Peripheral Tissue Injury Research Articles

Regulation of the β-endorphin precursor proopiomelanocortin in lymphocytes in a rat model of inflammatory pain

Our previous studies have shown that monocytes/macrophages, granulocytes, and lymphocytes release opioid peptides in the presence of different releasing factors at the site of peripheral tissue injury or inflammation and thereby contribute to opioid-mediated reduction of pain. We are interested in the regulation of β-endorphin and its precursor proopiomelanocortin (POMC) at the transcriptional and posttranslational level in lymphocytes, as such cells play a role in chronic inflammation. We hypothesized that (i) POMC gene expression in the lymph node draining inflamed tissue is up-regulated in inflammation, and (ii) that the precursor is cleaved by the prohormone convertases (PC)1 and PC2 similar to neuroendocrine cells in the pituitary gland. We found elevated POMC gene expression and β-endorphin levels in cells of lymph nodes draining inflamed tissue, as assessed by qPCR and radioimmunoassay. Our PCR and immunocytochemistry data show that PC1 mRNA and protein expression, respectively, are induced after induction of inflammation. PC2 required no stimulation and was detectable using PCR and immunocytochemistry, both, in cells from nai¨ve and activated lymph nodes. Our findings indicate that β-endorphin synthesis in lymphocytes may depend on the presence of PC1/3, while PC2 alone does not seem to be sufficient. Functional experiments are necessary to verify the specific roles of these enzymes for POMC processing in cells of the immune system.

Different Peripheral Tissue Injury Induces Differential Phenotypic Changes of Spinal Activated Microglia

The purpose of this study is to investigate the possible different cellular marker expression associated with spinal cord microglial activation in different pain models. Immunohistochemistry and western blotting analysis of CD45, CD68, and MHC class I antigen as well as CD11b and Iba-1 in the spinal cord were quantitatively compared among widely used three pain animal models, complete Freund's adjuvant (CFA) injection, formalin injection, and chronic constriction injury (CCI) models. The results showed that significant upregulated expressions of CD45 and MHC class I antigen in spinal microglia as well as morphological changes with increased staining with CD11b and Iba-1 were seen in CCI and formalin models and not found in CFA-induced inflammatory pain model. CD68 expression was only detected in CCI model. Our findings suggested that different peripheral tissue injuries produced differential phenotypic changes associated with spinal microglial activation; peripheral nerve injury might induce spinal microglia to acquire these immunomolecular phenotypic changes.

A randomised trial comparing the cost effectiveness of different emergency department healthcare professionals in soft tissue injury management

ObjectivesTo evaluate the cost effectiveness of soft tissue injury management by emergency nurse practitioners (ENPs) and extended scope physiotherapists (ESPs) compared with the routine care provided by doctors in an...

Enhancement by Interleukin-1β of AMPA and NMDA Receptor-Mediated Currents in Adult Rat Spinal Superficial Dorsal Horn Neurons

BackgroundProinflammatory cytokine interleukin-1β (IL-1β) released from spinal microglia plays an important role in the maintenance of acute and chronic pain states. However, the cellular basis of this action remains poorly understood. Using whole-cell patch-clamp recordings, we examined the action of IL-1β on AMPA- and NMDA-receptor-mediated currents recorded from substantia gelatinosa (SG) neurons of adult rat spinal cord slices which are key sites for regulating nociceptive transmission from the periphery.ResultsAMPA- and NMDA-induced currents were increased in peak amplitude by IL-1β in a manner different from each other in SG neurons. These facilitatory actions of IL-1β were abolished by IL-1 receptor (IL-1R) antagonist (IL-1ra), which by itself had no detectable effects on AMPA- and NMDA-induced currents. The AMPA- but not NMDA-induced current facilitated by IL-1β was recovered to control level 30 min after IL-1β washout and largely depressed in Na+-channel blocker tetrodotoxin-containing or nominally Ca2+-free Krebs solution. Minocycline, a microglia inhibitor, blocked the facilitatory effect of IL-1β on AMPA- but not NMDA-induced currents, where minocycline itself depressed NMDA- but had not any effects on AMPA-induced currents.ConclusionsIL-1β enhances AMPA and NMDA responses in SG neurons through IL-1R activation; the former but not latter action is reversible and due to an increase in neuronal activity in a manner dependent on extracellular Ca2+ and minocycline. It is suggested that AMPA and NMDA receptors are positively modulated by IL-1β in a manner different from each other; the former but not latter is mediated by a neurotransmitter released as a result of an increase in neuronal activity. Since IL-1β contributes to nociceptive behavior induced by peripheral nerve or tissue injury, the present findings also reveal an important cellular link between neuronal and glial cells in the spinal dorsal horn.

The Efficacy of Preemptive Ketamine Administration in Bilateral Superficial Cervical Plexus Block After Thyroid Surgery

Background: Peripheral tissue injury initiates peripheral sensitization; in addition, it triggers excitability of the central neurons known as central sensitization. N-methyl–D-aspartate (NMDA) receptors are largely involved in the pathogenesis of central sensitization. The concept of preemptive local anesthetic administration seems hopeful in management of postoperative pain. The addition of ketamine as NMDA receptors antagonist reduces the incidence of chronic pain and the chance for development of hyperalgesia and allodynia. Our study hypothesis is to evaluate effects of adding ketamine to bupivacaine in bilateral superficial cervical plexus block (BSCPB) on acute and chronic pain after thyroid surgery. Patients and Methods: Sixty (ASA I, II) 18 to 60 years old undergoing thyroid surgery were simply randomized into two equal groups, thirty patients received BSCPB using 9 ml bupivacaine 0.25% solution mixed with 1 ml normal saline (Bupivacaine group) and thirty patients received BSCPB using 9 ml bupivacaine 0.25% solution mixed with 1 ml ketamine 50 mg/ml (Ketamine group). Patients were instructed about the use of a 10 cm Visual Analog Scale (VAS) (0=no pain to 10=worst possible pain). Pain level was recorded at PACU admission every 3 h for the first 24 hours. The analgesic requirement during the first 24 h after surgery was recorded. Any side effects were recorded. The incidences of chronic pain, wound hyperalgesia and allodynia after six months were recorded. Results: Intraoperative fentanyl requirements were significantly reduced in ketamine group. At post-anesthesia care unit, acetaminophen requirements during the first 24 hours after surgery were significantly reduced in ketamine group. The incidence of wound hyperalgesia and allodynia were significantly lower in ketamine group. Conclusion: Pre-incisional BSCPB using bupivacaine 0.25% in addition to 50 mg ketamine demonstrated significant reduction in intraoperative and postoperative analgesic requirement after thyroid surgery. The incidences of chronic pain, wound hyperalgesia and allodynia were significantly reduced after six months in ketamine group.

Inducible Nitric Oxide Synthase Contributes to Immune Dysfunction Following Trauma

Trauma results in a persistent depression in adaptive immunity, which contributes to patient morbidity and mortality. This state of immune paralysis following trauma is characterized by a change in cell-mediated immunity, specifically a depression in T-cell function and a shift toward TH2 T-cell phenotype. Upregulation of inducible nitric oxide synthase (iNOS) is well recognized after injury and contributes to the inflammatory response and organ damage early after trauma. However, it is unknown whether iNOS plays a role in adaptive immune dysfunction after trauma. This study utilized a murine model of severe peripheral tissue injury to show that iNOS is rapidly upregulated in macrophages and a (Gr-1-CD11b) myeloid-derived suppressor cell subpopulation in the spleen. Through the use of iNOS knockout mice, a specific iNOS inhibitor, and a nitric oxide (NO) scavenger, this study demonstrates that iNOS-derived NO is required for the depression in T-lymphocyte proliferation, interferon γ, and interleukin 2 production within the spleen at 48 h after trauma. These findings support the hypothesis that iNOS regulates immune suppression following trauma and suggest that targeting the sustained production of NO by iNOS may attenuate posttraumatic immune depression.

Activation of peripheral P2X receptors is sufficient to induce central sensitization in rat medullary dorsal horn nociceptive neurons

Central sensitization and purinergic receptor mechanisms have been implicated as important processes in acute and chronic pain conditions following injury or inflammation of peripheral tissues. This study has documented that application of the P2X1,2/3,3 receptor agonist αβ-meATP (100mM) to the rat tooth pulp induces central sensitization in medullary dorsal horn nociceptive neurons that is reflected in significant increases in mechanoreceptive field size and responses to noxious stimuli and decreased mechanical activation threshold. Furthermore, these responses can be blocked by pulp application of the P2X1,2/3,3 antagonist TNP-ATP and also attenuated by medullary application of TNP-ATP. These results suggest that activation of P2X1,2/3,3 receptors in orofacial tissues plays a critical role in producing central sensitization in medullary dorsal horn nociceptive neurons.

Interleukin-1 Receptor-Associated Kinase M-Deficient Mice Demonstrate an Improved Host Defense during Gram-negative Pneumonia

Pneumonia is a common cause of morbidity and mortality and the most frequent source of sepsis. Bacteria that try to invade normally sterile body sites are recognized by innate immune cells through pattern recognition receptors, among which toll-like receptors (TLRs) feature prominently. Interleukin-1 receptor (IL-1R)-associated kinase (IRAK)-M is a proximal inhibitor of TLR signaling expressed by epithelial cells and macrophages in the lung. To determine the role of IRAK-M in host defense against bacterial pneumonia, IRAK-M-deficient (IRAK-M(-/-)) and normal wild-type (WT) mice were infected intranasally with Klebsiella pneumoniae. IRAK-M mRNA was upregulated in lungs of WT mice with Klebsiella pneumonia, and the absence of IRAK-M resulted in a strongly improved host defense as reflected by reduced bacterial growth in the lungs, diminished dissemination to distant body sites, less peripheral tissue injury and better survival rates. Although IRAK-M(-/-) alveolar macrophages displayed enhanced responsiveness toward intact K. pneumoniae and Klebsiella lipopolysaccharide (LPS) in vitro, IRAK-M(-/-) mice did not show increased cytokine or chemokine levels in their lungs after infection in vivo. The extent of lung inflammation was increased in IRAK-M(-/-) mice shortly after K. pneumoniae infection, as determined by semiquantitative scoring of specific components of the inflammatory response in lung tissue slides. These data indicate that IRAK-M impairs host defense during pneumonia caused by a common gram-negative respiratory pathogen.

Amino acid transport system A is involved in inflammatory nociception in rats

Previous studies have indicated that central sensitization is a state of increased excitability of nociceptive neurons in the spinal dorsal horn following peripheral tissue injury and/or inflammation and astrocytes play an important role in the central sensitization. The current study investigated the role of amino acid transport system A in central sensitization and hyperalgesia induced by intraplantar injection of formalin in rats. Formalin (5%, 50μl) injected subcutaneously into the unilateral hindpaw pad induced typical biphase nociceptive behaviors, including licking/biting and flinching of the injected paw and an increase of glial fibrillary acid protein (GFAP, an activated astrocyte marker) expression in spinal dorsal horn, and these effects could be attenuated by intrathecal injection of the competitive inhibitor of amino acid system A transporter, methylaminoisobutyric acid (MeAIB, 0.1, 0.3, 0.5, and 0.7mmol), in a dose-dependent manner. Intrathecal injection of vehicle (PBS) had no effect on the formalin-induced nociceptive behaviors and increase of the GFAP. These findings suggest that amino acid transport system A is involved in inflammation-induced nociception, and inhibition of this transporter system results in inhibition of the central sensitization and hyperalgesia.

Ketamine as Adjunctive Anesthesia in Refractory Complex Regional Pain Syndrome Patients: A Case Series

Complex regional pain syndrome most often follows peripheral soft tissue and nerve injury, fractures, and surgical procedures. The pain is out of proportion to the severity of the injury, spreads beyond a nerve or root territory and increases over time. In general, recommendations for anesthesia for these patients requiring surgery include sympathetic blockade or intravenous regional anesthesia as well as sympathetic blockade in conjunction with lidocaine. Quite often surgery for these patients seriously aggravates their condition. This is a retrospective evaluation of a case series of the use of ketamine as adjunctive anesthesia in twenty five refractory long standing complex regional pain syndrome patients. All patients met the International Association for the Study of Pain criteria for diagnosis. Ketamine was administered intravenously over four hours from the start of the procedure with midazolam and clonidine in addition to their standard anesthesia. At the end of the procedure, an additional dose of midazolam was administered. Lorazepam was used for restlessness if necessary for three nights after the procedure. All twenty five patients had no exacerbation of their symptoms and signs and no spread of their CRPS. This study supports the effective use of ketamine, midazolam and clonidine as adjunctive anesthesia in severe refractory CRPS patients undergoing a surgical procedure.

A randomised trial comparing the clinical effectiveness of different emergency department healthcare professionals in soft tissue injury management

ObjectivesTo evaluate the clinical effectiveness of soft tissue injury management by emergency nurse practitioners (ENPs) and extended scope physiotherapists (ESPs) compared to the routine care provided by doctors in a...

Contribution of Microglia and Astrocytes to the Central Sensitization, Inflammatory and Neuropathic Pain in the Juvenile Rat

BackgroundThe development of pain after peripheral nerve and tissue injury involves not only neuronal pathways but also immune cells and glia. Central sensitization is thought to be a mechanism for such persistent pain, and ATP involves in the process. We examined the contribution of glia to neuronal excitation in the juvenile rat spinal dorsal horn which is subjected to neuropathic and inflammatory pain.ResultsIn rats subjected to neuropathic pain, immunoreactivity for the microglial marker OX42 was markedly increased. In contrast, in rats subjected to inflammatory pain, immunoreactivity for the astrocyte marker glial fibrillary acidic protein was increased slightly. Optically-recorded neuronal excitation induced by single-pulse stimulation to the dorsal root was augmented in rats subjected to neuropathic and inflammatory pain compared to control rats. The bath application of a glial inhibitor minocycline and a p38 mitogen-activated protein kinase inhibitor SB203580 inhibited the neuronal excitation in rats subjected to neuropathic pain. A specific P2X1,2,3,4 antagonist TNP-ATP largely inhibited the neuronal excitation only in rats subjected to neuropathic pain rats. In contrast, an astroglial toxin L-alpha-aminoadipate, a gap junction blocker carbenoxolone and c-Jun N-terminal kinase inhibitor SP600125 inhibited the neuronal excitation only in rats subjected to inflammatory pain. A greater number of cells in spinal cord slices from rats subjected to neuropathic pain showed Ca2+ signaling in response to puff application of ATP. This Ca2+ signaling was inhibited by minocycline and TNP-ATP.ConclusionsThese results directly support the notion that microglia is more involved in neuropathic pain and astrocyte in inflammatory pain.

Priming of adult pain responses by neonatal pain experience: maintenance by central neuroimmune activity

Adult brain connectivity is shaped by the balance of sensory inputs in early life. In the case of pain pathways, it is less clear whether nociceptive inputs in infancy can have a lasting influence upon central pain processing and adult pain sensitivity. Here, we show that adult pain responses in the rat are 'primed' by tissue injury in the neonatal period. Rats that experience hind-paw incision injury at 3 days of age, display an increased magnitude and duration of hyperalgesia following incision in adulthood when compared with those with no early life pain experience. This priming of spinal reflex sensitivity was measured by both reductions in behavioural withdrawal thresholds and increased flexor muscle electromyographic responses to graded suprathreshold hind-paw stimuli in the 4 weeks following adult incision. Prior neonatal injury also 'primed' the spinal microglial response to adult injury, resulting in an increased intensity, spatial distribution and duration of ionized calcium-binding adaptor molecule-1-positive microglial reactivity in the dorsal horn. Intrathecal minocycline at the time of adult injury selectively prevented both the hyperalgesia and early microglial reactivity associated with prior neonatal injury. The enhanced neuroimmune response seen in neonatally primed animals could also be demonstrated in the absence of peripheral tissue injury by direct electrical stimulation of tibial nerve fibres, confirming that centrally mediated mechanisms contribute to these long-term effects. These data suggest that early life injury may predispose individuals to enhanced sensitivity to painful events.

Intranasal Application of Xenon Reduces Opioid Requirement and Postoperative Pain in Patients Undergoing Major Abdominal Surgery

Both central sensitization after peripheral tissue injury and the development of opioid tolerance involve activation of N-methyl-D-aspartate (NMDA) receptors. At subanesthetic doses the NMDA receptor antagonist xenon suppresses pain-evoked sensitization of pain-processing areas in the central nervous system. Although numerous studies describe the effect of NMDA receptor antagonists on postoperative pain, clinical studies elucidating their intraoperative analgesic potency when applied in a low dosage are still largely missing. To analyze the analgesic effect of low-dose xenon using new application methods, the authors tested nasally applied xenon as an add-on treatment for analgesia in 40 patients undergoing abdominal hysterectomy. Within a randomized double-blind placebo-controlled study design, intraoperative and postoperative requirement of opioids as well as postoperative subjective experiences of pain were measured as primary outcome variables. Intranasal application of xenon significantly reduced intraoperative opioid requirement (mean difference [MD] -2.0 μg/min; 95% CI [CI95]-0.53 to -3.51, Bonferroni correction adjusted P value [pcorr]= 0.028) without relevant side effects and significantly reduced postoperative pain (MD -1.34 points on an 11-point rating scale; CI95 -0.60 to -2.09, pcorr = 0.002). However, postoperative morphine consumption (MD -8.8 μg/min; CI95 1.2 to -18.8, pcorr = 0.24) was not significantly reduced in this study. Low-dose xenon significantly reduces intraoperative analgesic use and postoperative pain perception. Because NMDA receptor antagonists suppress central sensitization, prevent the development of opioid tolerance, and reduce postoperative pain, the intraoperative usage of NMDA receptor antagonists such as xenon is suggested to improve effectiveness of pain management within a concept of multimodal analgesia.

Central sensitization of nociceptive neurons in rat medullary dorsal horn involves purinergic P2X7 receptors.

Central sensitization is a crucial process underlying the increased neuronal excitability of nociceptive pathways following peripheral tissue injury and inflammation. Our previous findings have suggested that extracellular adenosine 5'-triphosphate (ATP) molecules acting at purinergic receptors located on presynaptic terminals (e.g., P2X2/3, P2X3 subunits) and glial cells are involved in the glutamatergic-dependent central sensitization induced in medullary dorsal horn (MDH) nociceptive neurons by application to the tooth pulp of the inflammatory irritant mustard oil (MO). Since growing evidence indicates that activation of P2X7 receptors located on glia is involved in chronic inflammatory and neuropathic pain, the aim of the present study was to test in vivo for P2X7 receptor involvement in this acute inflammatory pain model. Experiments were carried out in anesthetized Sprague-Dawley male rats. Single unit recordings were made in MDH functionally identified nociceptive neurons for which mechanoreceptive field, mechanical activation threshold and responses to noxious stimuli were tested. We found that continuous intrathecal (i.t.) superfusion over MDH of the potent P2X7 receptor antagonists brilliant blue G and periodated oxidized ATP could each significantly attenuate the MO-induced MDH central sensitization. MDH central sensitization could also be produced by i.t. superfusion of ATP and even more effectively by the P2X7 receptor agonist benzoylbenzoyl ATP. Superfusion of the microglial blocker minocycline abolished the MO-induced MDH central sensitization, consistent with reports that dorsal horn P2X7 receptors are mostly expressed on microglia. In control experiments, superfusion over MDH of vehicle did not produce any significant changes. These novel findings suggest that activation of P2X7 receptors in vivo may be involved in the development of central sensitization in an acute inflammatory pain model.

Peripheral Tissue Trauma Triggers an Inflammatory Response Causing Intestinal Microvascular Serum Leak Which Disrupts Gastrointestinal Motility

Introduction: Combat and civilian trauma is the leading cause of death for individuals in the prime of their life. Gastrointestinal dysfunction plays a key role in the detrimental sequelae of trauma (systemic inflammatory response, feeding intolerance, reflux/aspiration pneumonia and bacterial overgrowth/dissemination through mucosal barrier failure), but the mechanisms through which peripheral tissue injury can induce these responses is unclear. Aims: To investigate the mechanism of trauma-induced gastrointestinal dysfunction in a precisely controllable non-narcotic, tissue-bone matrix (TBX) trauma model, which is known to reproducibly display significant gastrointestinal dysmotility. Methods: A non-narcotic murine tissue trauma model was constructed by the dorsal subcutaneous implantation of minced donor syngeneic tissue-bone matrix (TBX) precisely adjusted to 17.5% body weight and studied after 21 hrs. Inflammatory mediators in serum, fresh TBX and TBX wound fluid at 21hrs were measured by electrochemiluminescence detection and intestinal muscularis microvascular leak was microscopically quantified in whole-mounts after i.v. injection of FITC-dextran (70k MW). Gastrointestinal transit and jejunal circular muscle contractility was assessed after injection of normal mouse serum (i.p. 100μl q1h x 8). Results: Compared to normal serum, TNF α was only acutely elevated in fresh TBX fluid (1.1±0.01, 4.1±0.22 and 1.1±0.01 ng/ml) and IL 1β exhibited increased levels in both fresh TBX fluid and in TBX wound fluid (1.9±0.22, 107.6±1.45 and 92.2±6.12 ng/ml). Whereas, IL-6 (80.4±10.0, 158.5±4.08 and 26851.1±4883.39 ng/ml) and kerotinocyte chemokine (KC; 237.5±47.14, 110.4±1.59 and 9763.2±817.29 ng/ml) were significantly increased in the re-harvested TBX wound fluid after 21 hours of implantation. The systemic response to the implanted TBX resulted in significant serum elevations in IL-6, KC and IL-10 compared to control and sham surgical groups at 21 hrs (N=6 each), as well as causing significant intestinal muscularis microvascular leak. Interestingly, i.p. injections of normal serum into naive mice recapitulated the TBX-induced dysmotility causing delayed gastrointestinal transit (9.8±0.15 vs. 3.4±0.22) and a 49.5% suppression in bethanechol stimulated jejunal muscle strip contractility compared to saline injections (N=6). Conclusion: Peripheral tissue injury and consequent systemic inflammatory response cause intestinal muscularis microvascular leak and dysmotility, which can be recapitulated by intraperitoneal injection of exogenous normal serum. These novel findings demonstrate the key regulatory effect of intestinalmicrovascular leak on gastrointestinal motility in trauma.

Effects of environmental salinity, biopsy, and GH and IGF-I administration on the expression of immune and osmoregulatory genes in the gills of Atlantic salmon (Salmo salar)

Immune-endocrine interactions are thought to be important for fish health, especially following injury of peripheral tissues. We investigated the influences of gill biopsy (surgical removal of several gill filaments with minimal bleeding) on mRNA levels of osmoregulatory and immune genes in peripheral tissues of Atlantic salmon (Salmo salar) smolts in freshwater (FW) and seawater (SW). The effects of growth hormone (GH) and insulin-like growth factor (IGF)-I, which are known as both osmoregulatory and immunomodulatory hormones, were also examined in FW- and SW-acclimated fish. Compared with the intact gill arch of the same fish, the residuary filaments after biopsy showed significant reduction in Na+,K+-ATPase (NKA) and cystic fibrosis transmembrane conductance regulator (CFTR) mRNA levels in FW fish. In contrast, mRNA levels of these genes in the filaments with biopsy were increased in SW fish. Increased caspase gene transcription was observed in the cut filaments of SW fish, but not in those of FW fish. Lysozyme gene transcription was stimulated in the residuary gill filaments after biopsy in both FW and SW. Administration of salmon GH or IGF-I increased mRNA levels of NKA, CFTR, caspase, and lysozyme in the gills after biopsy in FW fish. In SW-acclimated fish, there was no significant effect of GH or IGF-I on the transcription of osmoregulatory or immune genes. The results in this study showed tight relationships between immunity, osmoregulation, and endocrine system in fish gills, and that nonlethal gill biopsy can be used for investigations of fish health.

Peripheral Nerve Blockade

Peripheral Nerve Blockade

In vitro Experiments with the Triangular Flap Cutter Applied to Functional Tracheoesophageal Shunt for Voice Rehabilitation after Total Laryngectomy

Backgrounds: Since the introduction and practice of functional tracheoesophageal shunt (FTES) for voice rehabilitation after total laryngectomy, patients have often suffered from fistula-related complications such as aspiration, tract stenosis and infection partly as a result of nonstandardized or incorrectly made flap operation. In striving to solve these problems as far as possible, a triangular flap cutter (TFC) was developed to perform the flap operation. Methods: Flap operations were performed using a TFC on 10 tracheoesophageal models (pigs) and 10 fresh esophageal models (esophageal cancer patients, with their informed consent) and incision parameters and incision effects were detected. Results: Perfect triangular flaps were achieved in 18 out of 20 cases using the TFC with minimal peripheral tissue injury (average time, 2–3 min). Of the 2 unsuccessful cases, 1 case exhibited insertion failure and the other experienced flap creation failure due to clinical contraindication for TFC use and insufficient operational skills, respectively. Conclusions: The TFC is a new device, which offers the unique advantage of precise incision for the creation of a flap, with the potential to resolve fistula-related problems and improve operation efficiency.

Activation of Mitogen-Activated Protein Kinase in Descending Pain Modulatory System

The descending pain modulatory system is thought to undergo plastic changes following peripheral tissue injury and exerts bidirectional (facilitatory and inhibitory) influence on spinal nociceptive transmission. The mitogen-activated protein kinases (MAPKs) superfamily consists of four main members: the extracellular signal-regulated protein kinase1/2 (ERK1/2), the c-Jun N-terminal kinases (JNKs), the p38 MAPKs, and the ERK5. MAPKs not only regulate cell proliferation and survival but also play important roles in synaptic plasticity and memory formation. Recently, many studies have demonstrated that noxious stimuli activate MAPKs in several brain regions that are components of descending pain modulatory system. They are involved in pain perception and pain-related emotional responses. In addition, psychophysical stress also activates MAPKs in these brain structures. Greater appreciation of the convergence of mechanisms between noxious stimuli- and psychological stress-induced neuroplasticity is likely to lead to the identification of novel targets for a variety of pain syndromes.