Involvement Of Glial Cells Research Articles

A New Outlook on Mental Illnesses: Glial Involvement Beyond the Glue.

Mental illnesses have long been perceived as the exclusive consequence of abnormalities in neuronal functioning. Until recently, the role of glial cells in the pathophysiology of mental diseases has largely been overlooked. However recently, multiple lines of evidence suggest more diverse and significant functions of glia with behavior-altering effects. The newly ascribed roles of astrocytes, oligodendrocytes and microglia have led to their examination in brain pathology and mental illnesses. Indeed, abnormalities in glial function, structure and density have been observed in postmortem brain studies of subjects diagnosed with mental illnesses. In this review, we discuss the newly identified functions of glia and highlight the findings of glial abnormalities in psychiatric disorders. We discuss these preclinical and clinical findings implicating the involvement of glial cells in mental illnesses with the perspective that these cells may represent a new target for treatment.

GnRH Episodic Secretion Is Altered by Pharmacological Blockade of Gap Junctions: Possible Involvement of Glial Cells.

Episodic release of GnRH is essential for reproductive function. In vitro studies have established that this episodic release is an endogenous property of GnRH neurons and that GnRH secretory pulses are associated with synchronization of GnRH neuron activity. The cellular mechanisms by which GnRH neurons synchronize remain largely unknown. There is no clear evidence of physical coupling of GnRH neurons through gap junctions to explain episodic synchronization. However, coupling of glial cells through gap junctions has been shown to regulate neuron activity in their microenvironment. The present study investigated whether glial cell communication through gap junctions plays a role in GnRH neuron activity and secretion in the mouse. Our findings show that Glial Fibrillary Acidic Protein-expressing glial cells located in the median eminence in close vicinity to GnRH fibers expressed Gja1 encoding connexin-43. To study the impact of glial-gap junction coupling on GnRH neuron activity, an in vitro model of primary cultures from mouse embryo nasal placodes was used. In this model, GnRH neurons possess a glial microenvironment and were able to release GnRH in an episodic manner. Our findings show that in vitro glial cells forming the microenvironment of GnRH neurons expressed connexin-43 and displayed functional gap junctions. Pharmacological blockade of the gap junctions with 50 μM 18-α-glycyrrhetinic acid decreased GnRH secretion by reducing pulse frequency and amplitude, suppressed neuronal synchronization and drastically reduced spontaneous electrical activity, all these effects were reversed upon 18-α-glycyrrhetinic acid washout.

Mechanisms of long-term cognitive dysfunction of sepsis: from blood-borne leukocytes to glial cells.

Several mechanisms are associated with brain dysfunction during sepsis; one of the most important are activation of microglia and astrocytes. Activation of glial cells induces changes in permeability of the blood-brain barrier, secretion of inflammatory cytokines, and these alterations could induce neuronal dysfunction. Furthermore, blood-borne leukocytes can also reach the brain and participate in inflammatory response. Mechanisms involved in sepsis-associated brain dysfunction were revised here, focusing in neuroinflammation and involvement of blood-borne leukocytes and glial cells in this process.

Glia-related genes and their contribution to schizophrenia.

Schizophrenia, a debilitating disease with 1% prevalence in the general population, is characterized by major neuropsychiatric symptoms, including delusions, hallucinations, and deficits in emotional and social behavior. Previous studies have directed their investigations on the mechanism of schizophrenia towards neuronal dysfunction and have defined schizophrenia as a 'neuron-centric' disorder. However, along with the development of genetics and systematic biology approaches in recent years, the crucial role of glial cells in the brain has also been shown to contribute to the etiopathology of schizophrenia. Here, we summarize comprehensive data that support the involvement of glial cells (including oligodendrocytes, astrocytes, and microglial cells) in schizophrenia and list several acknowledged glia-related genes or molecules associated with schizophrenia. Instead of purely an abnormality of neurons in schizophrenia, an additional 'glial perspective' provides us a novel and promising insight into the causal mechanisms and treatment for this disease.

Inhibitory Effects of Scolopendra Pharmacopuncture on the Development and Maintenance of Neuropathic Pain in Rats: Possible Involvement of Spinal Glial Cells

Scolopendra extracts were used for pharmacopuncture at the Kidney 1 acupoint to investigate the role of Scolopendra pharmacopuncture (SPP) in both the development and maintenance of neuropathic pain induced by L5 spinal nerve ligation in rats and the contribution of spinal glial cells. A single treatment and five once-daily treatments with SPP were given to evaluate its effects on the development and maintenance stages of neuropathic pain, respectively, which was followed by behavioral tests. Immunohistochemistry and Western blotting tests were also carried out. A single treatment of SPP delayed spinal nerve ligation-induced mechanical allodynia and thermal hyperalgesia and induced a profound decrease in the expression of ionized calcium binding adaptor protein in the lumbar spinal cord. Repeated SPP treatments reliably suppressed mechanical allodynia and thermal hyperalgesia at later time points, and these results correlated mainly with decreases in glial fibrillary acidic protein. Intriguingly, ionized calcium binding adaptor protein expression was also reduced after repeated SPP. These results illustrate that neuropathic pain in the development and maintenance stages is alleviated by SPP treatment, which may be ascribed principally to deactivations of microglia and astroglia, respectively. Additionally, microglial inactivation seems to be partially involved in preventing neuropathic pain in the maintenance stage.

Activated Microglia-Induced Deficits in Excitatory Synapses Through IL-1β: Implications for Cognitive Impairment in Sepsis.

Recent clinical studies have shown that sepsis survivors may develop long-term cognitive impairments. The cellular and molecular mechanisms involved in these events are not well understood. This study investigated synaptic deficits in sepsis and the involvement of glial cells in this process. Septic animals showed memory impairment and reduced numbers of hippocampal and cortical excitatory synapses, identified by synaptophysin/PSD-95 co-localization, 9 days after disease onset. The behavioral deficits and synaptophysin/PSD-95 co-localization were rescued to normal levels within 30 days post-sepsis. Septic mice presented activation of microglia and reactive astrogliosis, which are hallmarks of brain injury and could be involved in the associated synaptic deficits. We treated neuronal cultures with conditioned medium derived from cultured astrocytes (ACM) and microglia (MCM) that were either non-stimulated or stimulated with lipopolysaccharide (LPS) to investigate the molecular mechanisms underlying synaptic deficits in sepsis. ACM and MCM increased the number of synapses between cortical neurons in vitro, and these effects were antagonized by LPS stimulation. LPS-MCM reduced the number of synapses by 50%, but LPS-ACM increased the number of synapses by 500%. Analysis of the composition of these conditioned media revealed increased levels of IL-1β in LPS-MCM. Furthermore, inhibition of IL-1β signaling through the addition of a soluble IL-1β receptor antagonist (IL-1 Ra) fully prevented the synaptic deficit induced by LPS-MCM. These results suggest that sepsis induces a transient synaptic deficit associated with memory impairments mediated by IL-1β secreted by activated microglia.

Cytotoxicity of the Diterpene 14-O-Methyl-ryanodanol from Erythroxylum passerinum in an Astrocytic Cells Model

Plant secondary metabolites, such as, specifically, alkaloids and terpenes, may present psychoactive properties that modify the function of the central nervous system (CNS) and induce neurotoxicity. Neurotoxicity involves the response of glial cells, mainly astrocytes, which play a fundamental role in the control of homeostasis of the CNS. Some Erythroxylum species are indigenous to the state of Bahia in Brazil. This study investigated the cytotoxic activity of the diterpene AEP-1, extracted from the fruit of E. passerinum in a GL-15 cell line, astrocytic, glial cells model. The effects on cell viability, analyzed by the MTT assay, demonstrated a dose-dependent cytotoxic effect, with maximum effect at 500 μg/mL of AEP-1, and with a reduction of about 40 and 47% on cellular viability after 24 h and 72 h treatment, respectively. Evidence for induction of apoptosis by AEP-1 was first obtained when GL-15 glial cells were incubated with 250 μg/mL AEP-1 causing reniform and/or pyknotic nuclei and apoptotic bodies revealed by chromatin staining with Hoechst 33258. Increase in DNA fragmentation was also observed by comet assays in cells incubated with 500 μg/mL of AEP-1. Moreover, cells exposed to a sub toxic dose of AEP-1 (250 μg/mL) showed significant changes in morphology--contraction of the cytoplasm and expansion of cellular projections--signifying the presence of astrocytic cytoskeletal protein and glial fibrillary acidic protein (GFAP). These findings indicated astrocytic cells as the target for terpene AEP-1 and suggest the involvement of glial cells with psychoactive symptoms observed in humans and animals after consumption of fruits of plants of the genus Erythroxylum.

Morphological approach to assess the involvement of astrocytes in prion propagation.

Transmissible Spongiform Encephalopathies (TSEs) are a group of neurodegenerative disorders affecting animals and humans and for which no effective treatment is available to date. Vacuolation, neuronal/neurite degeneration, deposition of pathological prion protein (PrPsc) and gliosis are changes typically found in brains from TSE affected individuals. However, the actual role of this last feature, microgliosis and astrocytosis, has not been precisely determined. The overall objective of this work is to assess the involvement of glial cells as components of the host protective system in prion propagation; specifically, to analyze the behavior of astroglial cells in prion progression. To achieve this aim, histopathological and immunohistochemical techniques were carried out on samples from cerebella using Scrapie as the prototype of natural TSEs as this made it possible to assess different stages of the disease; specifically, ages and genotypes from Scrapie-affected animals corresponding to different sources, by using optical, confocal and electron microscopy. The results provided in the present study demonstrate the indisputable involvement of astroglia in prion progression by showing specific changes of this glial population matching up to the evolution of the disease. Moreover, cerebellar lesions mainly associated to Purkinje cells that have not previously been reported in animal prion diseases in natural transmission are described here. The close relationship between PrPsc and GFAP hiperimmunoreactivity and Purkinje cells, alongside the evident thickening of their neurites at terminal stages demonstrated in this study, suggest that these neurons are the main target of this neurodegenerative disease.

Role of spinal P2Y6 and P2Y11 receptors in neuropathic pain in rats: possible involvement of glial cells.

BackgroundThe participation of spinal P2X receptors in neuropathic pain is well recognized. However, the role of P2Y receptors has been less studied. The purpose of this study was to investigate the contribution of spinal P2Y6,11 receptors following peripheral nerve damage induced by spinal nerve ligation. In addition, we determined the expression of P2Y6,11 receptors in the dorsal spinal cord in presence of the selective P2Y6,11 receptors antagonists. Furthermore, we evaluated the participation of spinal microglia and astrocytes in the pronociceptive role of P2Y6,11 receptors.ResultsSpinal administration of the selective P2Y6 (MRS2578, 10–100 μM) and P2Y11 (NF340, 0.3–30 μM) receptor antagonists reduced tactile allodynia in spinal nerve ligated rats. Nerve injury increased the expression of P2Y6,11 receptors at 7, 14 and 21 days after injury. Furthermore, intrathecal administration of MRS2578 (100 μM/day) and NF340 (30 μM/day) for 3 days significantly reduced spinal nerve injury-induced increase in P2Y6,11 receptors expression, respectively. Spinal treatment (on day 14 after injury) with minocycline (100 μg/day) or fluorocitrate (1 nmol/day) for 7 days reduced tactile allodynia and spinal nerve injury-induced up-regulation in Iba-1 and GFAP, respectively. In addition, minocycline reduced nerve injury-induced up-regulation in P2Y6,11 receptors whereas that fluorocitrate diminished P2Y11, but not P2Y6, receptors up-regulation. Intrathecal treatment (on day 21 after injury) with the selective P2Y6 (PSB0474, 3–30 μM) and P2Y11 (NF546, 1–10 μM) receptor agonists produced remarkable tactile allodynia in nerve ligated rats previously treated with minocycline or fluorocitrate for 7 days.ConclusionsOur data suggest that spinal P2Y6 is present in spinal microglia while P2Y11 receptors are present in both spinal microglia and astrocytes, and both receptors are up-regulated in rats subjected to spinal nerve injury. In addition, our data suggest that the spinal P2Y6 and P2Y11 receptors participate in the maintenance of neuropathic pain.

Glial Cells are Involved in Itch Processing

Recent discoveries in itch neurophysiology include itch-selective neuronal pathways, the clinically relevant non-histaminergic pathway, and elucidation of the notable similarities and differences between itch and pain. Potential involvement of glial cells in itch processing and the possibility of glial modulation of chronic itch have recently been identified, similarly to the established glial modulation of pain processing. This review outlines the similarities and differences between itch and pain, and how different types of central and peripheral glial cells may be differentially involved in the development of chronic itch akin to their more investigated role in chronic pain. Improvements are needed in the management of chronic itch, and future basic and interventional studies on glial activity modulation would both enhance our understanding of mechanisms underlying the chronification of itch and provide novel opportunities for the prevention or treatment of this debilitating and common condition.

Protective Effects of Phytochemical Antioxidants Against Neurotoxin-Induced Degeneration of Dopaminergic Neurons

The specific toxicity to dopaminergic neurons of psychostimulants and neurotoxins has been extensively studied in vivo and in vitro, and findings have been used to establish animal models of amphetamine psychosis or Parkinson’s disease. The multiple mechanisms of neurotoxicity operating in these disorders are known to involve oxidative stress or neuroinflammation, producing the characteristic behavioral and neuropathlogical changes arising from injured dopaminergic neurons and glial cells. A number of studies have shown that glia-targeting antioxidants play important roles in protecting against the neurotoxicity caused by psychostimulants or neurotoxins. Phytochemicals, which are non-nutritive plant chemicals, protect dopaminergic neurons and glial cells from damage caused by psychostimulants or neurotoxins. The objective of this review was to evaluate the involvement of glial cells in dopaminergic neuron–specific toxicity and to explore the neuroprotective activity of phytochemicals in terms of anti-inflammatory and antioxidant action.

The involvement of midbrain astrocyte in the development of morphine tolerance

AimsSystemic administration of opiate analgesics such as morphine remains the most effective treatment for alleviating severe pain across a range of conditions including acute pain. However, chronic or repeated administration of opiate analgesics results in the development of analgesic tolerance. Glial cells such as microglia and astrocytes are known to release various inflammatory cytokines and neurotrophic factors leading to regulation of neuronal function. Recently, glial cells were reported to play important roles in the development of analgesic tolerance to morphine. Here, we focused on the involvement of midbrain glial cells, particularly astrocytes, in the development of analgesic tolerance to morphine. Main methodsMice were treated with morphine (10mg/kg, s.c.) or vehicle once a day for 5days. Pentoxifylline (an inhibitor of glial activation; 20mg/kg, i.p. or 50 and 100μg/mouse, i.c.v.) was administered 30min before morphine treatment. Flavopiridol (a cyclin-dependent kinase inhibitor; 5nmol/mouse, i.c.v.) was administered 10min before and 10h after morphine treatment. The analgesic effect of morphine was measured using the tail flick method. Key findingsThe development of analgesic tolerance to morphine was gradually observed during daily treatment of morphine for 5days in mice. On days 1 and 3 after repeated morphine treatment, astrocyte marker glial fibrillary acidic protein expression levels were significantly increased, as determined by western blot analyses. These phenomena were significantly inhibited following pre-treatment with pentoxifylline or flavopiridol. SignificanceWe demonstrated that midbrain astrocytes play an important role in the development of analgesic tolerance to morphine.

Nicotine uses neuron-glia communication to enhance hippocampal synaptic transmission and long-term memory.

Nicotine enhances synaptic transmission and facilitates long-term memory. Now it is known that bi-directional glia-neuron interactions play important roles in the physiology of the brain. However, the involvement of glial cells in the effects of nicotine has not been considered until now. In particular, the gliotransmitter D-serine, an endogenous co-agonist of NMDA receptors, enables different types of synaptic plasticity and memory in the hippocampus. Here, we report that hippocampal long-term synaptic plasticity induced by nicotine was annulled by an enzyme that degrades endogenous D-serine, or by an NMDA receptor antagonist that acts at the D-serine binding site. Accordingly, both effects of nicotine: the enhancement of synaptic transmission and facilitation of long-term memory were eliminated by impairing glial cells with fluoroacetate, and were restored with exogenous D-serine. Together, these results show that glial D-serine is essential for the long-term effects of nicotine on synaptic plasticity and memory, and they highlight the roles of glial cells as key participants in brain functions.

Gender-specific perturbations in modulatory inputs to motoneurons in a mouse model of amyotrophic lateral sclerosis

The fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) is characterised by loss of motoneurons of the brainstem and spinal cord, and corticospinal neurons of the motor cortex. There is also increasing evidence of involvement of glial cells and interneurons, with non-cell autonomous disease mechanisms now thought to contribute to motoneuron degeneration in ALS. Given the apparent involvement of altered motoneuron excitability in ALS and the recent demonstration that motoneuron excitability is controlled by C-boutons, a specific class of synaptic input recently shown to originate from a small cluster of spinal interneurons, we hypothesised that perturbations in C-bouton inputs to motoneurons may contribute to altered excitability and the eventual degeneration of motoneurons in ALS. To begin to assess this we performed a detailed, developmental study of the anatomy of C-boutons in a mouse model of ALS (G93A SOD1 mutant). We found that C-bouton number is unchanged in ALS mice compared to wildtype littermates at any age. In contrast, we found that the size of C-boutons increases in ALS mice between postnatal day (P)8 and P30, with boutons remaining larger throughout symptomatic stages (P120–P140). Interestingly, we found that C-boutons are only enlarged in male mice. We found no evidence of concomitant changes in clusters of postsynaptic proteins known to align with C-boutons (Kv2.1 K+ channels and m2-type muscarinic receptors). In conclusion, these data support the involvement of pre-symptomatic changes in C-bouton anatomy in ALS pathogenesis and in particular mechanisms underlying the male bias of this disease.

Involvement of Glial Cells in the Autoregulation of Optic Nerve Head Blood Flow in Rabbits

To investigate the involvement of glial cells in the autoregulation of optic nerve head (ONH) blood flow in response to elevated intraocular pressure (IOP). Rabbit eyes were treated with an intravitreal injection of l-2-aminoadipic acid (LAA), a gliotoxic compound. Twenty-four hours after the injection IOP was artificially elevated from a baseline of 20 to 50 or 70 mm Hg and maintained at each IOP level for 30 minutes. ONH blood flow was measured by laser speckle flowgraphy every 10 minutes. Ocular perfusion pressure (OPP) was calculated to investigate the relationship between ONH blood flow and OPP. To evaluate the effects of LAA on the function and morphology of retinal neurons and glial cells, electroretinogram (ERG) was monitored after injections of LAA (2.0 and 6.0 mM) or saline as a control. Histologic and immunohistochemical examinations were then performed. In the LAA-treated eyes, histologic changes selectively occurred in the retinal Müller cells and ONH astrocytes. There was not any significant reduction of amplitude or elongation of implicit time of each parameter in the ERG after LAA injection compared with control. ONH blood flow in LAA-treated eyes was significantly decreased with a reduction of OPP during IOP elevation to 50 and 70 mm Hg, whereas blood flow was maintained in control eyes during IOP elevation to 50 mm Hg. These results indicate the involvement of glial ells in the autoregulation of ONH blood flow during IOP elevation.

Cannabinoid agonist WIN 55,212-2 prevents the development of paclitaxel-induced peripheral neuropathy in rats. Possible involvement of spinal glial cells

Spinal glial activation contributes to the development and maintenance of chronic pain states, including neuropathic pain of diverse etiologies. Cannabinoid compounds have shown antinociceptive properties in a variety of neuropathic pain models and are emerging as a promising class of drugs to treat neuropathic pain. Thus, the effects of repeated treatment with WIN 55,212-2, a synthetic cannabinoid agonist, were examined throughout the development of paclitaxel-induced peripheral neuropathy. Painful neuropathy was induced in male Wistar rats by intraperitoneal (i.p.) administration of paclitaxel (1mg/kg) on four alternate days. Paclitaxel-treated animals received WIN 55,212-2 (1mg/kg, i.p.) or minocycline (15mg/kg, i.p.), a microglial inhibitor, daily for 14days, simultaneous with the antineoplastic. The development of hypersensitive behaviors was assessed on days 1, 7, 14, 21 and 28 following the initial administration of drugs. Both the activation of glial cells (microglia and astrocytes) at day 29 and the time course of proinflammatory cytokine release within the spinal cord were also determined. Similar to minocycline, repeated administration of WIN 55,212-2 prevented the development of thermal hyperalgesia and mechanical allodynia in paclitaxel-treated rats. WIN 55,212-2 treatment also prevented spinal microglial and astrocytic activation evoked by paclitaxel at day 29 and attenuated the early production of spinal proinflammatory cytokines (interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α). Our results confirm changes in the reactivity of glial cells during the development of peripheral neuropathy induced by paclitaxel and support a preventive effect of WIN 55,212-2, probably via glial cells reactivity inactivation, on the development of this neuropathy.

A new in vitro injury model of mouse neurons induced by mechanical scratching

The mixed culture of neurons and glial cells has been widely used as a mechanical insult model for the study of neuron injury in vitro. However, a better model is desirable to eliminate the interference of glial cells during the study. Here we report a new model with exclusive cerebellar granule neurons (CGNs), which can be used for the study of in vitro neuron injury without involvement of glial cells. We found that after scratching insult, there was a decrease in both the survival rate and vitality of injured CGNs. Meanwhile, pathological changes were observed by electron microscopy. With this new model, we also tested the effects of neurotrophin-3 (NT-3) on neuroprotection. The result showed that the vitality of injured CGNs was enhanced by the administration of NT-3. These findings demonstrate that this new model is useful for investigation of the precise effect of mechanical damage on neurons excluding other factors, and to detect the neuroprotective effect of certain factors on mechanically injured neurons.

Salvinorin A Reduces Mechanical Allodynia and Spinal Neuronal Hyperexcitability Induced by Peripheral Formalin Injection

BackgroundSalvinorin A (SA), the main active component of Salvia Divinorum, is a non-nitrogenous kappa opioid receptor (KOR) agonist. It has been shown to reduce acute pain and to exert potent antinflammatory effects. This study assesses the effects and the mode of action of SA on formalin-induced persistent pain in mice. Specifically, the SA effects on long-term behavioural dysfuctions and changes in neuronal activity occurring at spinal level, after single peripheral formalin injection, have been investigated. Moreover, the involvement of microglial and glial cells in formalin-induced chronic pain condition and in SA-mediated effects has been evaluated.ResultsFormalin induced a significant decrease of mechanical withdrawal threshold at the injected and contralateral paw as well as an increase in the duration and frequency, and a rapid decrease in the onset of evoked activity of the nociceptive neurons 7 days after formalin injection. SA daily treatment significantly reduced mechanical allodynia in KOR and cannabinoid receptor 1 (CB1R) sensitive manner. SA treatment also normalized the spinal evoked activity. SA significantly reduced the formalin-mediated microglia and astrocytes activation and modulated pro and anti-inflammatory mediators in the spinal cord.ConclusionSA is effective in reducing formalin-induced mechanical allodynia and spinal neuronal hyperactivity. Our findings suggest that SA reduces glial activation and contributes in the establishment of dysfunctions associated with chronic pain with mechanisms involving KOR and CB1R. SA may provide a new lead compound for developing anti-allodynic agents via KOR and CB1R activation.

Neural mobilization reverses behavioral and cellular changes that characterize neuropathic pain in rats.

BackgroundThe neural mobilization technique is a noninvasive method that has proved clinically effective in reducing pain sensitivity and consequently in improving quality of life after neuropathic pain. The present study examined the effects of neural mobilization (NM) on pain sensitivity induced by chronic constriction injury (CCI) in rats. The CCI was performed on adult male rats, submitted thereafter to 10 sessions of NM, each other day, starting 14 days after the CCI injury. Over the treatment period, animals were evaluated for nociception using behavioral tests, such as tests for allodynia and thermal and mechanical hyperalgesia. At the end of the sessions, the dorsal root ganglion (DRG) and spinal cord were analyzed using immunohistochemistry and Western blot assays for neural growth factor (NGF) and glial fibrillary acidic protein (GFAP).ResultsThe NM treatment induced an early reduction (from the second session) of the hyperalgesia and allodynia in CCI-injured rats, which persisted until the end of the treatment. On the other hand, only after the 4th session we observed a blockade of thermal sensitivity. Regarding cellular changes, we observed a decrease of GFAP and NGF expression after NM in the ipsilateral DRG (68% and 111%, respectively) and the decrease of only GFAP expression after NM in the lumbar spinal cord (L3-L6) (108%).ConclusionsThese data provide evidence that NM treatment reverses pain symptoms in CCI-injured rats and suggest the involvement of glial cells and NGF in such an effect.

Behavioral and Morphological Evidence for the Involvement of Glial Cells in the Antinociceptive Effect of Najanalgesin in a Rat Neuropathic Pain Model

Neuropathic pain is a devastating neurological disease that seriously affects patients' quality of life. Despite a high level of incidence, the underlying mechanisms of neuropathic pain are still poorly understood. However, recent evidence supports the prominent role of spinal glial cells in neuropathic pain states. In our laboratory, we observed that najanalgesin, a novel peptide isolated from the venom of Naja naja atra, exerts significant analgesic effects on acute pain in mice and neuropathic pain in rats. The objective of the present study was to determine whether spinal glia are associated with the antinociceptive effect of najanalgesin in an L5 spinal nerve ligation (SNL) rodent model of neuropathic pain. Mechanical allodynia developed after surgery, and hypersensitivity was significantly attenuated by the intrathecal administration of najanalgesin. The inhibitory effect of najanalgesin was significantly (p<0.05) enhanced after pretreatment with fluorocitrate (a glial cell antagonist). In addition, the astrocyte activation was attenuated following najanalgesin treatment in the dorsal horn of neuropathic rats, as assessed by immunohistology and Western blotting. The tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) content of cerebral spinal fluid and cell culture supernatants changed significantly after najanalgesin administration. The results suggest that najanalgesin may exert its anti-allodynic effect by altering astrocyte cell function.