Local anesthetic lidocaine induces growth suppression of HeLa cells by decreasing and changing the cellular localization of the proliferation marker Ki-67.

Although surgery is a basic therapy for cancer, it causes inflammation and immunosuppression, often resulting in recurrence and metastasis. Previous studies have suggested that anesthetic management influences the prognosis of cancer surgery patients. Administration of local anesthetics, such as lidocaine, for pain control reportedly improves their clinical outcomes; however, the precise underlying mechanism has not been fully elucidated. The growth of human embryonic kidney (HEK) 293T and cervical cancer HeLa cells was inhibited by lidocaine treatment and these cell lines showed different sensitivities for lidocaine. Ki-67 is a significant prognostic marker of cancer because it is expressed in the nucleus of actively proliferating cells. In lidocaine-treated HeLa cells, Ki-67 was detected not only in the nucleus but also in the cytoplasm. In addition, lidocaine-induced cytoplasmic Ki-67 partly colocalized with the increased ER chaperone, glucose-regulated protein 78, which is crucial for protein folding and maintenance of cellular homeostasis. Furthermore, lidocaine decreased Ki-67 levels and increased the population of HeLa cells in the G0/G1 phase. These results indicate that lidocaine plays a significant role in growth suppression by regulating the expression and distribution of Ki-67.

Impact of GAD65 and/or GAD67 deficiency on perinatal development in rats.

GABA is a major neurotransmitter in the mammalian central nervous system. Glutamate decarboxylase (GAD) synthesizes GABA from glutamate, and two isoforms of GAD, GAD65, and GAD67, are separately encoded by the Gad2 and Gad1 genes, respectively. The phenotypes differ in severity between GAD single isoform-deficient mice and rats. For example, GAD67 deficiency causes cleft palate and/or omphalocele in mice but not in rats. In this study, to further investigate the functional roles of GAD65 and/or GAD67 and to determine the contribution of these isoforms to GABA synthesis during development, we generated various kinds of GAD isoform(s)-deficient rats and characterized their phenotypes. The age of death was different among Gad mutant rat genotypes. In particular, all Gad1-/- ; Gad2-/- rats died at postnatal day 0 and showed little alveolar space in their lungs, suggesting that the cause of their death was respiratory failure. All Gad1-/- ; Gad2-/- rats and 18% of Gad1-/- ; Gad2+/- rats showed cleft palate. In contrast, none of the Gad mutant rats including Gad1-/- ; Gad2-/- rats, showed omphalocele. These results suggest that both rat GAD65 and GAD67 are involved in palate formation, while neither isoform is critical for abdominal wall formation. The GABA content in Gad1-/- ; Gad2-/- rat forebrains and retinas at embryonic day 20 was extremely low, indicating that almost all GABA was synthesized from glutamate by GADs in the perinatal period. The present study shows that Gad mutant rats are a good model for further defining the role of GABA during development.

Reduction of Arterial Oxygen Saturation Among Rescuers During Cardiopulmonary Resuscitation in a Hypobaric Hypoxic Environment.

We experienced a case involving prolonged cardiopulmonary resuscitation (CPR) during cardiac arrest on Mt. Fuji (3776 m), demanding lengthy exertion by the rescuers performing CPR. Considering the effects of exertion on the rescuers, we examined their percutaneous arterial oxygen saturation during simulated CPR and compared the effects of compression-only and conventional CPR at 3700 m above sea level. The effects of CPR on the physical condition of rescuers were examined at the summit of Mt. Fuji: three rescue staff equipped with pulse-oximeters performed CPR with or without breaths using a CPR mannequin. At 3700 m, the rescuers' heart rate increased during CPR regardless of the presence or absence of rescue breathing. Percutaneous arterial oxygen saturation measured in such an environment was reduced only when CPR without rescue breathing was performed. Scores on the Borg scale, a subjective score of fatigue, after CPR in a 3700 m environment were 13 to 15 of 20 (somewhat hard to hard). Performing CPR at high altitude exerts a significant physical effect upon the condition of rescuers. Compression-only CPR at high altitude may cause a deterioration in rescuer oxygenation, whereas CPR with rescue breathing might ameliorate such deterioration.

Spinal Activation of Tropomyosin Receptor Kinase-B Recovers the Impaired Endogenous Analgesia in Neuropathic Pain Rats.

BACKGROUND: Although endogenous analgesia plays an important role in controlling pain states, chronic pain patients exhibit decreased endogenous analgesia compared to healthy individuals. In rats, noxious stimulus-induced analgesia (NSIA), which is an indicator of endogenous analgesia, diminished 6 weeks after spinal nerve ligation (SNL6W). A recent study in rats with deleted noradrenergic fibers demonstrated that the noradrenergic fibers were essential to NSIA. It has also been reported that brain-derived neurotrophic factor increased spinal noradrenergic fibers. Therefore, this study examined the effect of TrkB activation, which is the receptor for brain-derived neurotrophic factor, on impaired NSIA in SNL6W rats. In addition, we also examined the effect of endogenous analgesia on acute incisional pain. METHODS: After 5 daily intraperitoneal injections of 7,8-dihydroxyflavone (7,8-DHF, TrkB agonist, 5 mg/kg), NSIA was examined by measuring the withdrawal threshold increment in the left (contralateral to nerve ligation) hindpaw at 30 minutes after capsaicin injection (250 µg) in the forepaw. K252a (TrkB antagonist, 2 µg) was administrated intrathecally for 5 days. Idazoxan (α2 adrenoceptor antagonist, 30 µg), atropine (muscarinic antagonist, 30 µg), and propranolol (nonselective ß adrenoceptor antagonist, 30 µg) were administered intrathecally for 15 minutes before capsaicin injection. Microdialysis and immunohistochemistry were performed to examine the noradrenergic plasticity in the spinal dorsal horn. A hindpaw incision was performed on the left (contralateral to nerve ligation) hindpaw. Data were analyzed by 1-way analyses of variance or 2-way repeated-measures 1-way analysis of variance followed by a Student t test with Bonferroni correction. RESULTS: Five daily intraperitoneal injections of 7,8-DHF restored the attenuated NSIA in SNL6W rats (n = 7, P = .002; estimated treatment effect [95% CI]: 62.9 [27.0-98.7] g), with this effect blocked by 5 daily intrathecal coadministrations of K252a (n = 6, P < .001; -57.8 [-78.3 to -37.2] g). This effect was also inhibited by a single intrathecal administration of idazoxan (n = 8, P < .001; -61.6 [-92.4 to -30.9] g) and atropine (n = 8, P = .003; -52.6 [-73.3 to -31.9] g), but not by propranolol. Furthermore, 7,8-DHF increased the noradrenergic fiber in the spinal dorsal horn and the noradrenaline release in response to the capsaicin injection in the forepaw in SNL6W rats. In addition, repeated injections of 7,8-DHF prevented delayed recovery from incisional pain in SNL6W rats. CONCLUSIONS: Spinal activation of TrkB may recover the attenuated endogenous analgesia by improving the adrenergic plasticity, thereby leading to prevention of pain prolongation after surgery.

Assessment of the skin tissue structure using an ultrasonic diagnostic imaging device in patients undergoing open surgery.

BACKGROUND: Perioperative skin injury is a major issue; therefore, several preventative measures have been developed. However, no previous studies have visualized the effects of stromal edema caused by surgical invasion of skin tissue, and therefore, the details remain unknown. We used an ultrasonic diagnostic imaging device to clarify changes in the skin tissue structure of patients after open surgery. MATERIALS AND METHODS: Twenty subjects who underwent open hepatectomy were enrolled. We selected the lateral abdomen, upper arms, and lower legs as ultrasonic imaging measurement sites. We performed measurements on the day before surgery and on postoperative days 1, 3, and 5. We calculated the epidermal/dermal tissue thickness, subcutaneous tissue thickness, and skin tissue thickness. We performed a one-way analysis of variance with repeated measurements for each of the postoperatively measured values on the basis of the preoperative values. Significantly different variables were subjected to the Bonferroni method. We evaluated ultrasonic imaging findings and skin injury. RESULTS: Epidermal/dermal tissue thickness at all measurement sites exhibited sustained thickening on postoperative day 5 compared to that preoperatively. The lateral abdomen exhibited thickening of the subcutaneous tissue and skin tissue on postoperative day 1. In addition, increased echogenicity, increased opacity of the layer structure, and a cobblestone appearance occurred during the postoperative course. Postoperatively, 80% of subjects exhibited skin injury. CONCLUSION: We evaluated the effects of surgical invasion on skin tissue over time. Continual observation and protective skincare are necessary near the surgical wound, where significant invasiveness occurs. Prevention of skin injury due to skin tissue thickening requires further study.

Repeated Administration of Duloxetine Suppresses Neuropathic Pain by Accumulating Effects of Noradrenaline in the Spinal Cord.

BACKGROUND: Antidepressants are used to treat neuropathic pain and although the detailed mechanisms of their effects are unclear, the descending noradrenergic inhibitory system might play an important role. We tested our hypothesis that repeated administration of duloxetine suppresses neuropathic pain by restoring the descending noradrenergic inhibitory system in rats 6 weeks after spinal nerve ligation (SNL). METHODS: We subcutaneously injected SNL rats with duloxetine (10 mg kg day) daily for 3 consecutive days and assessed behavioral hypersensitivity and noxious stimulus-induced analgesia (NSIA) activated by subcutaneous injection of capsaicin. We also performed microdialysis studies of the spinal cord, noradrenaline measurements of homogenized lumbar spinal tissue, and immunohistochemistry of the locus coeruleus. RESULTS: Three daily injections of duloxetine attenuated the mechanical hyperalgesia induced by SNL (SNL treated with vehicle: 88 ± 9.4 g versus SNL treated with duloxetine: 148 ± 13 g, P < .001; estimated treatment effect of duloxetine [95% confidence interval {CI}], 65 [50.6-79.4]; n = 6/group, on day 4) and recovered the decreased NSIA (vehicle: 154 ± 10 g versus duloxetine: 213 ± 33 g, P < .001; 71.3 [57.4-85.2]; n = 6/group, 30 minutes after injection). The noradrenaline content in the dorsal spinal cord increased bilaterally (SNL treated with vehicle: 946.7 ± 203.6 pg/g versus SNL treated with duloxetine: 1593.5 ± 181.4 pg/g, P < .001; 646.79 pg/g [481.61-811.97] on the ipsilateral side; SNL treated with vehicle: 845.0 ± 164.7 pg/g versus SNL treated with vehicle: 1557.2 ± 237.4 pg/g, P < .001; 712.17 pg/g [449.31-975.02] on the contralateral side). Intrathecal injection (IT) of the α2-adrenoceptor antagonist idazoxan reversed both the antihyperalgesic effect (before IT: 133 ± 5.7 g versus 30 minutes after IT: 85.8 ± 6.5 g, P < .001, -47 [-39.1 to -54.8], n = 6/group, and NSIA; vehicle-IT: 219 ± 7.4 g versus idazoxan-IT: 153 ± 10 g, P < .001; -65.8 g [-25.2 to -77.4] n = 6/group, 30 minutes after forepaw injection of capsaicin). Duloxetine treatment did not alter the noradrenaline release in the spinal cord after capsaicin injection (P = .415), or the fraction of nuclei positive for phosphorylated cyclic adenosine monophosphate response element binding protein in the locus coeruleus (P = 1.00 duloxetine versus vehicle 120 minutes after forepaw injection of vehicle and P = 1.00 duloxetine versus vehicle 120 minutes after forepaw injection of capsaicin). CONCLUSIONS: These findings suggest that 3 daily injections of duloxetine suppressed hyperalgesia and recovered impaired NSIA in rats 6 weeks after nerve injury. Both effects of duloxetine were reversed by IT of an α2-adrenoceptor antagonist. These findings suggest the inhibitory effects of duloxetine against neuropathic pain depend on recovery of the noradrenergic descending inhibitory system, especially in the spinal cord.

Cardiorespiratory dynamics of rescuers during cardiopulmonary resuscitation in a hypoxic environment.

OBJECTIVE: We had previously experienced a case involving prolonged cardiopulmonary resuscitation (CPR) on Mt. Fuji (3776 m), demanding strenuous work by the rescuers. The objective of this study was to compare the effect of compression-only and conventional CPR on oxygen saturation of rescuers in a hypoxemic environment. METHODS: Changes in percutaneous arterial oxygen saturation (SpO2) and heart rate during CPR action were measured in a hypobaric chamber with barometric pressure adjusted to be equivalent to 3700 m above sea level (630-640 hPa). Thirty-three volunteers performed CPR with or without breaths using a CPR mannequin. RESULTS: In a 3700-m-equivalent environment, SpO2 was reduced only when CPR was performed without breaths (P < .05, one-way analysis of variance (ANOVA) post hoc Tukey test). Heart rate increased during CPR regardless of the presence or absence of breaths. Mean scores on the Borg scale, a subjective measure of fatigue, after CPR action in the 3700-m-equivalent environment were significantly higher (15 ±â€¯2) than scores after CPR performed at sea level (11 ±â€¯2, P < .01, paired t-test). No lethal dysrhythmia was found in subjects with a wearable electrode shirt. CONCLUSIONS: Prolonged CPR at high altitude exerts a significant physical effect upon the condition of rescuers. Compression-only CPR at high altitude may deteriorate rescuer oxygenation, whereas CPR with breaths might ameliorate such deterioration.

The history and progress of local anesthesia: multiple approaches to elongate the action.

Analgesia and temporary inhibition of motor activity without interfering with central nervous function have been the essential merits of local anesthesia. Local anesthetics originated from cocaine have played a major role in local analgesia. However, the relatively short duration of action of local anesthetics has been a concern in intra- and post-operative analgesia. From the early age of modern local anesthesia, physicians and medical scientists had been struggling to control the active duration of local anesthetics. Such approach includes: development of long-acting local anesthetics, with physical tourniquet techniques, co-administration of other medicines such as vaso-constrictive agents or analgesics, development of mechanical devices to continuously or intermittently administer local anesthetics, and utilization of pharmaceutical drug delivery systems. In this review, the historical sequence of studies that have been performed in an effort to elongate the action of local anesthetics is presented, referring to epoch-making medical and scientific studies.

Repeated Administration of Amitriptyline in Neuropathic Pain: Modulation of the Noradrenergic Descending Inhibitory System.

BACKGROUND: The tricyclic antidepressant amitriptyline, the serotonin and noradrenaline reuptake inhibitor duloxetine, and gabapentinoids are first-line drugs for treatment of neuropathic pain. The analgesic effect of these drugs relates to brainstem-spinal descending noradrenergic systems. However, amitriptyline utilizes a variety of mechanisms for analgesia in neuropathic pain, and it is unclear which mechanism is most important. In the present study, we investigated the role of descending noradrenergic systems in the analgesic effect of these drugs for treatment of neuropathic pain. We also examined whether amitriptyline modifies the descending noradrenergic systems. METHODS: Seven days after L5 spinal nerve ligation (SNL), rats received N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 50 mg/kg) to degenerate noradrenergic fibers. The rats then received 5 daily intraperitoneal injections of amitriptyline (10 mg/kg), duloxetine (10 mg/kg), pregabalin (10 mg/kg), or gabapentin (50 mg/kg) from 21 days after SNL surgery. Paw withdrawal thresholds were determined to assess the effect of the drugs on hyperalgesia after SNL. To determine whether 5 daily injections of amitriptyline activated noradrenergic neurons in the locus coeruleus (LC) and spinal cord with or without DSP-4 treatment, we performed immunohistochemistry using antibodies for c-Fos and dopamine beta-hydroxylase (DßH). RESULTS: Five daily injections of amitriptyline, duloxetine, pregabalin, and gabapentin exerted antihyperalgesic effects in SNL rats (P < .001; estimated treatment effect of amitriptyline [99% confidence interval]: 59.9 [35.1-84.7] g). The antihyperalgesic effects of duloxetine, pregabalin, and gabapentin were reversed by pretreatment with DSP-4 (P < .001, respectively). However, antihyperalgesia was still observed after treatment of amitriptyline in SNL rats with DSP-4 pretreatment (P < .001, 59.7 [30.0-89.3] g), and this analgesic effect was not reversed by the α2-adrenoceptor antagonist idazoxan (30 µg). Additionally, 5 daily injections of amitriptyline increased the ratio of c-Fos-immunoreactive (IR) cells in noradrenergic LC neurons in SNL rats with or without DSP-4 pretreatment (P < .001, respectively). Five daily injections of amitriptyline increased DßH-IR in the LC and the spinal dorsal horn of SNL rats (P < .001, respectively). With DSP-4 pretreatment, DßH-IR was dramatically decreased with or without 5 daily injections of amitriptyline (P < .001). CONCLUSIONS: Five daily injections of amitriptyline produced antihyperalgesic effects against neuropathic pain despite suppression of noradrenergic descending inhibitory systems. Amitriptyline activated LC neurons and increased noradrenergic fibers density in SNL rats. These results suggest that amitriptyline could still produce analgesia under pathological dysfunction of the descending noradrenergic system. Amitriptyline may enhance the analgesic effect of drugs for neuropathic pain that require normal descending noradrenergic inhibition to produce analgesia, such as serotonin and noradrenaline reuptake inhibitors and gabapentinoids.

Amitriptyline, but Not Pregabalin, Reverses the Attenuation of Noxious Stimulus-Induced Analgesia After Nerve Injury in Rats.

BACKGROUND: Noxious stimulus-induced analgesia (NSIA) is a type of conditioned pain modulation in rats that has been used to assess endogenous pain control systems. The descending noradrenergic system is involved in NSIA, and nerve injury induces plastic changes of descending noradrenergic neurons. Thus, we hypothesized that nerve injury would affect NSIA strength and that amitriptyline and pregabalin, which often are used for treating neuropathic pain, might further modulate NSIA through effects on the descending noradrenergic system. METHODS: We examined the change in NSIA over time after right L5 spinal nerve ligation (SNL) in rats by measuring the contralateral hind paw withdrawal threshold after left forepaw capsaicin injection. In addition, we examined NSIA after 5 daily intraperitoneal injection of amitriptyline or pregabalin. Microdialysis studies were performed to measure noradrenaline levels after left forepaw capsaicin injection in the left spinal dorsal horn in noninjured rats, SNL rats, and SNL rats that had received 5 daily intraperitoneal injections of amitriptyline or pregabalin. RESULTS: NSIA was dramatically attenuated 5 and 6 weeks after SNL (P < 0.001). The noradrenaline level in the lumbar spinal cord was significantly increased in noninjured rats receiving forepaw injection of capsaicin compared with vehicle injection (P < 0.001), but not in rats 6 weeks after SNL surgery. Five daily intraperitoneal injections of amitriptyline (10 mg/kg/d) or pregabalin (10 mg/kg/d) at 5 weeks after SNL gradually increased the ipsilateral hindpaw withdrawal threshold (P < 0.001). At 6 weeks after SNL, amitriptyline, but not pregabalin, reversed the attenuation of NSIA by SNL (P < 0.001) and increased the spinal noradrenaline level after forepaw injection of capsaicin (P = 0.005). CONCLUSIONS: These data suggest that endogenous analgesia in neuropathic pain states is strongly decreased from a certain time after nerve injury and that amitriptyline reverses the attenuation of endogenous analgesia through effects on the descending noradrenergic system.

Impaired Pain-evoked Analgesia after Nerve Injury in Rats Reflects Altered Glutamate Regulation in the Locus Coeruleus.

BACKGROUND: Patients with neuropathic pain show reduced endogenous analgesia induced by a conditioned noxious stimulus. Here, the authors tested whether peripheral nerve injury impairs descending noradrenergic inhibition from the locus coeruleus (LC) after L5-L6 spinal nerve ligation (SNL) in rats. METHODS: A subdermal injection of capsaicin was used to examine noxious stimulation-induced analgesia (NSIA), evoked LC glutamate and spinal noradrenaline release, and evoked LC neuronal activity in normal and SNL rats. The authors also examined the role of presynaptic metabotropic glutamate receptors or the astroglial glutamate transporter-1 (GLT-1). RESULTS: SNL increased basal extracellular glutamate concentration in the LC (170.1%; 95% CI, 44.7 to 295.5; n = 15) and basal spinal cord noradrenaline release (252.1%; 95% CI, 113.6 to 391.3; n = 15), which was associated with an increased tonic LC neuronal activity and a down-regulation of GLT-1 in the LC. SNL reduced NSIA (-77.6%; 95% CI, -116.4 to -38.8; n = 14) and capsaicin evoked release of glutamate in the LC (-36.2%; 95% CI, -49.3 to -23.2; n = 8) and noradrenaline in the spinal cord (-38.8%; 95% CI, -45.1 to -32.5; n = 8). Capsaicin-evoked LC neuronal activation was masked in SNL rats. Removing autoinhibition of glutamatergic terminals by metabotropic glutamate receptor blockade or increasing GLT-1 expression by histone deacetylase inhibition restored NSIA in SNL rats. SNL-induced impairment of NSIA was mimicked in normal rats by knockdown of GLT-1 in the LC. CONCLUSIONS: These results suggest that increased extracellular glutamate in the LC consequent to down-regulation of GLT-1 contributes to LC dysfunction and impaired pain-evoked endogenous analgesia after nerve injury.

Individual differences in acute pain-induced endogenous analgesia predict time to resolution of postoperative pain in the rat.

BACKGROUND: Chronic postsurgical pain, a significant public health problem, occurs in 10 to 50% of patients undergoing major surgery. Acute pain induces endogenous analgesia termed conditioned pain modulation (CPM), and the strength of CPM preoperatively predicts the likelihood of chronic postsurgical pain. The relation between CPM and recovery from surgery has not been examined in preclinical models. METHODS: CPM was assessed in individual rats and correlated with each animal's time course of recovery of hypersensitivity after partial spinal nerve ligation. The role of descending noradrenergic pathways in the spinal cord to mechanisms of CPM and recovery was tested using idazoxan to block noradrenergic receptors or antidopamine ß-hydroxylase-conjugated saporin to ablate these pathways. Behavioral hypersensitivity, static weight bearing, and spinal glial activation were measured after partial spinal nerve ligation. RESULTS: The strength of CPM varied over two-fold between individuals and was directly correlated with the slope of recovery from hypersensitivity after surgery (P < 0.0001; r = 0.660). CPM induced the release of norepinephrine in the spinal cord and was partially blocked by intrathecal idazoxan or dopamine ß-hydroxylase-saporin. Dopamine ß-hydroxylase-saporin also slowed recovery and enhanced spinal glial activation after partial spinal nerve ligation surgery. Ongoing activation of these pathways was critical to sustained recovery because intrathecal dopamine ß-hydroxylase-saporin given 7 weeks after recovery reinstituted hypersensitivity, while having no effect in animals without previous surgery. CONCLUSION: Collectively, these studies provide a clear back-translation from clinical observations of CPM and chronic postsurgical pain and suggest that the ability to engage ongoing descending endogenous noradrenergic signaling may be critical in determining time course of recovery from hypersensitivity after surgery.

Considerations for resuscitation at high altitude in elderly and untrained populations and rescuers.

With the development of transportation technologies, elderly people with chronic diseases are increasingly enjoying trekking and tours of nature resorts that include mountain highlands. Because of problems related to circulation, respiration, metabolism, and/or the musculoskeletal system in this population, the impact of high altitude on cardiopulmonary function is increased. Alpine accidents, therefore, tend to be more common in this population, and cases of cardiopulmonary arrest (CPA) at high altitudes seem to be increasing. However, relatively few studies have described cardiopulmonary resuscitation (CPR) at high altitudes. Although insufficient studies are available to standardize CPR guidelines at high altitude at this time, the aim of this review is to summarize previous studies relevant to physiologic changes after exposure to high-altitude environments and exercise, which may be a risk factor for CPA in elderly trekkers. In addition, we summarize our previous studies that described the effect of CPR procedures on cardiopulmonary function in untrained rescuers. The available data suggest that prolonged CPR at high altitudes requires strenuous work from rescuers and negatively affects their cardiopulmonary physics and subjectively measured fatigue. Alpine rescue teams should therefore be well prepared for their increased physical burden and difficult conditions. Elderly travelers should be made aware of their increased risk of CPA in alpine settings. The use of mechanical devices to assist CPR should be considered wherever possible.

Rat model of attention-deficit hyperactivity disorder exhibits delayed recovery from acute incisional pain due to impaired descending noradrenergic inhibition.

Chronic pain and attention-deficit hyperactivity disorder (ADHD) frequently coexist. However, the common pathology is still unclear. Attenuated noradrenergic endogenous analgesia can produce acute pain chronification, and dysfunction of noradrenergic systems in the nervous system is relevant to ADHD symptoms. Noxious stimuli-induced analgesia (NSIA) is measured to estimate noradrenergic endogenous analgesia in spontaneously hypertensive rats (SHR) as an ADHD model and control. Recovery of pain-related behaviors after paw incision was assessed. Contributions of noradrenergic systems were examined by in vivo microdialysis and immunohistochemistry. The SHR showed attenuated NSIA and needed a more extended period for recovery from acute pain. These results suggest ADHD patients exhibit acute pain chronification due to pre-existing attenuated noradrenergic endogenous analgesia. Immunohistochemistry suggests abnormal noradrenaline turnover and downregulation of the target receptor (alpha2a adrenoceptor). Standard ADHD treatment with atomoxetine restored NSIA and shortened the duration of hypersensitivity after the surgery in the SHR. NSIA protocol activated the locus coeruleus, the origin of spinal noradrenaline, of both strains, but only the control exhibited an increase in spinal noradrenaline. This result suggests dysfunction in the noradrenaline-releasing process and can be recognized as a novel mechanism of attenuation of noradrenergic endogenous analgesia.

Balance of older trekkers: data on alpine accidents and performance as assessed using a video game machine.

The number of alpine accidents involving older trekkers has increased markedly in developed countries in recent years. More than 76.8% of the trekkers involved in alpine accidents in Japan were older than 40 years, with some experiencing a stroke or myocardial infarction while trekking at altitude. In the present study, we surveyed social trends in trekkers by interview at a popular mountain site, Mt Tanigawa (1963 m in altitude). The total number of trekkers interviewed was 511, and more than 60% of these were older than 40 years. Of trekkers older than 60 years, 42% complained of conditions such as hypertension or diabetes. In 2 volunteer groups (10 younger subjects and 10 older subjects), physical condition was assessed before and after trekking. Significant body weight loss induced by dehydration was observed more often in older subjects than in younger subjects (P < .05). Balance, as measured using the Nintendo WiiFit (Nintendo, Kyoto, Japan), worsened in the older group (P < .05). Local police records for 2009 showed that the total number of alpine accidents was 65. Injuries provoked by stumbling, slipping, and falling accounted for 51% of these, and 82% of casualties were older than 40 years, with 35% being older than 60 years. In conclusion, many older people involved in nonchallenging middle-altitude trekking have problems with regard to overall health and balance. Alpine accidents caused by myocardial infarction, stroke, or hypoglycemia tend to be more common in this population. Alpine rescue teams should be well prepared for this, and older trekkers should be made aware of their increased risk of injury in alpine settings.

Effects of cardiopulmonary resuscitation at high altitudes on the physical condition of untrained and unacclimatized rescuers.

OBJECTIVE: The authors experienced a case of prolonged cardiopulmonary resuscitation (CPR) on Mount Fuji (3776 m) that demanded strenuous work by the rescuers. The objective of this study was to provide information regarding the physiologic effects on the rescuers of performing CPR at moderate altitude. METHODS: The effects of CPR at 2700 m and 3700 m above sea level on the physical condition of the rescuers were studied in 8 male volunteers. RESULTS: Cardiopulmonary resuscitation for 5 minutes at 3700 m significantly reduced arterial blood oxygen saturation and increased rate-pressure products (P < .05). Scores on the Borg scale, a subjective score of fatigue, after CPR action at 2700 m (P < .05) and 3700 m (P < .01) were higher than the scores at sea level. CONCLUSIONS: Prolonged CPR at high altitude exerts a significant physical effect upon the condition of rescuers. A role for mechanical devices should be considered wherever possible.

The efficacy of duloxetine depends on spinal cholinergic plasticity in neuropathic pain model rats.

Antidepressants, such as duloxetine, are widely used to treat chronic pain, including neuropathic pain; however, their efficacy is unsatisfactory. In our previous studies, we showed that in a spinal nerve ligation (SNL) rat model, the descending noradrenergic inhibitory system, which involves in the anti-hypersensitivity mechanism of antidepressants, decrease its activity over time following peripheral nerve injury. In this study, we hypothesized that the analgesic effects of duloxetine may diminish following the attenuation of the descending noradrenergic inhibitory system. The analgesic effects of duloxetine in SNL model rats at the early (SNL2W) and chronic (SNL6W) phases following spinal nerve ligation were compared. Male Sprague-Dawley rats were randomly assigned to the SNL2W or SNL6W groups and used to evaluate the anti-allodynic effects of duloxetine using the von Frey filament test. The anti-allodynic effects of duloxetine at a dose of 10 mg/kg were lower in SNL6W rats than in SNL2W rats. Basal noradrenaline concentrations in rat spinal dorsal horns were higher in the SNL6W group than in the SNL2W group, and there was no difference in the increase in spinal noradrenaline concentrations between the 2 groups following duloxetine administration. In addition, we found that duloxetine-induced acetylcholine (ACh) release and choline acetyltransferase (ChAT) expression in the spinal dorsal horn decreased in SNL6W rats. At a dose of 30 mg/kg, duloxetine showed anti-allodynic effects even in SNL6W rats and induced ACh release in the spinal cord. Furthermore, these anti-allodynic effects were completely inhibited by intrathecal atropine (muscarinic antagonist) administration. Moreover, 5 daily intraperitoneal injections of the TrkB agonist, 7,8-dihydroxyflavone (5 mg/kg), not only restored ChAT expression, but also decreased the anti-allodynic effects of duloxetine. These findings suggest that the attenuation of the anti-allodynic effects of duloxetine at the chronic phase of SNL may be due to impaired spinal acetylcholine-mediated analgesia. In addition, the activation of BDNF-TrkB signaling may be beneficial in reversing this impairment.

Spinal γ-Aminobutyric Acid Interneuron Plasticity Is Involved in the Reduced Analgesic Effects of Morphine on Neuropathic Pain.

Systemic administration of morphine increases serotonin (5-HT) in the spinal dorsal horn (SDH), which attenuates the analgesic effects of morphine on neuropathic pain through spinal 5-HT3 receptors. We hypothesized that dysfunction of the descending serotonergic system, including the periaqueductal gray (PAG), contributes to attenuate the efficacy of morphine on neuropathic pain through spinal 5-HT3 receptors and GABA neurons. Morphine (100 ng) injected into the PAG produced analgesic effects in normal rats, but not in spinal nerve ligation (SNL) rats. In vivo microdialysis showed that PAG morphine increased the SDH 5-HT concentration in both groups. Intrathecal injection of the 5-HT3 receptor antagonist ondansetron and the GABAA receptor antagonist bicuculline attenuated the analgesic effects of PAG morphine in normal rats, but increased the effects in SNL rats. The increased analgesic effect of PAG morphine induced by bicuculline was reversed by pretreatment with the tropomyosin receptor kinase B (TrkB) antagonist K252a. Activation of spinal 5-HT3 receptors by 2-methyl-5-HT increased the GABA concentration in both groups. Morphine activates GABAergic interneurons in the SDH by activating descending serotonergic neurons. Functional changes in GABAA receptors from inhibitory to facilitatory through the activation of TrkB receptors may contribute to the attenuated efficacy of morphine against neuropathic pain. PERSPECTIVE: Although morphine provides strong analgesia against acute pain, it has limited efficacy against neuropathic pain. This article demonstrates that functional changes in GABAA receptors in the spinal dorsal horn after nerve injury might strongly contribute to the attenuation of opioid-induced analgesia for neuropathic pain.

Randomized active-controlled study of a single preoperative administration of duloxetine to treat postoperative pain and numbness after posterior lumbar interbody fusion surgery.

BACKGROUND: This prospective, randomized, double-blinded, active controlled trial assessed whether a single preoperative administration of 40 mg of duloxetine could decrease postoperative pain and numbness after posterior lumbar interbody fusion surgery (PLIF). METHODS: Patients with an American Society of Anesthesiologists physical status I or II undergoing PLIF were included. At 2 hours before inducing anesthesia, patients were administered 40 mg duloxetine or 4 mg diazepam (control drug). Postoperative pain and other symptoms were evaluated on the basis of a visual analog scale, amount of fentanyl used, fentanyl dose request times, rate of use of adjunctive analgesics (diclofenac sodium or pentazocine), and lower limb numbness score (0-3) during the first 2 postoperative days. RESULTS: Forty-six patients were randomly assigned to the duloxetine and diazepam groups (n = 23 each); 6 were lost to follow-up, and analysis was performed on data from 22 patients in the duloxetine group and 18 in the diazepam group. No significant differences were detected in the patient background, postoperative visual analog scale score at rest in the lumbar region and lower limbs, fentanyl use, rate of analgesic adjuvant use, or incidence of side effects. The numbness score in the lower limbs, however, was significantly lower in the duloxetine group. CONCLUSION: A single preoperative 40-mg dose of duloxetine did not improve postoperative pain after PLIF, but did improve lower limb numbness. Duloxetine may suppress neuropathic pain-like symptoms after PLIF surgery.

Local anesthetic lidocaine-inducible gene, growth differentiation factor-15 suppresses the growth of cancer cell lines.

Administration of local anesthetics, such as lidocaine, in the perioperative period improves outcomes of cancer patients. However, its precise mechanism is still unresolved. The growth of human cancer cell lines, including HeLa cells, are suppressed by lidocaine treatment. We identified that growth differentiation factor-15 (GDF-15) was commonly upregulated in lidocaine-treated cancer cell lines. GDF-15 is a divergent member of the transforming growth factor-ß (TGF-ß) superfamily and it is produced as an unprocessed pro-protein form and then cleaved to generate a mature form. In lidocaine-treated HeLa cells, increased production of GDF-15 in the endoplasmic reticulum (ER) was observed and unprocessed pro-protein form of GDF-15 was secreted extracellularly. Further, lidocaine induced apoptosis and apoptosis-inducible Tribbles homologue 3 (TRIB3) was also commonly upregulated in lidocaine-treated cancer cell lines. In addition, transcription factor C/EBP homologous protein (CHOP), which is a positive regulator of not only GDF-15 but TRIB3 was also induced by lidocaine. Lidocaine-induced growth suppression and apoptosis was suppressed by knockdown of GDF-15 or TRIB3 expression by small interference RNA (siRNA). These observations suggest that lidocaine suppresses the growth of cancer cells through increasing GDF-15 and TRIB3 expression, suggesting its potential application as cancer therapy.