The Japanese Epidemiologic Study for Perioperative Anaphylaxis, a prospective nationwide study: clinical signs, severity, and therapeutic agents.

BACKGROUND: Diagnosis of perioperative anaphylaxis is difficult because of its non-specific and variable signs and symptoms. Therapeutic agents used to treat anaphylaxis and anaesthesiologist responses also vary depending on the case, which might affect outcomes; however, only a few studies have focused on these factors. METHODS: This prospective study of perioperative anaphylaxis, a part of the Japanese Epidemiologic Study for Perioperative Anaphylaxis, investigated the clinical signs, its severity, therapeutic drugs, epinephrine administration, and anaesthesiologist responses in cases of perioperative anaphylaxis to assess trends and variability. Shock index was used to assess severity of cardiovascular collapse. RESULTS: In 43 patients analysed in this study, cardiovascular signs (88.4%) were the most frequent, followed by skin (81.4%) and respiratory signs (60.5%). The presence of signs increased during the clinical course. The median time from the first signs to diagnosis of anaphylaxis was 10 (5.0-17.8) min. The rates of epinephrine use were 30.2% (unused), 48.8% (i.v.), and 20.9% (i.m.). The median time from diagnosis of anaphylaxis to epinephrine administration was 7 (inter-quartile range: 1.5-8.0) min. Antihistamines and corticosteroids were each used in 69.8% of cases. The worst shock index was higher in patients who received i.v. epinephrine (2.77 [0.90] mean [standard deviation]) than in both no epinephrine use cases (1.35 [0.41]) and i.m. epinephrine cases (1.89 [0.77] (P<0.001]). CONCLUSIONS: The clinical signs and treatments of perioperative anaphylaxis are variable, and the choice regarding epinephrine administration is based on symptom severity. CLINICAL TRIAL REGISTRATION: UMIN000035350.

Subanesthetic Dose of Propofol Activates the Reward System in Rats.

BACKGROUND: Propofol has addictive properties, even with a single administration, and facilitates dopamine secretion in the nucleus accumbens (NAc). Activation of the dopaminergic circuits of the midbrain reward system, including the ventral tegmental area (VTA) and NAc, plays a crucial role in addiction. However, the effects of propofol on synaptic transmission and biochemical changes in the VTA-NAc circuit remain unclear. METHODS: We investigated the effects of subanesthetic doses of propofol on rat VTA neurons and excitatory synaptic transmission in the NAc using slice patch-clamp experiments. Using immunohistochemistry and western blot analyses, we evaluated the effects of intraperitoneal propofol administration on the expression of addiction-associated transcription factor ΔFosB (truncated form of the FBJ murine osteosarcoma viral oncogene homolog B protein) in the NAcs in 5-week-old rats. RESULTS: In the current-clamp mode, a subanesthetic dose (0.5-5 µmol/L) of propofol increased the action potential frequency in about half the VTA neurons (excited neurons: control: 9.4 ± 3.0 Hz, propofol 0.5 µmol/L: 21.5 ± 6.0 Hz, propofol 5 µmol/L: 14.6 ± 5.3 Hz, wash: 2.0 ± 0.7 Hz, n = 14/27 cells; unchanged/suppressed neurons: control: 1.68 ± 0.94 Hz, propofol 0.5 µmol/L: 1.0 ± 0.67 Hz, propofol 5 µmol/L: 0.89 ± 0.87 Hz, wash: 0.16 ± 0.11 Hz, n = 13/27 cells). In the voltage-clamp mode, about half the VTA principal neurons showed inward currents with 5 µmol/L of propofol (inward current neurons: control: -20.5 ± 10.0 pA, propofol 0.5 µmol/L: -62.6 ± 14.4 pA, propofol 5 µmol/L: -85.2 ± 18.3 pA, propofol 50 µmol/L: -17.1 ± 39.2 pA, washout: +30.5 ± 33.9 pA, n = 6/11 cells; outward current neurons: control: -33.9 ± 14.6 pA, propofol 0.5 µmol/L: -29.5 ± 16.0 pA, propofol 5 µmol/L: -0.5 ± 20.9 pA, propofol 50 µmol/L: +38.9 ± 18.5 pA, washout: +40.8 ± 32.1 pA, n = 5/11 cells). Moreover, 0.5 µmol/L propofol increased the amplitudes of evoked excitatory synaptic currents in the NAc, whereas >5 µmol/L propofol decreased them (control: 100.0 ± 2.0%, propofol 0.5 µmol/L: 118.4 ± 4.3%, propofol 5 µmol/L: 98.3 ± 3.3%, wash [within 10 min]: 70.7 ± 3.3%, wash [30 minutes later]: 89.9 ± 2.5%, n = 13 cells, P < .001, Dunnett's test comparing control and propofol 0.5 µmol/L). Intraperitoneally administered subanesthetic dose of propofol increased ΔFosB expression in the NAc, but not in VTA, 2 and 24 hours after administration, compared with the Intralipid control group (propofol 2 hours: 0.94 ± 0.15, 24 hours: 0.68 ± 0.07; Intralipid 2 hours: 0.40 ± 0.03, 24 hours: 0.37 ± 0.06, P = .0002 for drug in the 2-way analysis of variance). CONCLUSIONS: Even a single administration of a subanesthetic dose of propofol may cause rewarding change in the central nervous system. Thus, there is a potential propofol rewarding effect among patients receiving anesthesia or sedation with propofol, as well as among health care providers exposed to propofol.

Epidural Administration of Ropivacaine Reduces the Amplitude of Transcranial Electrical Motor-Evoked Potentials: A Double-Blinded, Randomized, Controlled Trial.

BACKGROUND: An epidurally administered local anesthetic acts primarily on the epidural nerve roots and can act directly on the spinal cord through the dural sleeve. We hypothesized that epidurally administered ropivacaine would reduce the amplitude of transcranial electrical motor-evoked potentials by blocking nerve conduction in the spinal cord. Therefore, we conducted a double-blind, randomized, controlled trial. METHODS: Thirty adult patients who underwent lung surgery were randomly allocated to 1 of 3 groups, based on the ropivacaine concentration: the 0.2% group, the 0.375% group, and the 0.75% group. The attending anesthesiologists, neurophysiologists, and patients were blinded to the allocation. The epidural catheter was inserted at the T5-6 or T6-7 interspace by a paramedian approach, using the loss of resistance technique with normal saline. General anesthesia was induced and maintained using propofol and remifentanil. Transcranial electrical motor-evoked potentials were elicited by a train of 5 pulses with an interstimulus interval of 2 milliseconds by using a constant-voltage stimulator and were recorded from the tibialis anterior muscle. Somatosensory-evoked potentials (SSEPs) were evoked by electrical tibial nerve stimulation at the popliteal fossa. After measuring the baseline values of these evoked potentials, 10 mL of epidural ropivacaine was administered at the 0.2%, 0.375%, or 0.75% concentration. The baseline amplitudes and latencies recorded before administering ropivacaine were defined as 100%. Our primary end point was the relative amplitude of the motor-evoked potentials at 60 minutes after the epidural administration of ropivacaine. We analyzed the amplitudes and latencies of these evoked potentials by using the Kruskal-Wallis test and used the Dunn multiple comparison test as the post hoc test for statistical analysis. RESULTS: The data are expressed as the median (interquartile range). Sixty minutes after epidurally administering ropivacaine, the motor-evoked potential amplitude was lower in the 0.75% group (7% [3%-18%], between-group difference P < .001) and in the 0.375% group (52% [43%-59%]) compared to that in the 0.2% group (96% [89%-105%]). The latency of SSEP was longer in the 0.75% group compared to that in the 0.2% group, but the amplitude was unaffected. CONCLUSIONS: Epidurally administered high-dose ropivacaine lowered the amplitude of motor-evoked potentials and prolonged the onset latencies of motor-evoked potentials and SSEPs compared to those in the low-dose group. High-dose ropivacaine can act on the motor pathway through the dura mater.

Low-dose droperidol suppresses transcranial electrical motor-evoked potential amplitude: a retrospective study.

Low-dose droperidol has been widely used as an antiemetic during and after surgery. Although high-dose droperidol affects motor-evoked potential, the effects of low-dose droperidol on motor-evoked potential amplitude are unclear. The aim of this study was to investigate whether low-dose droperidol affects motor-evoked potential amplitude. We retrospectively reviewed the data of patients who underwent spine surgery under general anesthesia with motor-evoked potential monitoring from February 2016 to 2017. The outcome was the motor-evoked potential amplitude of the bilateral abductor pollicis brevis muscle, tibialis anterior muscle, and abductor hallucis muscle within 1 and 1-2 h after droperidol administration, compared with the baseline motor-evoked potential value. Thirty-four patients were analyzed. The median dose of droperidol was 21 µg/kg. The motor-evoked potential amplitudes of all muscles were significantly reduced after droperidol administration and recovered to baseline values within 2 h. The reduction of all motor-evoked potential amplitudes after droperidol administration was 37-45% of baseline values. There were no significant differences in other drugs administered. There were no serious adverse effects of droperidol administration. Motor-evoked potential amplitude was suppressed by low-dose droperidol. During intraoperative motor-evoked potential monitoring in spine surgery, anesthesiologists should pay careful attention to the timing of administration of droperidol, even at low doses. Based on the results of this study, we are conducting a randomized controlled trial.

Propofol reduces the amplitude of transcranial electrical motor-evoked potential without affecting spinal motor neurons: a prospective, single-arm, interventional study.

PURPOSE: Propofol inhibits the amplitudes of transcranial electrical motor-evoked potentials (TCE-MEP) in a dose-dependent manner. However, the mechanisms of this effect remain unknown. Hence, we investigated the spinal mechanisms of the inhibitory effect of propofol on TCE-MEP amplitudes by evaluating evoked electromyograms (H-reflex and F-wave) under general anesthesia. METHODS: We conducted a prospective, single-arm, interventional study including 15 patients scheduled for spine surgery under general anesthesia. Evoked electromyograms of the soleus muscle and TCE-MEPs were measured at three propofol concentrations using target-controlled infusion (TCI: 2.0, 3.0, and 4.0 µg/mL). The primary outcome measure was the left H-reflex amplitude during TCI of 4.0- compared to 2.0-µg/mL propofol administration. RESULTS: The median [interquartile range] amplitudes of the left H-reflex were 4.71 [3.42-6.60] and 5.6 [4.17-7.46] in the 4.0- and 2.0-µg/mL TCI groups (p = 0.4, Friedman test), respectively. There were no significant differences in the amplitudes of the right H-reflex and the bilateral F-wave among these groups. However, the TCE-MEP amplitudes significantly decreased with increased propofol concentrations (p < 0.001, Friedman test). CONCLUSION: Propofol did not affect the amplitudes of the H-reflex and the F-wave, whereas TCE-MEP amplitudes were reduced at higher propofol concentrations. These results suggested that propofol can suppress the TCE-MEP amplitude by inhibiting the supraspinal motor pathways more strongly than the excitability of the motor neurons in the spinal cord.

Acute spatial spread of NO-mediated potentiation during hindpaw ischaemia in mice.

KEY POINTS: Neuropathic pain spreads spatially beyond the injured sites, and the mechanism underlying the spread has been attributed to inflammation occurring in the spinal cord. However, the spatial spread of spinal/cortical potentiation induced by conduction block of the peripheral nerves can be observed prior to inflammation. In the present study, we found that spreading potentiation and hypersensitivity acutely induced by unilateral hindpaw ischaemia are nitric oxide (NO)-dependent and that NO is produced by ischaemia and quickly diffuses within the spinal cord. We also found that NO production induced by ischaemia is not observed in the presence of an antagonist for group II metabotropic glutamate receptors (mGluRs) and that neuronal NO synthase-positive dorsal horn neurons express group II mGluRs. These results suggest strongly that NO-mediated spreading potentiation in the spinal cord is one of the trigger mechanisms for neuropathic pain. ABSTRACT: Cortical/spinal responses to hindpaw stimulation are bilaterally potentiated by unilateral hindpaw ischaemia in mice. We tested the hypothesis that hindpaw ischaemia produces nitric oxide (NO), which diffuses in the spinal cord to induce spatially spreading potentiation. Using flavoprotein fluorescence imaging, we confirmed that the spreading potentiation in hindpaw responses was induced during ischaemia in the non-stimulated hindpaw. This spreading potentiation was blocked by spinal application of l-NAME, an inhibitor of NO synthase (NOS). Furthermore, no spreading potentiation was observed in neural NOS (nNOS) knockout mice. Spinal application of an NO donor was enough to induce cortical potentiation and mechanical hypersensitivity. The spatial distribution of NO during unilateral hindpaw ischaemia was visualized using 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM). An increase in fluorescence derived from the complex of DAF-FM with NO was observed on the ischaemic side of the spinal cord. A similar but smaller increase was also observed on the contralateral side. Somatosensory potentiation after hindpaw ischaemia is known to be inhibited by spinal application of LY354740, an agonist of group II metabotropic glutamate receptors (mGluRs). We confirmed that the spinal DAF-FM fluorescence increases during hindpaw ischaemia were not observed in the presence of LY354740. We also confirmed that approximately half of the nNOS-positive neurons in the superficial laminae of the dorsal horn expressed mGluR2 mRNA. These results suggest that disinhibition of mGluR2 produces NO which in turn induces a spreading potentiation in a wide area of the spinal cord. Such spreading, along with the consequent non-specific potentiation in the spinal cord, may trigger neuropathic pain.

A functional coupling between CRMP1 and Nav1.7 for retrograde propagation of Semaphorin3A signaling.

Semaphorin3A (Sema3A) is a secreted type of axon guidance molecule that regulates axon wiring through complexes of neuropilin-1 (NRP1) with PlexinA protein receptors. Sema3A regulates the dendritic branching through tetrodotoxin (TTX)-sensitive retrograde axonal transport of PlexA proteins and tropomyosin-related kinase A (TrkA) complex. We here demonstrate that Nav1.7 (encoded by SCN9A), a TTX-sensitive Na+ channel, by coupling with collapsin response mediator protein 1 (CRMP1), mediates the Sema3A-induced retrograde transport. In mouse dorsal root ganglion (DRG) neurons, Sema3A increased co-localization of PlexA4 and TrkA in the growth cones and axons. TTX treatment and RNAi knockdown of Nav1.7 sustained Sema3A-induced colocalized signals of PlexA4 and TrkA in growth cones and suppressed the subsequent localization of PlexA4 and TrkA in distal axons. A similar localization phenotype was observed in crmp1-/- DRG neurons. Sema3A induced colocalization of CRMP1 and Nav1.7 in the growth cones. The half maximal voltage was increased in crmp1-/- neurons when compared to that in wild type. In HEK293 cells, introduction of CRMP1 lowered the threshold of co-expressed exogenous Nav1.7. These results suggest that Nav1.7, by coupling with CRMP1, mediates the axonal retrograde signaling of Sema3A.

Neurosteroid dehydroepiandrosterone sulphate enhances pain transmission in rat spinal cord dorsal horn.

BACKGROUND: The neurosteroid dehydroepiandrosterone sulphate (DHEAS) activates the sigma-1 receptor, inhibits gamma-aminobutyric acid A (GABAA) and glycine receptors, and induces hyperalgesic effects. Although its effects have been studied in various tissues of the nervous system, its synaptic mechanisms in nociceptive pathways remain to be elucidated. METHODS: The threshold of mechanical hypersensitivity and spontaneous pain behaviour was assessed using the von Frey test in adult male Wistar rats after intrathecal administration of DHEAS. We also investigated the effects of DHEAS on synaptic transmission in the spinal dorsal horn using slice patch-clamp electrophysiology. RESULTS: Intrathecally administered DHEAS elicited dose-dependent mechanical hyperalgesia and spontaneous pain behaviours (withdrawal threshold: saline; 51.0 [20.1] g, 3 µg DHEAS; 14.0 [7.8] g, P<0.01, 10 µg DHEAS; 6.9 [5.2] g, 15 min after administration, P<0.001). DHEAS at 100 µM increased the frequency of miniature postsynaptic currents in the rat dorsal spinal horn; this increase was extracellular Ca2+-dependent but not sigma-1 and N-methyl-d-aspartate receptor-dependent. DHEAS suppressed the frequency of miniature inhibitory postsynaptic currents in a GABAA receptor- and sigma-1 receptor-dependent manner. CONCLUSIONS: These results suggest that DHEAS participates in the pathophysiology of nociceptive synaptic transmission in the spinal cord by potentiation of glutamate release and inhibition of the GABAA receptor.

Impact of pectoral nerve block on postoperative pain and quality of recovery in patients undergoing breast cancer surgery: A randomised controlled trial.

BACKGROUND: In recent years, thoracic wall nerve blocks, such as the pectoral nerve (PECS) block and the serratus plane block have become popular for peri-operative pain control in patients undergoing breast cancer surgery. The effect of PECS block on quality of recovery (QoR) after breast cancer surgery has not been evaluated. OBJECTIVES: To evaluate the ability of PECS block to decrease postoperative pain and anaesthesia and analgesia requirements and to improve postoperative QoR in patients undergoing breast cancer surgery. DESIGN: Randomised controlled study. SETTING: A tertiary hospital. PATIENTS: Sixty women undergoing breast cancer surgery between April 2014 and February 2015. INTERVENTIONS: The patients were randomised to receive a PECS block consisting of 30 ml of levobupivacaine 0.25% after induction of anaesthesia (PECS group) or a saline mock block (control group). The patients answered a 40-item QoR questionnaire (QoR-40) before and 1 day after breast cancer surgery. MAIN OUTCOME MEASURES: Numeric Rating Scale score for postoperative pain, requirement for intra-operative propofol and remifentanil, and QoR-40 score on postoperative day 1. RESULTS: PECS block combined with propofol-remifentanil anaesthesia significantly improved the median [interquartile range] pain score at 6 h postoperatively (PECS group 1 [0 to 2] vs. Control group 1 [0.25 to 2.75]; P = 0.018]. PECS block also reduced propofol mean (± SD) estimated target blood concentration to maintain bispectral index (BIS) between 40 and 50 (PECS group 2.65 (± 0.52) vs. Control group 3.08 (± 0.41) µg ml; P < 0.001) but not remifentanil consumption (PECS group 10.5 (± 4.28) vs. Control group 10.4 (± 4.68) µg kg h; P = 0.95). PECS block did not improve the QoR-40 score on postoperative day 1 (PECS group 182 [176 to 189] vs. Control group 174.5 [157.75 to 175]). CONCLUSION: In patients undergoing breast cancer surgery, PECS block combined with general anaesthesia reduced the requirement for propofol but not that for remifentanil, due to the inability of the PECS block to reach the internal mammary area. Further, PECS block improved postoperative pain but not the postoperative QoR-40 score due to the factors that cannot be measured by analgesia immediately after surgery, such as rebound pain. TRIAL REGISTRATION: This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000013435).

Acetaminophen Metabolite N-Acylphenolamine Induces Analgesia via Transient Receptor Potential Vanilloid 1 Receptors Expressed on the Primary Afferent Terminals of C-fibers in the Spinal Dorsal Horn.

BACKGROUND: The widely used analgesic acetaminophen is metabolized to N-acylphenolamine, which induces analgesia by acting directly on transient receptor potential vanilloid 1 or cannabinoid 1 receptors in the brain. Although these receptors are also abundant in the spinal cord, no previous studies have reported analgesic effects of acetaminophen or N-acylphenolamine mediated by the spinal cord dorsal horn. We hypothesized that clinical doses of acetaminophen induce analgesia via these spinal mechanisms. METHODS: We assessed our hypothesis in a rat model using behavioral measures. We also used in vivo and in vitro whole cell patch-clamp recordings of dorsal horn neurons to assess excitatory synaptic transmission. RESULTS: Intravenous acetaminophen decreased peripheral pinch-induced excitatory responses in the dorsal horn (53.1 ± 20.7% of control; n = 10; P < 0.01), while direct application of acetaminophen to the dorsal horn did not reduce these responses. Direct application of N-acylphenolamine decreased the amplitudes of monosynaptic excitatory postsynaptic currents evoked by C-fiber stimulation (control, 462.5 ± 197.5 pA; N-acylphenolamine, 272.5 ± 134.5 pA; n = 10; P = 0.022) but not those evoked by stimulation of Aδ-fibers. These phenomena were mediated by transient receptor potential vanilloid 1 receptors, but not cannabinoid 1 receptors. The analgesic effects of acetaminophen and N-acylphenolamine were stronger in rats experiencing an inflammatory pain model compared to naïve rats. CONCLUSIONS: Our results suggest that the acetaminophen metabolite N-acylphenolamine induces analgesia directly via transient receptor potential vanilloid 1 receptors expressed on central terminals of C-fibers in the spinal dorsal horn and leads to conduction block, shunt currents, and desensitization of these fibers.

Motor Training Promotes Both Synaptic and Intrinsic Plasticity of Layer II/III Pyramidal Neurons in the Primary Motor Cortex.

Motor skill training induces structural plasticity at dendritic spines in the primary motor cortex (M1). To further analyze both synaptic and intrinsic plasticity in the layer II/III area of M1, we subjected rats to a rotor rod test and then prepared acute brain slices. Motor skill consistently improved within 2 days of training. Voltage clamp analysis showed significantly higher α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-d-aspartate (AMPA/NMDA) ratios and miniature EPSC amplitudes in 1-day trained rats compared with untrained rats, suggesting increased postsynaptic AMPA receptors in the early phase of motor learning. Compared with untrained controls, 2-days trained rats showed significantly higher miniature EPSC amplitude and frequency. Paired-pulse analysis further demonstrated lower rates in 2-days trained rats, suggesting increased presynaptic glutamate release during the late phase of learning. One-day trained rats showed decreased miniature IPSC frequency and increased paired-pulse analysis of evoked IPSC, suggesting a transient decrease in presynaptic γ-aminobutyric acid (GABA) release. Moreover, current clamp analysis revealed lower resting membrane potential, higher spike threshold, and deeper afterhyperpolarization in 1-day trained rats-while 2-days trained rats showed higher membrane potential, suggesting dynamic changes in intrinsic properties. Our present results indicate dynamic changes in glutamatergic, GABAergic, and intrinsic plasticity in M1 layer II/III neurons after the motor training.

Ultrasound-guided ilioinguinal/iliohypogastric block did not reduce emergence delirium after ambulatory pediatric inguinal hernia repair: a prospective randomized double-blind study.

PURPOSE: Emergence delirium (ED) is a common postoperative complication of ambulatory pediatric surgery done under general anesthesia with sevoflurane. However, perioperative analgesic techniques have been shown to reduce sevoflurane-induced ED. The primary objective of this investigation was to examine whether an ultrasound-guided ilioinguinal/iliohypogastric (II/IH) nerve block for ambulatory pediatric inguinal hernia repair could reduce the incidence of sevoflurane-induced ED. METHODS: The subjects of this prospective randomized double-blind study were 40 boys ranging in age from 1 to 6 years, who were scheduled to undergo ambulatory inguinal hernia repair. The patients were randomized to either receive or not to receive an ultrasound-guided II/IH nerve block (Group B and Group NB, respectively). General anesthesia was maintained with sevoflurane and nitrous oxide. The primary outcome assessed was ED, evaluated using the Pediatric Anesthesia Emergence Delirium (PAED) scale 30 min after emergence from general anesthesia. The secondary outcomes assessed were postoperative pain, evaluated using the Behavioral Observational Pain Scale (BOPS), and the amount of intra-operative sevoflurane given. RESULTS: The median PAED scale scores did not differ between Groups B and NB at 30 min (P = 0.41). BOPS scores also did not differ significantly between the groups, but the mean amount of intraoperative sevoflurane given was significantly lower in Group B than in Group NB (P < 0.01). CONCLUSIONS: Ultrasound-guided II/IH nerve block for ambulatory pediatric inguinal hernia repair did not reduce ED, but it did decrease the amount of intra-operative sevoflurane needed. CLINICAL TRIAL REGISTRATION: UMIN000008586.

Spinal cord stimulation modulates supraspinal centers of the descending antinociceptive system in rats with unilateral spinal nerve injury.

BACKGROUND: The descending antinociceptive system (DAS) is thought to play crucial roles in the antinociceptive effect of spinal cord stimulation (SCS), especially through its serotonergic pathway. The nucleus raphe magnus (NRM) in the rostral ventromedial medulla is a major source of serotonin [5-hydroxytryptamine (5-HT)] to the DAS, but the role of the dorsal raphe nucleus (DRN) in the ventral periaqueductal gray matter is still unclear. Moreover, the influence of the noradrenergic pathway is largely unknown. In this study, we evaluated the involvement of these serotonergic and noradrenergic pathways in SCS-induced antinociception by behavioral analysis of spinal nerve-ligated (SNL) rats. We also investigated immunohistochemical changes in the DRN and locus coeruleus (LC), regarded as the adrenergic center of the DAS, and expression changes of synthetic enzymes of 5-HT [tryptophan hydroxylase (TPH)] and norepinephrine [dopamine ß-hydroxylase (DßH)] in the spinal dorsal horn. RESULTS: Intrathecally administered methysergide, a 5-HT1- and 5-HT2-receptor antagonist, and idazoxan, an α2-adrenergic receptor antagonist, equally abolished the antinociceptive effect of SCS. The numbers of TPH-positive serotonergic and phosphorylated cyclic AMP response element binding protein (pCREB)-positive neurons and percentage of pCREB-positive serotonergic neurons in the DRN significantly increased after 3-h SCS. Further, the ipsilateral-to-contralateral immunoreactivity ratio of DßH increased in the LC of SNL rats and reached the level seen in naïve rats, even though the number of pCREB-positive neurons in the LC was unchanged by SNL and SCS. Moreover, 3-h SCS did not increase the expression levels of TPH and DßH in the spinal dorsal horn. CONCLUSIONS: The serotonergic and noradrenergic pathways of the DAS are involved in the antinociceptive effect of SCS, but activation of the DRN might primarily be responsible for this effect, and the LC may have a smaller contribution. SCS does not potentiate the synthetic enzymes of 5HT and norepinephrine in the neuropathic spinal cord.

Relationship between ventral lumbar disc protrusion and contrast medium leakage during sympathetic nerve block.

Ventral disc protrusions have been neglected because they are asymptomatic. Lumbar sympathetic nerve block (LSNB) is one of the clinical choices for refractory low back pain treatment. Leakage of the contrast medium may occur and lead to complications, especially when using a neurolytic agent. In this study, we retrospectively reviewed the magnetic resonance images (MRIs) of 52 consecutive patients with refractory low back pain due to lumbar spinal canal stenosis who underwent LSNB, and graded ventral disc protrusion at the L1/2 to L5/S1 vertebral discs on a three-point scale (grade 0 = no protrusion, grade 1 = protrusion without migration, grade 2 = protrusion with migration). We also determined if there was leakage of contrast medium in LSNB. Ventral disc protrusion was observed in all patients, and 75 % (39/52) had grade 2 protrusion in the L1/2-L3/4 vertebral discs. Moreover, the incidence of contrast medium leakage was significantly higher at the vertebrae that had grade 2 protrusion than at those with less protrusion. We revealed a higher incidence of ventral disc protrusion of the lumbar vertebrae than previously reported, and that the incidence of leakage in LSNB increased when ventral disc protrusion was present. To avoid complications, attention should be paid to ventral disc protrusions before performing LSNB.

Role of nerve growth factor-tyrosine kinase receptor A signaling in paclitaxel-induced peripheral neuropathy in rats.

The mechanisms underlying paclitaxel-induced peripheral neuropathy remain unknown. Nerve growth factor (NGF) is a representative neurotrophic factor that maintains neuronal function, promotes survival, and mediates neuropathic pain. We investigated expression levels of NGF and its receptors in the dorsal root ganglia (DRG) and spinal dorsal horn (DH) following paclitaxel treatment. Intraperitoneal (I.P.) administration of paclitaxel induced significant mechanical hypersensitivity and cold allodynia in rats, significantly increased the expression of NGF and its receptor tyrosine kinase receptor A (trkA) in the DRG, and increased NGF expression in the DH. In contrast, paclitaxel treatment did not alter the mRNA levels of NGF or its receptors in the DRG, DH, sciatic nerve, or hindpaw skin. Moreover, expression of NEDD4-2, a negative regulator of trkA, was significantly increased in the DRG of paclitaxel-treated rats. Intrathecal (I.T.) administration of the tyrosine kinase receptor inhibitor k252a significantly alleviated mechanical hypersensitivity in paclitaxel-treated rats. Our results suggest that NGF-trkA signaling is involved in mechanical allodynia in paclitaxel-induced neuropathy.

Isoflurane impairs learning and hippocampal long-term potentiation via the saturation of synaptic plasticity.

BACKGROUND: General anesthesia induces long-lasting cognitive and learning deficits. However, the underlying mechanism remains unknown. The GluA1 subunit of AMPAR is a key molecule for learning and synaptic plasticity, which requires trafficking of GluA1-containing AMPARs into the synapse. METHODS: Adult male rats were exposed to 1.8% isoflurane for 2 h and subjected to an inhibitory avoidance task, which is a hippocampus-dependent contextual fear learning paradigm (n = 16 to 39). The in vitro extracellular field potential of hippocampal synapses between the Schaffer collateral and the CA1 was evaluated using a multielectrode recorder (n = 6 per group). GluA1 expression in the synaptoneurosome was assessed using Western blotting (n = 5 to 8). The ubiquitination level of GluA1 was evaluated using immunoprecipitation and Western blotting (n = 7 per group). RESULTS: Seven days after exposure to 1.8% isoflurane for 2 h (Iso1.8), the inhibitory avoidance learning (control vs. Iso1.8; 294 ± 34 vs. 138 ± 28, the mean ± SEM [%]; P = 0.002) and long-term potentiation (125.7 ± 6.1 vs. 105.7 ± 3.3; P < 0.001) were impaired. Iso1.8 also temporarily increased GluA1 in the synaptoneurosomes (100 ± 9.7 vs. 138.9 ± 8.9; P = 0.012) and reduced the GluA1 ubiquitination, a main degradation pathway of GluA1 (100 ± 8.7 vs. 71.1 ± 6.1; P = 0.014). CONCLUSIONS: Isoflurane impairs hippocampal learning and modulates synaptic plasticity in the postanesthetic period. Increased GluA1 may reduce synaptic capacity for additional GluA1-containing AMPARs trafficking.

Anesthesia experience in an adult Silver-Russell syndrome: a case report.

BACKGROUND: There are no reports of anesthesia use in adult patients with Silver-Russell syndrome (SRS). Here, we report our experience with anesthesia in an adult patient with SRS complicated by chronic respiratory failure. CASE PRESENTATION: A 33-year-old woman was clinically diagnosed with SRS. She had severe chronic respiratory failure, complicated by superior mesenteric artery syndrome. Percutaneous gastrostomy was scheduled for nutritional management under epidural anesthesia; however, soon after esophagogastroduodenoscopy was started, she lost consciousness and spontaneous respiration. The patient was urgently intubated and converted to general anesthesia. The end-tidal carbon dioxide tension was > 90 mmHg at intubation. CONCLUSIONS: Adult SRS patients with chronic respiratory failure have a risk of CO2 narcosis. SRS also requires preparation for difficult airway management during the perioperative period.

Effect of Remimazolam on Transcranial Electrical Motor-evoked Potential in Spine Surgery: A Prospective, Preliminary, Dose-escalation Study.

BACKGROUND: Some anesthetic drugs reduce the amplitude of transcranial electrical motor-evoked potentials (MEPs). Remimazolam, a new benzodiazepine, has been suggested to have little effect on MEP amplitude. This prospective, preliminary, dose-escalation study aimed to assess whether remimazolam is associated with lower MEP amplitude in a dose-dependent manner. METHODS: Ten adult patients scheduled for posterior spinal fusion were included in this study. General anesthesia was induced with a continuous infusion of remifentanil and remimazolam. After the patient lost consciousness, the infusion rate of remimazolam was set to 1 mg/kg/h, and the patient underwent tracheal intubation. Baseline MEPs were recorded under 1 mg/kg/h of remimazolam in a prone position. Thereafter, the infusion rate of remimazolam was increased to 2 mg/kg/h, with a bolus of 0.1 mg/kg. Ten minutes after the increment, the evoked potentials were then recorded again. The primary endpoint was the MEP amplitude recorded in the left gastrocnemius muscle at 2 time points. RESULTS: There was no difference in MEP amplitude recorded from the left gastrocnemius muscle before and after increasing remimazolam (median [interquartile range]: 0.93 [0.65 to 1.25] mV and 0.70 [0.43 to 1.26] mV, respectively; P=0.08). The average time from the cessation of remimazolam administration to neurological examination after surgery was 4 minutes using flumazenil. CONCLUSIONS: This preliminary study suggests that increasing remimazolam from 1 to 2 mg/kg/h might have an insignificant effect on transcranial electric MEPs.