Research Application of Laser-induced Shock Wave for Studying Blast-induced Cochlear Injury.

The ear is the organ most susceptible to explosion overpressure, and cochlear injuries frequently occur after blast exposure. Blast exposure can lead to sensorineural hearing loss (SNHL), which is an irreversible hearing loss that negatively affects the quality of life. Detailed blast-induced cochlear pathologies, such as the loss of hair cells, spiral ganglion neurons, cochlear synapses, and disruption of stereocilia, have been previously documented. However, determining cochlear sensorineural deterioration after a blast injury is challenging because animals exposed to blast overpressure usually experience tympanic membrane perforation (TMP), which causes concurrent conductive hearing loss. To evaluate pure sensorineural cochlear dysfunction, we developed an experimental animal model of blast-induced cochlear injury using a laser-induced shock wave. This method avoids TMP and concomitant systemic injuries and reproduces the functional decline in the SNHL component in an energy-dependent manner after LISW exposure. This animal model could be a platform for elucidating the pathological mechanisms and exploring potential treatments for blast-induced cochlear dysfunction.

Blast-Induced Central Auditory Neurodegeneration Affects Tinnitus Development Regardless of Peripheral Cochlear Damage.

Blast exposure causes serious complications, the most common of which are ear-related symptoms such as hearing loss and tinnitus. The blast shock waves can cause neurodegeneration of the auditory pathway in the brainstem, as well as the cochlea, which is the primary receptor for hearing, leading to blast-induced tinnitus. However, it is still unclear which lesion is more dominant in triggering tinnitus, the peripheral cochlea or the brainstem lesion owing to the complex pathophysiology and the difficulty in objectively measuring tinnitus. Recently, gap detection tests have been developed and are potentially well-suited for determining the presence of tinnitus. In this study, we investigated whether the peripheral cochlea or the central nervous system has a dominant effect on the generation of tinnitus using a blast-exposed mouse model with or without earplugs, which prevent cochlear damage from a blast transmitted via the external auditory canal. The results showed that the earplug (+) group, in which the cochlea was neither physiologically nor histologically damaged, showed a similar extent of tinnitus behavior in a gap prepulse inhibition of acoustic startle reflex test as the earplug (-) group, in which the explosion caused a cochlear synaptic loss in the inner hair cells and demyelination of auditory neurons. In contrast, both excitatory synapses labeled with VGLUT-1 and inhibitory synapses labeled with GAD65 were reduced in the ventral cochlear nucleus, and demyelination in the medial nucleus of the trapezoid body was observed in both groups. These disruptions significantly correlated with the presence of tinnitus behavior regardless of cochlear damage. These results indicate that the lesion in the brainstem could be dominant to the cochlear lesion in the development of tinnitus following blast exposure.

A case of novel combined variations of the renal and testicular vessels.

Variations in the pattern of urogenital vessels can arise as a single occurrence or as a combination, which may increase the risk of unexpected injury during surgical procedures. Multiple variations in the renal and testicular vessels, in a novel combination, were observed during dissection of an 87-year-old Japanese male cadaver. In the present case, the patient had two renal arteries on each side. On the right side, the superior and inferior renal arteries emerged from the abdominal aorta at the L1 and L4 vertebrae levels, respectively. On the left side, the superior renal artery originated from the abdominal aorta at the level of the L1/L2 intervertebral disc, whereas the inferior renal artery arose at L4. The right testicular artery emerged from the abdominal aorta at the level of the L2 vertebra and crossed the inferior vena cava posteriorly. The venous system also exhibited some variations. The left renal vein passed posteriorly to the abdominal aorta and opened into the inferior vena cava at the level of the L2 vertebra. On the course to the inferior vena cava, the left renal vein was connected only to the first lumbar, azygos, and hemiazygos veins; blood was not collected from the left testicular and suprarenal veins, which usually open to the left renal vein. The patient had two right testicular veins. The lateral one opened into the angle between the right renal vein and the inferior vena cava at the level of the L2 vertebra, and the medial one drained into the inferior vena cava at a level slightly lower than the lateral one. Knowledge of the possible anatomical variations may be beneficial for performing safe retroperitoneal surgery and understanding the development of these vessels.

[Inter-laboratory Study on the Modified Methods for Analyzing Bisphenol A Content for Migration Tests from Polycarbonate Food Apparatuses, Containers, and Packaging].

An inter-laboratory study involving 24 laboratories was conducted to validate the modified analytical method for the migration solution of heptane for the determination of bisphenol A migrating from polycarbonate food processing materials. In this study, two concentrations of samples were blindly coded. Each laboratory determined the analyte (bisphenol A, phenol and p-tert-butylphenol) concentration in each sample according to the established protocol. The obtained values were analyzed statistically using internationally accepted guidelines. Horwitz ratios were calculated based on the reproducibility relative standard deviation (RSDR), which was estimated from the inter-laboratory study, and predicted RSDR, which was calculated using the Horwitz/Thompson equation. Horwitz ratios of the two samples ranged from 0.15 to 0.37 for the three compounds, meeting the performance criteria of less than 2 set by the Codex Alimentarius for analytical method approval. These results showed that this modified analytical method shows good performance as an analytical method for the migration solution of heptane.

Cadaver investigation of the usefulness of the transstyloid diaphragm approach for high-position plaque carotid endarterectomy.

OBJECTIVES: Patients sometimes present with high cervical internal carotid artery (ICA) stenosis. This study demonstrates the usefulness of the transstyloid approach to expose the distal ICA by dissection of the styloid diaphragm covering the distal cervical ICA for carotid endarterectomy (CEA). In particular, the possible exposure length achieved by this approach was investigated using cadaveric heads. METHODS: The procedure of the transstyloid diaphragm approach was confirmed in 10 cadaveric heads (20 sides). After the carotid triangle was opened, both the posterior belly of the digastric muscle (PBDM) and the stylohyoid muscle could be divided. Then, the carotid sheath was dissected, and the glossopharyngeal nerve was identified crossing over the distal ICA. The revealed length of the ICA was measured with or without dissection of both the PBDM and the stylohyoid muscle. The specimens were dissected under the surgical microscope. RESULTS: The transstyloid diaphragm approach was achieved successfully in all specimens. The revealed lengths of the ICA with and without dissection of the styloid diaphragm were 53.7 ± 5.9 mm and 38.8 ± 2.9 mm (mean ± standard deviation), respectively. Therefore, the revealed length of the distal ICA was 14.9 ± 4.5 mm greater using the transstyloid diaphragm approach compared to the regular CEA approach. CONCLUSIONS: More of the ICA can be revealed by dissection of both the PBDM and the stylohyoid muscle. The transstyloid diaphragm approach might be helpful to reveal the distal ICA in cases of high cervical ICA stenosis.

Arterial branching pattern of the cranial mesenteric artery in the degu (Octodon degus).

BACKGROUND: The cranial mesenteric artery exhibits a species-specific ramification pattern that adapts to the morphology of the intestinal tract. The degu is a strictly herbivorous rodent with a well-developed large intestine with a spiral loop in the ascending colon; therefore, the cranial mesenteric artery likely demonstrates a degu-specific ramification pattern. Thus, we traced the cranial mesenteric artery to establish the detailed ramification pattern of the branches. METHODS: Eighteen male degus were injected with 0.3-0.8 ml of a latex mixture and water at a 1:1 ratio in conjunction with red acrylic paint coloring using a catheter inserted into the thoracic aorta. The cranial mesenteric artery was traced using a surgical microscope and photographed using a digital camera. RESULTS: The arteries emerging from the cranial mesenteric artery exhibited frequent variations in number, distribution area, anastomosis pattern, and branching order. In the most frequent cases (22%), the cranial mesenteric artery sequentially gave rise to caudal pancreaticoduodenal, middle colic, right colic, jejunal, and ileocolic arteries. The right and middle colic arteries exhibited four different ramification patterns. In the most common cases (67%), the middle and right colic arteries emerged independently from the cranial mesenteric artery. The former was distributed to the transverse and descending colon, whereas the latter sent branches to the spiral loop of the ascending colon. CONCLUSIONS: The complex ramification pattern of the right colic artery in the degu may be an adaptation to the characteristic running pattern of the ascending colon. Thus, we present the first comprehensive report of the arterial branching pattern of the cranial mesenteric artery in the degu.

Evans Blue and Fluorescein Isothiocyanate-Dextran Double Labeling Reveals Precise Sequence of Vascular Leakage and Glial Responses After Exposure to Mild-Level Blast-Associated Shock Waves.

Abstract Blast-induced shock waves (BSWs) are responsible for several aspects of psychiatric disorders that are collectively termed mild traumatic brain injury (mTBI). The pathophysiology of mTBI includes vascular leakage resulting from blood-brain barrier (BBB) disruption. In this study, the precise sequence of BBB breakdown was examined using an Evans blue and fluorescein isothiocyanate (FITC)-dextran double labeling technique. Evans blue solution was injected into the tail vein of male C57BL6/J mice just before and 4 h, 1 day, 3 days, and 7 days after a single BSW exposure at as low as 25-kPa peak overpressure. In contrast, the FITC-dextran solution was transcardially injected just before perfusion fixation. Differences in the labeling time-point revealed that BBB breakdown was initiated after approximately 3 h, with significant remodeling by 1 day, and continued until 7 days after BSW exposure. BBB breakdown was upregulated in three distinct regions, namely the brain surface and subsurface areas facing the skull, regions closely associated with capillaries, and the circumventricular organ and choroid plexus. These regions showed distinct responses to BSW; moreover, clusters of reactive astrocytes were closely associated with the sites of BBB breakdown. In severe cases, these reactive astrocytes recruited activated microglia. Our findings provide important insights into the pathogenesis underlying mTBI and indicate that even mild BSW exposure affects the whole brain.

[Effect of aspiration prevention surgery in three patients with multiple system atrophy who have been hospitalized for aspiration pneumonia].

Three patients with multiple system atrophy (MSA) who have been hospitalized for aspiration pneumonia underwent aspiration prevention surgery. Laryngeal closure was performed in 2 cases, and laryngotracheal separation was performed in 1 case. Two patients were able to continue oral intake. No recurrence of aspiration pneumonia was observed in all cases after the operation for about two years, and the reduction in the number of aspirations at night improved the patient's QOL and reduced the burden on the caregiver. It was considered that the appropriate time for surgery was when communication in vocal language became difficult. It was a time when the loss of vocal function was well accepted in 3 cases. Aspiration prevention surgery may be a useful treatment option because it may contribute to prolonging the prognosis of life by reducing the complications of respiratory infections.

Hippocampal Connectivity of the Presubiculum in the Common Marmoset (Callithrix jacchus).

The marmoset (a New World monkey) has recently received much attention as an experimental animal model; however, little is known about the connectivity of limbic regions, including cortical and hippocampal memory circuits, in the marmoset. Here, we investigated the neuronal connectivity of the marmoset, especially focusing on the connectivity between the hippocampal formation and the presubiculum, using retrograde and anterograde tracers (cholera toxin-B subunit and biotin dextran amine). We demonstrated the presence of a direct projection from the CA1 pyramidal cell layer to the deep layers of the presubiculum in the marmoset, which was previously identified in the rabbit brain, but not in the rat. We also found that the cells of origin of the subiculo-presubicular projections were localized in the middle part along the superficial-to-deep axis of the pyramidal cell layer of the distal subiculum in the marmoset, which was similar to that in both rats and rabbits. Our results suggest that, compared to the rat and rabbit brains, connections between the hippocampal formation and presubiculum are highly organized and characteristic in the marmoset brain.

OAT10/SLC22A13 Acts as a Renal Urate Re-Absorber: Clinico-Genetic and Functional Analyses With Pharmacological Impacts.

Dysfunctional missense variant of organic anion transporter 10 (OAT10/SLC22A13), rs117371763 (c.1129C>T; p.R377C), is associated with a lower susceptibility to gout. OAT10 is a urate transporter; however, its physiological role in urate handling remains unclear. We hypothesized that OAT10 could be a renal urate re-absorber that will be a new molecular target of urate-lowering therapy like urate transporter 1 (URAT1, a physiologically-important well-known renal urate re-absorber) and aimed to examine the effect of OAT10 dysfunction on renal urate handling. For this purpose, we conducted quantitative trait locus analyses of serum urate and fractional excretion of uric acid (FEUA) using samples obtained from 4,521 Japanese males. Moreover, we performed immunohistochemical and functional analyses to assess the molecular properties of OAT10 as a renal urate transporter and evaluated its potential interaction with urate-lowering drugs. Clinico-genetic analyses revealed that carriers with the dysfunctional OAT10 variant exhibited significantly lower serum urate levels and higher FEUA values than the non-carriers, indicating that dysfunction of OAT10 increases renal urate excretion. Given the results of functional assays and immunohistochemical analysis demonstrating the expression of human OAT10 in the apical side of renal proximal tubular cells, our data indicate that OAT10 is involved in the renal urate reabsorption in renal proximal tubules from urine. Additionally, we found that renal OAT10 inhibition might be involved in the urate-lowering effect of losartan and lesinurad which exhibit uricosuric effects; indeed, losartan, an approved drug, inhibits OAT10 more strongly than URAT1. Accordingly, OAT10 can be a novel potential molecular target for urate-lowering therapy.

CD4+ T-cell-derived IL-10 promotes CNS inflammation in mice by sustaining effector T cell survival.

Interleukin (IL)-10 is considered a prototypical anti-inflammatory cytokine, significantly contributing to the maintenance and reestablishment of immune homeostasis. Accordingly, it has been shown in the intestine that IL-10 produced by Tregs can act on effector T cells, thereby limiting inflammation. Herein, we investigate whether this role also applies to IL-10 produced by T cells during central nervous system (CNS) inflammation. During neuroinflammation, both CNS-resident and -infiltrating cells produce IL-10; yet, as IL-10 has a pleotropic function, the exact contribution of the different cellular sources is not fully understood. We find that T-cell-derived IL-10, but not other relevant IL-10 sources, can promote inflammation in experimental autoimmune encephalomyelitis. Furthermore, in the CNS, T-cell-derived IL-10 acts on effector T cells, promoting their survival and thereby enhancing inflammation and CNS autoimmunity. Our data indicate a pro-inflammatory role of T-cell-derived IL-10 in the CNS.

Measuring Task-Related Brain Activity With Event-Related Potentials in Dynamic Task Scenario With Immersive Virtual Reality Environment.

Measurement of event-related potentials (ERPs) in simulated and real environments is advantageous for understanding cognition and behavior during practice of goal-directed activities. Recently, instead of using task-irrelevant "probe stimuli" to elicit ERPs, extraction of ERPs directly from events that occur in simulated and real environments has drawn increased attention. Among the previous ERP studies using immersive virtual reality, only a few cases elicited ERPs from task-related events in dynamic task settings. Furthermore, as far as we surveyed, there were no studies that examined the source of ERPs or correlation between ERPs and behavioral performance in 360-degree immersive virtual reality using head-mounted display. In this study, EEG signals were recorded from 16 participants while they were playing the first-person shooter game with immersive virtual reality environment. Error related negativity (ERN) and correct-(response)-related negativity (CRN) elicited by shooting-related events were successfully extracted. We found the ERN amplitudes to be correlated with the individual shooting performance. Interestingly, the main source of the ERN was the rostral anterior cingulate cortex (ACC), which is different from previous studies where the signal source was often estimated to be the more caudal part of ACC. The obtained results are expected to contribute to the evaluation of cognitive functions and behavioral performance by ERPs in a simulated environment.

The Membrane-Like Structure From Extensor Tendon to the Nail in the Distal End of Digits: An Anatomical Study of Structure, Function, and Utility.

METHODS: The nail structures of 6 cadavers were investigated in each of the 10 digits of the hand. In the histological study, the thickness, length, and location of the SEP were measured in each digit of 3 cadavers. In the other 3 cadavers, the moving distance of the SEP was measured macroscopically with the distal interphalangeal joint in flexion at 0 to 60 degrees for confirmation of the function. This moving distance could be considered as an indicator of the SEP straining the surrounding (retaining) structure and improving the stability of the nail in pinches. RESULT: The SEP was recognized in all the digits. The average length of the SEPs was 2.38 ± 0.11 mm (mean ± SE). The average thickness of the SEPs was 0.35 ± 0.02 mm. The nail matrix and its feeding artery were found beneath the SEP in all digits. The average moving distance of the SEP was 1.38 ± 0.06 mm. This moving distance could be considered sufficiently large to support the role of SEP in the pinches compared with the excursion of the extensor tendon at the DIP joint in a previous report. CONCLUSIONS: The SEP has been shown to play an essential role in fingertip stabilization in pinches. It can serve as an anatomical marker to avoid iatrogenic damage to the nail matrix in surgical approaches.

Morphological characterization of cholinergic partition cells: A transmitter-specific tracing study by Cre/lox-dependent viral gene expression.

BACKGROUND: Partition cells are cholinergic interneurons located in lamina VII of the spinal cord. Some partition cells are the source of the cholinergic boutons, known as C-terminals or C-boutons, that modulate the activity of spinal motor neurons. Therefore, partition cells might play an important role in motor control. Previous studies categorized partition cells into three groups (medial, intermediate, and lateral partition cells) according to their distance from the central canal. However, the morphological characteristics of the three groups remain obscure. METHODS: To analyze the morphology of partition cells, we developed an efficient technique for visualization of specific neurons at single-cell level in particular positions using adenovirus vectors and Cre/lox mediated recombination. Cre/lox conditional vectors were injected into the spinal cord of choline acetyltransferase-Cre transgenic mice, and partition cells labeled by green fluorescent protein were reconstructed from histological serial sections at the single-cell level. RESULTS: This technique allowed for the visualization of partition cells at high resolution and revealed that partition cells had various patterns of dendrite orientations and fields. Most of the visualized partition cells had more than 60% of their dendrites located in lamina VII of the spinal cord. Partition cells had dendrites extending into various Rexed's laminae (V, VI, VII, VIII, IX, and X), but none of the cells had dendrites extending dorsal to lamina IV. The dendrites of partition cells terminated both ipsilaterally and bilaterally. We also found that C-terminals on motor neurons may be derived from the middle/outer group of partition cells. CONCLUSIONS: Our results indicated that partition cells have various morphological features of the dendritic pattern and may receive differential inputs. Our results suggested that C-terminals originate not only from medial but also from intermediate/lateral cholinergic partition cells. The present study suggests that intermediate/lateral partition cells modulate activities of motor neurons through C-terminal synapses.

First dorsal metacarpal artery perforator-based propeller flap: functional anatomy and clinical application in soft-tissue defects of the dorsal hand and digits.

BACKGROUND: Many approaches have been reported to repair soft-tissue defects of the hand using dorsal metacarpal artery flaps. Use of a perforator-based propeller flap from the first intermetacarpal space to the dorsum of the hand has been described. The aim of this study was to confirm the functional anatomy of a first dorsal metacarpal artery (FDMA) perforator flap. METHODS: Twenty-nine fixed cadaveric hands were dissected to determine the origin, course, and branches of the FDMA. Clinically, five cases of soft tissue defects of the hand underwent reconstructive surgery using an FDMA perforator-based propeller flap. RESULTS: The FDMA was found in 27 specimens (93%). The ulnar branch of the FDMA always supplied the cutaneous perforator (mean ± SD, 4.3 ± 1.6), and the most distal cutaneous perforating branch was found along the metacarpal long axis within 25 mm of the tip of the metacarpal head with high frequency (28/29, 97%). In the two hands that had aplasia of the FDMA, well-developed perforators arose directly from the radial artery and advanced to the metacarpal head. Seven hands (24%) had perforators arising from the palmar arterial system, penetrating through or passing close by the second metacarpal bone. In clinical application, all the flaps survived completely without major complications. CONCLUSIONS: The FDMA perforator-based propeller flap is minimally invasive and technically simple. It is expected to be a new option for hand reconstruction.

Interleukin-10 improves stroke outcome by controlling the detrimental Interleukin-17A response.

BACKGROUND: Lymphocytes have dichotomous functions in ischemic stroke. Regulatory T cells are protective, while IL-17A from innate lymphocytes promotes the infarct growth. With recent advances of T cell-subtype specific transgenic mouse models it now has become possible to study the complex interplay of T cell subpopulations in ischemic stroke. METHODS: In a murine model of experimental stroke we analyzed the effects of IL-10 on the functional outcome for up to 14 days post-ischemia and defined the source of IL-10 in ischemic brains based on immunohistochemistry, flow cytometry, and bone-marrow chimeric mice. We used neutralizing IL-17A antibodies, intrathecal IL-10 injections, and transgenic mouse models which harbor a deletion of the IL-10R on distinct T cell subpopulations to further explore the interplay between IL-10 and IL-17A pathways in the ischemic brain. RESULTS: We demonstrate that IL-10 deficient mice exhibit significantly increased infarct sizes on days 3 and 7 and enlarged brain atrophy and impaired neurological outcome on day 14 following tMCAO. In ischemic brains IL-10 producing immune cells included regulatory T cells, macrophages, and microglia. Neutralization of IL-17A following stroke reversed the worse outcome in IL-10 deficient mice and intracerebral treatment with recombinant IL-10 revealed that IL-10 controlled IL-17A positive lymphocytes in ischemic brains. Importantly, IL-10 acted differentially on αß and γδ T cells. IL-17A producing CD4+ αß T cells were directly controlled via their IL-10-receptor (IL-10R), whereas IL-10 by itself had no direct effect on the IL-17A production in γδ T cells. The control of the IL-17A production in γδ T cells depended on an intact IL10R signaling in regulatory T cells (Tregs). CONCLUSIONS: Taken together, our data indicate a key function of IL-10 in restricting the detrimental IL-17A-signaling in stroke and further supports that IL-17A is a therapeutic opportunity for stroke treatment.

Arterial supply to the rat colon.

Rats are often used as animal models in studies such as on intestinal transplantation and anastomosis healing, which require colectomy. Although detailed information regarding arterial supply is important to establish accurate and reproducible experimental procedures, this has not been studied in the rat colon. Therefore, we analysed the detailed arterial distribution pattern and its individual variations in the colon of 34 rats. The rat colon received colic branches of the ileocolic artery, and the right, middle and left colic arteries. The single left colic artery constantly arose from the caudal mesenteric artery and was distributed to the descending colon, whereas the others showed variations in number and distribution. The ileocolic artery gave rise to one (12%) or two (88%) colic branches supplying the proximal ascending colon, and these branches formed rich, mesh-like anastomoses along the initial portion of the ascending colon. One (74%) or two (26%) right colic arteries originated from the cranial mesenteric artery and supplied the ascending colon and right colic flexure. Moreover, one (38%), two (56%) or three (6%) middle colic arteries emerged from the cranial mesenteric artery and were distributed to the transverse colon, left colic flexure and proximal descending colon. In total, we categorized the individual variations in arterial branching and anastomosis into 11 patterns. Arterial supply to the rat colon showed a specific pattern and frequent individual variations. These findings thus provide essential information for establishing reproducible models of rat colic surgery.

Efferocytosis fuels malignant pleural effusion through TIMP1.

Malignant pleural effusion (MPE) results from the capacity of several human cancers to metastasize to the pleural cavity. No effective treatments are currently available, reflecting our insufficient understanding of the basic mechanisms leading to MPE progression. Here, we found that efferocytosis through the receptor tyrosine kinases AXL and MERTK led to the production of interleukin-10 (IL-10) by four distinct pleural cavity macrophage (Mφ) subpopulations characterized by different metabolic states and cell chemotaxis properties. In turn, IL-10 acts on dendritic cells (DCs) inducing the production of tissue inhibitor of metalloproteinases 1 (TIMP1). Genetic ablation of Axl and Mertk in Mφs or IL-10 receptor in DCs or Timp1 substantially reduced MPE progression. Our results delineate an inflammatory cascade-from the clearance of apoptotic cells by Mφs, to production of IL-10, to induction of TIMP1 in DCs-that facilitates MPE progression. This inflammatory cascade offers a series of therapeutic targets for MPE.

Efficacy of Body Armor in Protection Against Blast Injuries Using a Swine Model in a Confined Space with a Blast Tube.

The purpose of this study was to clarify whether or not body armor would protect the body of a swine model using a blast tube built at National Defense Medical College, which is the first such blast tube in Japan. Seventeen pigs were divided into two groups: the body armor group and the non-body armor group. Under intravenous anesthesia, the pigs were tightly fixed in the left lateral position on a table and exposed from the back neck to the upper lumbar back to the blast wave and wind with or without body armor, with the driving pressure of the blast tube set to 3.0 MPa. When the surviving and dead pigs were compared, blood gas analyses revealed significant differences in PaO2, PaCO2, and pH in the super-early phase. All pigs injured by the blast wave and wind had lung hemorrhage. All 6 animals in the body armor group and 6 of the 11 animals in the control group survived for 3 hours after injury. Respiratory arrest immediately after exposure to the blast wave was considered to influence the mortality in our pig model. Body armor may have a beneficial effect in protecting against respiratory arrest immediately after an explosion.

Extracellular signal-regulated kinases 2 (Erk2) and Erk5 in the central nervous system differentially contribute to central sensitization in male mice.

Nervous systems are designed to become extra sensitive to afferent nociceptive stimuli under certain circumstances such as inflammation and nerve injury. How pain hypersensitivity comes about is key issue in the field since it ultimately results in chronic pain. Central sensitization represents enhanced pain sensitivity due to increased neural signaling within the central nervous system (CNS). Particularly, much evidence indicates that underlying mechanism of central sensitization is associated with the change of spinal neurons. Extracellular signal-regulated kinases have received attention as key molecules in central sensitization. Previously, we revealed the isoform-specific function of extracellular signal-regulated kinase 2 (Erk2) in spinal neurons for central sensitization using mice with Cre-loxP-mediated deletion of Erk2 in the CNS. Still, how extracellular signal-regulated kinase 5 (Erk5) in spinal neurons contributes to central sensitization has not been directly tested, nor is the functional relevance of Erk5 and Erk2 known. Here, we show that Erk5 and Erk2 in the CNS play redundant and/or distinct roles in central sensitization, depending on the plasticity context (cell types, pain types, time, etc.). We used male mice with Erk5 deletion specifically in the CNS and found that Erk5 plays important roles in central sensitization in a formalin-induced inflammatory pain model. Deletion of both Erk2 and Erk5 leads to greater attenuation of central sensitization in this model, compared to deletion of either isoform alone. Conversely, Erk2 but not Erk5 plays important roles in central sensitization in neuropathic pain, a type of chronic pain caused by nerve damage. Our results suggest the elaborate mechanisms of Erk signaling in central sensitization.