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Introduction Despite being an occupational hazard, environmental exposure to lead (Pb) has been and will continue to be a major public health concern, because this metal is widely present in [...], BACKGROUND: The role of environmental factors in Alzheimer's disease (AD) pathogenesis remains elusive. Mounting evidence suggests that acute and past exposure to the environmental toxicant lead (Pb) is associated with longitudinal decline in cognitive function, brain atrophy, and greater brain [beta]-amyloid (A[beta]) deposition. However, the nature of Pb-induced amyloid deposition and how it contributes to AD development remain unclear. OBJECTIVES: This study investigates the role of Pb in the pathogenesis of cerebral amyloid angiopathy (CAA) and whether plasminogen activator inhibitor-1 (PAI-1) contributes to this process in the APP/PS1 mouse model. METHODS: Female APP/PS1 mice at 8 wk of age were administered either 50 mg/kg Pb-acetate (PbAc) (i.e., 27 mg Pb/kg) or an equivalent molar concentration of sodium acetate (NaAc) via oral gavage once daily for 8 wk. Amyloid deposition and vascular amyloid were determined by immuno-staining. In addition, A[beta] perivascular drainage, vascular binding assay, and microglial endocytosis were examined to determine underlying mechanisms. Furthermore, magnetic resonance imaging demyelination imaging was performed in vivo measure the level of demyelination. Finally, Y-maze and Morris water maze tests were assessed to evaluate the cognitive function of mice. RESULTS: APP/PS1 mice (an AD mice model) exposed to PbAc demonstrated more vascular amyloid deposition less neocortical myelination, and lower cognitive function, as well as greater vascular binding to A[beta]40, higher A[beta]40/A[beta]42 ratios, strikingly lower A[beta]40 levels in the perivascular drainage, and microglial endocytosis. Importantly, exposure to a specific PAI-1 inhibitor, tiplaxtinin, which previously was reported to lower CAA pathology in mice, resulted in less CAA-related outcomes following PbAc exposure. DISCUSSION: Our findings suggest that PbAc induced CAA/AD pathogenesis via the PAI-1 signaling in the APP/PS1 mouse model, and the inhibition of PAI-1 could be a potential therapeutic target for PbAc-mediated CAA/AD disorders. https://doi.org/10.1289/EHP14384

Regenerative pain medicine, which seeks to harness the body's own reparative capacity, is rapidly emerging as a field within pain medicine and orthopedics. It is increasingly appreciated that common analgesic mechanisms for these treatments depend on neuroimmune modulation. In this Review, we discuss recent progress in mechanistic understanding of nociceptive sensitization in chronic pain with a focus on neuroimmune modulation. We also examine the spectrum of regenerative outcomes, including preclinical and clinical outcomes. We further distinguish the analgesic mechanisms of regenerative therapies from those of cellular replacement, creating a conceptual and mechanistic framework to evaluate future research on regenerative medicine., While acute pain brings attention to injuries, chronic pain has no biological benefits. Chronic pain often arises from disease (e.g., arthritis, cancer) and trauma (e.g., nerve injury, spinal cord injury); [...]

Pattern recognition receptors (PRRs) are crucial for responses to infections and tissue damage; however, their role in autoimmunity is less clear. Herein we demonstrate that 2 C-type lectin receptors (CLRs) Mcl and Mincle play an important role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Congenic rats expressing lower levels of Mcl and Mincle on myeloid cells exhibited a drastic reduction in EAE incidence. In vivo silencing of Mcl and Mincle or blockade of their endogenous ligand SAP130 revealed that these receptors' expression in the central nervous system is crucial for T cell recruitment and reactivation into a pathogenic Th17/GM-CSF phenotype. Consistent with this, we uncovered MCL- and MINCLE-expressing cells in brain lesions of MS patients and we further found an upregulation of the MCL/MINCLE signaling pathway and an increased response following MCL/MINCLE stimulation in peripheral blood mononuclear cells from MS patients. Together, these data support a role for CLRs in autoimmunity and implicate the MCL/MINCLE pathway as a potential therapeutic target in MS., Introduction Multiple sclerosis (MS), a leading cause of neurological disability in young adults, is a chronic inflammatory disease of the central nervous system (CNS) characterized by autoimmune destruction of myelin [...]

Inflammation is the body's response to injury and infection, involving a complex biological response of the somatosensory, immune, autonomic, and vascular systems. Inflammatory mediators such as prostaglandin, proinflammatory cytokines, and chemokines induce pain via direct activation of nociceptors, the primary sensory neurons that detect noxious stimuli. Neurogenic inflammation is triggered by nerve activation and results in neuropeptide release and rapid plasma extravasation and edema, contributing to pain conditions such as headache. Neuroinflammation is a localized inflammation in the peripheral nervous system (PNS) and central nervous system (CNS). A characteristic feature of neuroinflammation is the activation of glial cells in dorsal root ganglia, spinal cord, and brain which leads to the production of proinflammatory cytokines and chemokines in the PNS and CNS that drives peripheral sensitization and central sensitization. Here, we discuss the distinct roles of inflammation, neurogenic inflammation, and neuroinflammation in the regulation of different types of pain conditions, with a special focus on neuroinflammation in postoperative pain and opioid-induced hyperalgesia., Author(s): Megumi Matsuda [sup.1] [sup.2] , Yul Huh [sup.1] , Ru-Rong Ji [sup.1] Author Affiliations: (Aff1) 0000000100241216, grid.189509.c, Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, [...]

Neuropathic pain is a common health problem that affects millions of people worldwide. Despite being studied extensively, the cellular and molecular events underlying the central immunomodulation and the pathophysiology of neuropathic pain is still controversial. The idea that 'glial cells are merely housekeepers' is incorrect and with respect to initiation and maintenance of neuropathic pain, microglia and astrocytes have important roles to play. Glial cells differentially express opioid receptors and are thought to be functionally modulated by the activation of these receptors. In this review, we discuss evidence for glia-opioid modulation of pain by focusing on the pattern of astrocyte and microglial activation throughout the progress of nerve injury/neuropathic pain. Activation of astrocytes and microglia is a key step in central immunomodulation in terms of releasing pro-inflammatory markers and propagation of a 'central immune response'. Inhibition of astrocytes before and after induction of neuropathic pain has been found to prevent and reverse neuropathic pain, respectively. Moreover, microglial inhibitors have been found to prevent (but not to reverse) neuropathic pain. As they are expressed by glia, opioid receptors are expected to have a role to play in neuropathic pain., Author(s): Salim Kadhim [sup.1] , John McDonald [sup.1] , David G. Lambert [sup.1] Author Affiliations: (Aff1) Department of Cardiovascular Sciences, Anaesthesia Critical Care and Pain Management, University of Leicester, Leicester [...]

Activation of non-neuronal microglia is thought to play a causal role in spinal processing of neuropathic pain. To specifically investigate microglia-mediated effects in a model of neuropathic pain and overcome the methodological limitations of previous approaches exploring microglia function upon nerve injury, we selectively ablated resident microglia by intracerebroventricular ganciclovir infusion into male CD11b-HSVTK-transgenic mice, which was followed by a rapid, complete, and persistent (23 weeks) repopulation of the CNS by peripheral myeloid cells. In repopulated mice that underwent sciatic nerve injury, we observed a normal response to mechanical stimuli, but an absence of thermal hypersensitivity ipsilateral to the injured nerve. Furthermore, we found that neuronal expression of calcitonin gene-related peptide (CGRP), which is a marker of neurons essential for heat responses, was diminished in the dorsal horn of the spinal cord in repopulated mice. These findings identify distinct mechanisms for heat and mechanical hypersensitivity and highlight a crucial contribution of CNS myeloid cells in the facilitation of noxious heat., Introduction Neuropathic pain refers to a complex chronic pain state resulting from damage to or dysfunction of the somatosensory system characterized by mechanical allodynia, hyperalgesia, and spontaneous pain in human [...]

Previous studies have shown that persistent limb immobilization using a cast increases nociceptive behavior to somatic stimuli in rats. However, the peripheral neural mechanisms of nociception remain unclear. Using single-fiber electrophysiological recordings in vitro, we examined the general characteristics of cutaneous C-fiber afferents in the saphenous nerve and their responsiveness to mechanical and heat stimuli in a rat model of immobilization-induced pain by subjecting the rats to hindlimb cast immobilization for 4 weeks. The mechanical response of C-fibers appeared to increase in the model; however, statistical analysis revealed that neither the response threshold nor the response magnitude was altered. The general characteristics and heat responses of the C-fibers were not altered. The number of microglia and cell diameters significantly increased in the superficial dorsal horn of the lumbar spinal cord. Thus, activated microglia-mediated spinal mechanisms are associated with the induction of nociceptive hypersensitivity in rats after persistent cast immobilization. Keywords: Cast immobilization, Hyperalgesia, C-fiber afferents, Single-fiber recording, Spinal microglia, Rats, Author(s): Hiroki Ota[sup.1,2], Haruna Takebe[sup.1], Kazue Mizumura[sup.3] and Toru Taguchi[sup.1,2] Background Experimental cast immobilization of the wrist for 4 weeks led to the development of pain during movement in 90% [...]

Moesin is a member of the ezrin, radixin and moesin (ERM) proteins that are involved in the formation and/or maintenance of cortical actin organization through their cross-linking activity between actin filaments and proteins located on the plasma membranes as well as through regulation of small GTPase activities. Microglia, immune cells in the central nervous system, show dynamic reorganization of the actin cytoskeleton in their process elongation and retraction as well as phagocytosis and migration. In microglia, moesin is the predominant ERM protein. Here, we show that microglial activation after systemic lipopolysaccharide application is partly inhibited in moesin knockout (Msn-KO) mice. We prepared primary microglia from wild-type and Msn-KO mice, and studied them to compare their phenotypes accompanying morphological changes and reorganization of the actin cytoskeleton induced by UDP-stimulated phagocytosis and ADP-stimulated migration. The Msn-KO microglia showed higher phagocytotic activity in the absence of UDP, which was not further increased by the treatment with UDP. They also exhibited decreased ADP-stimulated migration activities compared with the wild-type microglia. However, the Msn-KO microglia retained their ability to secrete tumor necrosis factor [alpha] and nitric oxide in response to lipopolysaccharide. Keywords: Microglia, Moesin, Actin cytoskeleton, Phagocytosis, Author(s): Tomonori Okazaki[sup.1], Daichi Saito[sup.1], Masatoshi Inden[sup.2], Kotoku Kawaguchi[sup.1], Sayuri Wakimoto[sup.1], Takashi Nakahari[sup.3] and Shinji Asano[sup.1] Introduction Microglia are immune cells resident in the central nervous system. Under normal or [...]

Diabetic peripheral neuropathy (DPN) is a chronic microvascular complication of diabetes. The purpose of this study is to find the underlying mechanism for the effects of acupuncture in DPN rats. Rats were rendered diabetic with a single injection of 35 mg/kg streptozotocin (STZ). These STZ-diabetic rats were treated with acupuncture for 20 min once daily. The therapeutic efficacy of acupuncture was assessed using mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) evaluations. After 14 days treatment, acupuncture markedly reduced the pathological injury in STZ-diabetic rats. Moreover, it significantly down-regulated P2X4 and OX42 expression along with the reduced levels of inflammatory factors (CXCR3, TNF-[alpha], IL-1[beta], IL-6), GSP and lipid metabolisms in the spinal cord of the DPN rats. Acupuncture could relieve DPN in rats by regulating P2X4 expression and inflammation in spinal microglia. Keywords: Acupuncture, Diabetic peripheral neuralgia, P2X4, Diabetic rat, Author(s): He-yong Tang[sup.1], Fan-jing Wang[sup.2], Jun-long Ma[sup.2], Hao Wang[sup.2], Guo-ming Shen[sup.1] and Ai-juan Jiang[sup.2,3] Background According to traditional Chinese medicine theory (TCMT), diabetes mellitus (DM) is referred to as Xiaokezheng [...]

Recent studies have implicated chemokines in microglial activation and pathogenesis of neuropathic pain. C-X-C motif chemokine 13 (CXCL13) is a B lymphocyte chemoattractant that activates CXCR5. Using the spinal nerve ligation (SNL) model of neuropathic pain, we found that CXCL13 was persistently upregulated in spinal cord neurons after SNL, resulting in spinal astrocyte activation via CXCR5 in mice. shRNA-mediated inhibition of CXCL13 in the spinal cord persistently attenuated SNL-induced neuropathic pain. Interestingly, CXCL13 expression was suppressed by miR-186-5p, a microRNA that colocalized with CXCL13 and was downregulated after SNL. Spinal overexpression of miR-186-5p decreased CXCL13 expression, alleviating neuropathic pain. Furthermore, SNL induced CXCR5 expression in spinal astrocytes, and neuropathic pain was abrogated in [Cxcr5.sup.-/-] mice. CXCR5 expression induced by SNL was required for the SNL-induced activation of spinal astrocytes and microglia. Intrathecal injection of CXCL13 was sufficient to induce pain hypersensitivity and astrocyte activation via CXCR5 and ERK. Finally, intrathecal injection of CXCL13-activated astrocytes induced mechanical allodynia in naive mice. Collectively, our findings reveal a neuronal/astrocytic interaction in the spinal cord by which neuronally produced CXCL13 activates astrocytes via CXCR5 to facilitate neuropathic pain. Thus, miR-186-5p and CXCL13/CXCR5-mediated astrocyte signaling may be suitable therapeutic targets for neuropathic pain., Introduction Chemokines are a family of small secreted proteins that are well-known regulators of peripheral immune cell trafficking (1). It has become evident that chemokines are also expressed in the [...]

Purpose Bortezomib (BTZ), a widely used chemotherapeutic drug, is closely associated with the development of painful peripheral neuropathy, but the mechanism underlying the induction of this disorder by BTZ remains largely unclear. To examine this association, we have evaluated the activation of mitogen-activated protein kinase (MAPK) family members in the spinal dorsal horn and the role of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) in BTZ-induced allodynia in rats. Methods Male Sprague-Dawley rats were used as the model animals. The paw withdrawal test, in which mechanical stimuli (von Frey hairs) is applied to the plantar surface of the hindpaw, was used to determine any changes in the paw withdrawal threshold of the treated rats. A PE-10 catheter was placed intrathecally to deliver TNF-α neutralizing antibody, IL-1 receptor antagonist (IL-1ra) or the c-Jun N-terminal kinase (JNK) inhibitor SP600125. The mRNA levels of various cytokines were measured by real-time quantitative PCR. The expression of TNF-α, IL-1β and mitogen-activated protein kinase (MAPK) family members in the spinal dorsal horn was measured by western blot analysis and immunohistochemistry. All data were expressed as the mean ± standard error of the mean and analyzed using the SPSS version 13.0 software program. Results The BTZ treatment induced an upsurge in the mRNA and protein levels of TNF-α in the neurons and IL-1β in the astrocytes in the spinal dorsal horn. It also significantly upregulated the phosphorylation of JNK but not of extracellular signal-regulated kinases (ERK) and p38-MAPK in astrocytes of the spinal dorsal horn. Inhibition of TNF-α or IL-1β ameliorated JNK activation and mechanical allodynia induced by BTZ. Co-administration of thalidomide (TNF-α synthesis inhibitor) and IL-1ra prevented BTZ-induced mechanical allodynia. Conclusion Our results suggest that the TNF-α or IL-1β/JNK pathway in the spinal dorsal horn may play a critical role in the development of painful peripheral neuropathy induced by BTZ., Author(s): Zhen-Yu Li[sup.2] , Yuan-Pei Zhang[sup.1] , Jie Zhang[sup.1] , Su-Bo Zhang[sup.1] , Dai Li[sup.1] , Zhen-Zhen Huang[sup.1] , Wen-Jun Xin[sup.1] Author Affiliations: (1) Department of Physiology and Pain Research [...]

Purpose Many patients suffer from chronic postsurgical pain (CPSP) following surgery, and the underlying mechanisms are poorly understood. In the present work, using the skin/muscle incision retraction (SMIR) model, the role of spinal TLR4/TNF-[alpha] pathway in the induction of CPSP was evaluated. Methods Mechanical allodynia induced by SMIR was established in adult male Sprague-Dawley rats. The von Frey test was performed to evaluate the role of TLR4/TNF-[alpha] pathway on the mechanical allodynia. Western-blot and immunohistochemistry methods were adopted to understand the molecular mechanisms. Results SMIR surgery decreased the ipsilateral 50 % paw withdrawal threshold, lasting for at least 20 days. Western-blot analysis and immunohistochemistry revealed that SMIR surgery significantly upregulated the expression of TLR4 (p < 0.01) in glial cells on the ipsilateral side of spinal cord and increased TLR4 occurred on day 5 and was maintained to the end of the experiment (day 20). Similarly, tumor necrosis factor-alpha (TNF-[alpha]) was significantly increased on days 5, 10, and 20 on the ipsilateral side of spinal dorsal horn following SMIR surgery. Intraperitoneal injection of an inhibitor of TNF-[alpha] synthesis thalidomide at 50 or 100 mg/kg dose (but not 10 mg/kg dose) significantly ameliorated the reduced paw withdrawal threshold induced by SMIR surgery. Importantly, intrathecal delivery of a specific TLR4 antagonist (LPS-RS) at dose of 25 [mu]g significantly attenuated mechanical allodynia and prevented the upregulation of TNF-[alpha] induced by SMIR surgery. Conclusions These findings suggest that the upregulation of TNF-[alpha] via TLR4 contributes to the development of CPSP in spinal dorsal horn., Author(s): Yang Sun[sup.2] , Mingmin Yang[sup.2] , Hao Tang[sup.1] , Zhongfu Ma[sup.1] , Yanbing Liang[sup.1] , Zhenyu Li[sup.1] Author Affiliations: (1) Department of General Internal Medicine, The First Affiliated Hospital [...]

Hypersensitivity to mechanical stimuli following surgery has been reported in patients who subsequently develop chronic pain after surgery. In animals, peripheral injury increases prostaglandin production in the spinal cord, and spinal cyclooxygenase inhibitors reduce hypersensitivity after injury. We therefore tested the hypothesis that spinal ketorolac reduces hypersensitivity and acute and chronic pain after hip arthroplasty (www.clinicaltrials.gov NCT 00621530). Sixty-two patients undergoing total hip arthroplasty with spinal anesthesia were randomized to receive 13.5 mg hyperbaric bupivacaine with spinal saline or 13.5 mg hyperbaric bupivacaine with 2 mg preservative-free ketorolac. The primary outcome was area of hypersensitivity surrounding the wound 48 h after surgery, but this only occurred in 4 patients, precluding assessment of this outcome. The groups did not differ in acute pain, acute opioid use, or pain incidence or severity at 2 and 6 months after surgery. There were no serious adverse events. Our results suggest that a single spinal dose of ketorolac does not substantially reduce acute surgical pain and is thus unlikely to reduce the risk of persistent incisional pain. Keywords Ketorolac * Pain * Spinal cord * Intrathecal injection * Human * Postoperative, A role of prostaglandin production in pain is well established. However, the importance of prostaglandins in many chronic pain conditions remains unknown, as do the sites where prostaglandins act. Cyclooxygenase [...]

Increasing evidence indicates that the pathogenesis of neuropathic pain is mediated through spinal cord microglia activation. The intracellular protease caspase-6 (CASP6) is known to regulate neuronal apoptosis and axonal degeneration; however, the contribution of microglia and CASP6 in modulating synaptic transmission and pain is unclear. Here, we found that CASP6 is expressed specifically in C-fiber axonal terminals in the superficial spinal cord dorsal horn. Animals exposed to intraplantar formalin or bradykinin injection exhibited CASP6 activation in the dorsal horn. Casp6-null mice had normal baseline pain, but impaired inflammatory pain responses. Furthermore, formalin-induced second-phase pain was suppressed by spinal injection of CASP6 inhibitor or CASP6-neutralizing antibody, as well as perisciatic nerve injection of CASP6 siRNA. Recombinant CASP6 (rCASP6) induced marked TNF-α release in microglial cultures, and most microglia within the spinal cord expressed Tnfa. Spinal injection of rCASP6 elicited TNF-α production and microglia-dependent pain hypersensitivity. Evaluation of excitatory postsynaptic currents (EPSCs) revealed that rCASP6 rapidly increased synaptic transmission in spinal cord slices via TNF-α release. Interestingly, the microglial inhibitor minocycline suppressed rCASP6 but not TNF-α-induced synaptic potentiation. Finally, rCASP6-activated microglial culture medium increased EPSCs in spinal cord slices via TNF-α. Together, these data suggest that CASP6 released from axonal terminals regulates microglial TNF-α secretion, synaptic plasticity, and inflammatory pain., Introduction Tissue injury results in pain hypersensitivity, as a result of peripheral sensitization (sensitization of primary sensory neurons) (1), (2) and central sensitization (sensitization of spinal cord and brain neurons) [...]

The development of opioid-induced analgesic tolerance and hyperalgesia is a clinical challenge for managing chronic pain. Adaptive changes in protein translation in the nervous system are thought to promote opioid tolerance and hyperalgesia; however, how opioids drive such changes remains elusive. Here, we report that mammalian target of rapamycin (mTOR), which governs most protein translation, was activated in rat spinal dorsal horn neurons after repeated intrathecal morphine injections. Activation was triggered through µ opioid receptor and mediated by intracellular PI3K/Akt. Spinal mTOR inhibition blocked both induction and maintenance of morphine tolerance and hyperalgesia, without affecting basal pain perception or locomotor functions. These effects were attributed to the attenuation of morphine-induced increases in translation initiation activity, nascent protein synthesis, and expression of some known key tolerance-associated proteins, including neuronal NOS (nNOS), in dorsal horn. Moreover, elevating spinal mTOR activity by knocking down the mTOR-negative regulator TSC2 reduced morphine analgesia, produced pain hypersensitivity, and increased spinal nNOS expression. Our findings implicate the ^ opioid receptor-triggered PI3K/Akt/mTOR pathway in promoting morphine-induced spinal protein translation changes and associated morphine tolerance and hyperalgesia. These data suggest that mTOR inhibitors could be explored for prevention and/or reduction of opioid tolerance in chronic pain management., Introduction Chronic pain is a major public health problem. About 116 million Americans (approximately 30% of the population) live with this disorder. The economic impact of chronic pain is equally [...]

Despite the development of effective chemotherapy and radiotherapy, surgery remains the mainstay treatment of many cancers, requiring anesthesia. Almost all cancer deaths after primary surgery are attributable to recurrence or metastases. Recently it has been hypothesized that the perioperative anesthetic management of cancer patients could potentially affect the risk of recurrence and metastases, which implies a key role for anesthesiologists in choosing anesthetic agents and techniques that optimize the balance between the metastatic potential of the tumor versus its elimination by antimetastatic immune defenses. This review summarizes available experimental information on the potential effects of common anesthetic agents and techniques on cancer metastases and the conflicting retrospective clinical data on regional anesthesia in various types of cancer. A number of prospective, randomized, multicenter, clinical trials are in progress, and their results are eagerly awaited. Keywords Anesthetic drugs and techniques * General and regional anesthesia * Cancer recurrence * Metastases, Introduction: cancer, a major killer The global burden of cancer is still increasing as a result of the growth of the aging population and in spite of well-developed modern medical [...]

Purpose The purpose of this study was to compare the effect of the long-term administration of flurbiprofen and fentanyl in the intensive care unit on natural killer cell cytotoxicity (NKCC), lymphocyte subsets and cytokine levels. Methods In this prospective study, patients scheduled for at least 48 h sedation after neck surgery were randomly assigned to two groups called group N and group F. Group N patients were sedated with propofol and flurbiprofen after surgery (n = 12), while group F patients were sedated with propofol and fentanyl (n = 13). The NKCC, lymphocyte subsets, and plasma levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 were measured before and at the end of surgery, on postoperative day (POD) 1 and POD2. Results The NKCC was significantly higher on POD1 in group N than in group F (14.5 ± 11.2 versus 6.3 ± 4.1%, p < 0.05), the difference between the groups disappearing on POD2. Lymphocyte subsets and plasma levels of cytokines were not significantly different between the two groups during the study period. Conclusions Transient suppressive effects on NKCC were observed in the fentanyl group as compared to the flurbiprofen group. This suggests that when choosing postoperative analgesics, physicians should bear in mind the potential immunosuppressive effects of these agents in patients requiring prolonged sedation in the intensive care unit. Keywords Natural killer cell cytotoxicity * Fentanyl * Flurbiprofen * Long-term sedation, Introduction There have been many reports showing that immunosuppression associated with surgical stress occurs during the perioperative period [1-3]. In addition, recent research has shown that anesthetic and analgesic drugs [...]

Purpose Morphine is a powerful analgesic but its effect is often diminished owing to the development of tolerance. It has been suggested that morphine activates microglia through its action on the toll-like receptor 4 (TLR4) in the spinal cord, leading to suppression of the morphine effect. However, it has not been examined whether the development of morphine tolerance is affected by the deletion and mutation of the TLR4 gene. Methods Mice were treated with morphine (60 mg/kg) or vehicle once daily for five consecutive days to induce morphine tolerance, which was assessed by the tail-flick test before and after the treatment period. The effect of the microglial inhibitor minocycline, and the effect of TLR4 mutation (C3H/HeJ mouse) and deletion (TLR4-knockout mouse) on the development of morphine tolerance were tested. The expression of the microglial activation marker, CD11b, in the spinal cords of TLR4-knockout and wild-type mice after morphine treatment for 5 days was assessed by reverse-transcription polymerase chain reaction. Results Minocycline attenuated the development of morphine tolerance in mice. Mutation or deletion of the TLR4 gene did not significantly affect the development of morphine tolerance. CD11b mRNA expression was increased after morphine treatment both in TLR4-knockout and wild-type mice. Conclusion Microglial activation caused by a mechanism independent of TLR4 is involved in the development of morphine tolerance. Further studies are necessary to clarify the cellular mechanisms of morphine-induced microglial activation. Keywords Morphine * Microglia * TLR4 * Minocycline, Introduction Opioids are the most powerful analgesic drugs used for acute and chronic pain management [1]. However, their clinical utility is often limited by the development of analgesic tolerance, in [...]

Itch, also known as pruritus, is a common, intractable symptom of several skin diseases, such as atopic dermatitis and xerosis. TLRs mediate innate immunity and regulate neuropathic pain, but their roles in pruritus are elusive. Here, we report that scratching behaviors induced by histamine-dependent and -independent pruritogens are markedly reduced in mice lacking the Tlr3 gene. TLR3 is expressed mainly by small-sized primary sensory neurons in dorsal root ganglions (DRGs) that coexpress the itch signaling pathway components transient receptor potential subtype V1 and gastrin-releasing peptide. Notably, we found that treatment with a TLR3 agonist induces inward currents and action potentials in DRG neurons and elicited scratching in WT mice but not Tlr3-/- mice. Furthermore, excitatory synaptic transmission in spinal cord slices and long-term potentiation in the intact spinal cord were impaired in Tlr3-/- mice but not Tlr7-/- mice. Consequently, central sensitization-driven pain hypersensitivity, but not acute pain, was impaired in Tlr3-/- mice. In addition, TLR3 knockdown in DRGs also attenuated pruritus in WT mice. Finally, chronic itch in a dry skin condition was substantially reduced in Tlr3-/- mice. Our findings demonstrate a critical role of TLR3 in regulating sensory neuronal excitability, spinal cord synaptic transmission, and central sensitization. TLR3 may serve as a new target for developing anti-itch treatment., Introduction Itch, also known as pruritus, is an unpleasant cutaneous sensation that evokes desire or reflex of scratching behavior, which is distinct from pain that elicits withdrawal reflex (1). Like [...]

Purpose This study was undertaken to examine the effect of gabapentin for preventing hyperalgesia induced by morphine and fentanyl withdrawal in rats. Methods To induce hyperalgesia, Sprague Dawley (SD) rats were subcutaneously injected with fentanyl four times at 15-min intervals (60 µg/kg per injection), resulting in total dose of 240 µg/kg over 1 h, and morphine 10 mg/kg twice daily for 7 days. The effect of gabapentin was detected with behavioral tail-flick and paw-withdrawal tests. Results Drug termination produced significant decrease in antinociception thresholds (P < 0.05 vs. saline group), indicating that the rats became sensitive to thermal stimuli. In rats that received combined treatment with fentanyl/ morphine and gabapentin (25/50 mg/kg), results demonstrated that there were no significant decreases in antinociception thresholds (vs. saline group) after opioid withdrawal. Gabapentin (50 mg/kg) could also prevent morphine tolerance. The 50% effective dose (ED50) value was 12.5 mg/kg in tail-flick and 13.6 mg/kg in paw-withdrawal tests. Conclusions The study showed that gabapentin can significantly prevented opioid-induced hyperalgesia (OIH) induced caused by fentanyl and morphine, suggesting a role for the addition of gabapentin in the perioperative period and during chronic pain treatment as an effective drug to prevent OIH. Keywords Gabapentin * Opioid * Morphine * Fentanyl * Hyperalgesia * Tolerance, Introduction Opioids are the most commonly used analgesics in pain treatment. However, accumulating evidence suggests that opioids produce not only an antinociceptive effect, but also increase sensitivity to noxious stimulation. [...]

Mendelian heritable pain disorders have provided insights into human pain mechanisms and suggested new analgesic drug targets. Interestingly, many of the heritable monogenic pain disorders have been mapped to mutations in genes encoding ion channels. Studies in transgenic mice have also implicated many ion channels in damage sensing and pain modulation. It seems likely that aberrant peripheral or central ion channel activity underlies or initiates many pathological pain conditions. Understanding the mechanistic basis of ion channel malfunction in terms of trafficking, localization, biophysics, and consequences for neurotransmission is a potential route to new pain therapies., Introduction Pain serves to protect the body from harm and promote healing of damaged tissues. Chronic pain, however, remains a major clinical challenge, which, if unmet, significantly diminishes quality of [...]

Despite intensive research into pain mechanisms and significant investment in research and development, the majority of analgesics available to prescribers and patients are based on mechanistic classes of compounds that have been known for many years. With considerable ingenuity and innovation, researchers continue to make the best of the mechanistic approaches available, with novel formulations, routes of administration, and combination products. Here we review some of the mechanisms and modalities of analgesics that have recently entered into clinical development, which, coupled with advances in the understanding of the pathophysiology of chronic pain, will hopefully bring the promise of new therapeutics that have the potential to provide improved pain relief for those many patients whose needs remain poorly met., Introduction Drug discovery and development continue to be a challenge, with increasingly high investments in R&D and increased numbers of submissions failing to translate into the delivery of novel chemical [...]

Background Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor that carries a 5-y survival rate of 5%. Attempts at eliciting a clinically relevant anti-GBM immune response in brain tumor patients have met with limited success, which is due to brain immune privilege, tumor immune evasion, and a paucity of dendritic cells QCs) within the central nervous system. Herein we uncovered a novel pathway for the activation of an effective anti-GBM immune response mediated by high-mobility-group box 1 (HMGB1), an alarmin protein released from dying tumor cells, which acts as an endogenous ligand for Toll-like receptor 2 (TLR2) signaling on bone marrow-derived GBM-infiltrating DCs. Methods and Findings Using a combined immunotherapy/conditional cytotoxic approach that utilizes adenoviral vectors (Ad) expressing Fms-like tyrosine kinase 3 ligand (FIt3L) and thymidine kinase (TK) delivered into the tumor mass, we demonstrated that [CD4.sup.+] and [CD8.sup.+]T cells were required for tumor regression and immunological memory. Increased numbers of bone marrow-derived, tumor-infiltrating myeloid DCs (mDCs) were observed in response to the therapy. Infiltration of mDCs into the GBM, clonal expansion of antitumor T cells, and induction of an effective anti-GBM immune response were TLR2 dependent. We then proceeded to identify the endogenous ligand responsible for TLR2 signaling on tumor-infiltrating mDCs. We demonstrated that HMGB1 was released from dying tumor cells, in response to Ad-TK (+ gancyclovir [GCV]) treatment. Increased levels of HMGB1 were also detected in the serum of tumor-bearing Ad-Flt3L/Ad-TK (+GCV)-treated mice. Specific activation of TLR2 signaling was induced by supernatants from Ad-TK (+GCV)-treated GBM cells; this activation was blocked by glycyrrhizin (a specific HMGB1 inhibitor) or with antibodies to HMGB1. HMGB1 was also released from melanoma, small cell lung carcinoma, and glioma cells treated with radiation or temozolomide. Administration of either glycyrrhizin or anti-HMGB1 immunoglobulins to tumor-bearing AdFIt3L and Ad-TK treated mice, abolished therapeutic efficacy, highlighting the critical role played by HMGB1-mediated TLR2 signaling to elicit tumor regression. Therapeutic efficacy of Ad-Flt3L and Ad-TK (+GCV) treatment was demonstrated in a second glioma model and in an intracranial melanoma model with concomitant increases in the levels of circulating HMGB1. Conclusions Our data provide evidence for the molecular and cellular mechanisms that support the rationale for the clinical implementation of antibrain cancer immunotherapies in combination with tumor killing approaches in order to elicit effective antitumor immune responses, and thus, will impact clinical neuro-oncology practice., Introduction The systemic immune system can be ignorant of antigens derived from tumors growing within the confines of the brain parenchyma [1] owing to the paucity of professional antigen presenting [...]

Watkins, Linda R., and Steven F. Maier. Beyond Neurons: Evidence That Immune and Glial Cells Contribute to Pathological Pain States. Physiol Rev 82: 981-1011, 2002; 10.1152/physerv.00011.2002.--Chronic pain can occur after [...]

Hypothesis A healthy gut with normal intestinal microflora is completely disrupted by oral antibiotics. The byproducts of harmful gut bacteria can interfere with brain development and may contribute to autism. Strategies to improve the gut microflora profile through dietary modification may help to alleviate gut disorders in autistic patients. Method Sixty young male western albino rats were divided into six equal groups. The first group served as the control; the second group was given an oral neurotoxic dose of propionic (PPA) (250 mg/kg body weight/day) for three days. The third group received an orogastric dose of ampicillin (50 mg/kg for three weeks) with a standard diet. Groups 4, 5 and 6 were given an orogastric dose of ampicillin and fed high-carbohydrate, high-protein and high-lipid diets, respectively, for 10 weeks. Biochemical parameters related to oxidative stress were investigated in brain homogenates from each group. Result The microbiology results revealed descriptive changes in the fecal microbiota of rats treated with ampicillin either alone or with the three dietary regimens. The results of PPA acid and ampicillin treatment showed significant increases in lipid peroxidation and catalase with decreases in glutathione and potassium compared with levels in the control group. A protein-rich diet was effective at restoring the glutathione level, while the carbohydrate-rich diet recovered lipid peroxidation and catalase activity. In addition, the three dietary regimens significantly increase the potassium level in the brain tissue of the test animals. Lactate dehydrogenase was remarkably elevated in all groups relative to the control. No outstanding effects were observed in glutathione S-transferase and creatine kinase. Conclusion The changes observed in the measured parameters reflect the neurotoxic effects of PPA and ampicillin. Lipid peroxide and catalase activity and the levels of glutathione and potassium are satisfactory biomarkers of PPA and ampicillin neurotoxicity. Based on the effects of the three dietary regimens, a balanced diet can protect against PPA or ampicillin-induced neurotoxicity that might induce autistic traits. These outcomes will help efforts directed at controlling the prevalence of autism, a disorder that has recently been associated with PPA neurotoxicity. Keywords: Autism, Ampicillin, Propionic acid, Neurotoxicity, Gut microbiota, Dietary regimens, Author(s): Afaf El-Ansary[sup.1,2] , Ramesa Shafi Bhat[sup.1] , Sooad Al-Daihan[sup.1] and Abeer M Al Dbass[sup.1] Background Human beings and their gut microbiota are in a symbiotic relationship, and a "super [...]

Background We investigated the interaction of Mycobacterium avium subspecies paratuberculosis, M. bovis and M. tuberculosis and different glial cells (enteric glial and microglial cells) in order to evaluate the infecting ability of these microorganisms and the effects produced on these cells, such as the evaluation of cytokines expression. Results Our experiments demonstrated the adhesion of M. paratuberculosis to the enteroglial cells and the induction of IL-1A and IL-6 expression; M. tuberculosis and M. bovis showed a good adhesive capability to the enteric cell line with the expression of the following cytokines: IL-1A and IL-1B, TNF-[alpha], G-CSF and GM-CSF; M. bovis induced the expression of IL-6 too. The experiment performed with the microglial cells confirmed the results obtained with the enteroglial cells after the infection with M. tuberculosis and M. bovis, whereas M. paratuberculosis stimulated the production of IL-1A and IL-1B. Conclusion Enteroglial and microglial cells, could be the target of pathogenic mycobacteria and, even if present in different locations (Enteric Nervous System and Central Nervous System), show to have similar mechanism of immunomodulation., Authors: Sara Cannas (corresponding author) [1]; Paola Molicotti [1]; Alessandra Bua [1]; Donatella Usai [1]; Leonardo A Sechi [1]; Antonio M Scanu [2]; Elisabetta Blasi [3]; Stefania Zanetti [1] Background [...]

Key Words review, interleukin-1, tumor necrosis factor, nerve growth factor, hyperalgesia, allodynia Abstract This review focuses on the powerful pain facilitatory effects produced by the immune system. Immune cells, activated [...]