel blocker that has been used to treat ventricular tachyarrhythmias since 1999 in Japan. Intravenous amiodarone was approved later than nifekalant in Japan, and it is still unclear which of the two agents is superior. The aim of this study was to compare the efficacy of nifekalant and amiodarone for resuscitation of out-of-hospital cardiopulmonary arrest caused by shock-resistant ventricular fibrillation. METHODS: From December 2005 to January 2011, ambulance services transported 283 out-of-hospital cardiopulmonary arrest patients to our hospital. Of these, 25 patients were treated with nifekalant or amiodarone in response to ventricular fibrillation that was resistant to two or more shocks. We undertook a retrospective analysis of these 25 patients. RESULTS: We enrolled 20 men and 5 women with a mean age (± standard deviation) of 61.1 ± 16.4 years. All 25 patients were treated with tracheal intubation and intravenous epinephrine. Fourteen patients received nifekalant and 11 patients received amiodarone. The rates of return of spontaneous circulation (ROSC) (nifekalant, 5/14, versus amiodarone, 4/11; P = 0.97) and survival to discharge (nifekalant, 4/14, versus amiodarone, 2/11; P = 0.89) were not significantly different between the two groups. The time from nifekalant or amiodarone administration to ROSC was 6.0 ± 6.6 and 20.3 ± 10.0 min, respectively, which was significantly different (P < 0.05). CONCLUSION: In this small sample size study, nifekalant, compared with amiodarone, is equally effective for ROSC and survival to discharge after shock-resistant ventricular fibrillation and can achieve ROSC more quickly. Further prospective studies are needed to confirm our results.

Chlorogenic acid administered intrathecally alleviates mechanical and cold hyperalgesia in a rat neuropathic pain model.

Chlorogenic acid (CGA), one of the most abundant dietary polyphenols, is known to have various physiological properties. Although CGA is reported to have an antinociceptive effect on acute and inflammatory pain, little is known about its effect on neuropathic pain or its action site. The aim of the present study was to determine whether intrathecally administered CGA can ameliorate hyperalgesia in a neuropathic pain model. Chronic constriction injury to the sciatic nerve was induced in male Sprague-Dawley rats. CGA (0.5, 1, or 2mg) was administered intrathecally to examine the effects on mechanical, thermal, and cold hyperalgesia using the electronic von Frey test, plantar test, and cold plate test, respectively. A rotarod test was also performed to assess motor function. To identify the neurotransmitter pathway involved in the spinal action of CGA, the present study examined the effect of intrathecal pretreatment with several antagonists of spinal pain processing receptors on the action of CGA in the electronic von Frey test and cold plate test. Spinally applied CGA dose-dependently alleviated mechanical and cold hyperalgesia. Conversely, CGA had no effect on thermal hyperalgesia. At the highest dose, CGA affected motor performance. The antihyperalgesic action of CGA was partially reversed by bicuculline, an γ-aminobutyric acidA (GABAA) receptor antagonist, at a dose that did not affect baseline behavioral responses. These findings suggest that CGA ameliorates mechanical and cold hyperalgesia partly by activating GABAergic transmission in the spinal cord, and that CGA may be useful for novel treatments for neuropathic pain.