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1.
The long-standing belief that the spinal cord serves merely as a conduit for information traveling to and from the brain is changing. Over the past decade, research has shown that the spinal cord is sensitive to response–outcome contingencies, demonstrating that spinal circuits have the capacity to modify behavior in response to differential environmental cues. If spinally transected rats are administered shock contingent on leg extension (controllable shock), they will maintain a flexion response that minimizes shock exposure. If, however, this contingency is broken, and shock is administered irrespective of limb position (uncontrollable shock), subjects cannot acquire the same flexion response. Interestingly, each of these treatments has a lasting effect on behavior; controllable shock enables future learning, while uncontrollable shock produces a long-lasting learning deficit. Here we suggest that the mechanisms underlying learning and the deficit may have evolved from machinery responsible for the spinal processing of noxious information. Experiments have shown that learning and the deficit require receptors and signaling cascades shown to be involved in central sensitization, including activation of NMDA and neurokinin receptors, as well as CaMKII. Further supporting this link between pain and learning, research has also shown that uncontrollable stimulation results in allodynia. Moreover, systemic inflammation and neonatal hindpaw injury each facilitate pain responding and undermine the ability of the spinal cord to support learning. These results suggest that the plasticity associated with learning and pain must be placed in a balance in order for adaptive outcomes to be observed.  相似文献   

2.
Spinal glial activation contributes to pathological pain states   总被引:1,自引:0,他引:1  
Chronic pain, a pathological state, affects millions of people worldwide. Despite decades of study on the neuronal processing of pain, mechanisms underlying the creation and maintenance of enhanced pain states after injury or inflammation remain far from clear. In the last decade, however, the discovery that glial activation amplifies pain has challenged classic neuronal views of "pain". This review focuses on recent developments in understanding that spinal cord glia are involved in pathological pain. We overview the action of spinal glia (both microglia and astrocytes) in several persistent pain models, and provide new evidence that spinal glia activation contributes to the development and maintenance of arthritic pain facilitation. We also attempt to discuss some critical questions, such as how signals are conveyed from primary afferents to spinal glia following peripheral nerve injury and inflammation. What causes glia to become activated after peripheral/central injury/inflammation? And how the activated glia alter neuronal sensitivity and pain processing? Answers to these questions might open a new approach for treatment of pathological pain.  相似文献   

3.
The secondary loss of neurons and glia over the first 24 h after spinal cord injury (SCI) contributes to the permanent functional deficits that are the unfortunate consequence of SCI. The progression of this acute secondary cell death in specific neuronal and glial populations has not previously been investigated in a quantitative manner. We used a well-characterized model of SCI to analyze the loss of ventral motoneurons (VMN) and ventral funicular astrocytes and oligodendrocytes at 15 min and 4, 8, and 24 h after an incomplete midthoracic contusion injury in the rat. We found that both the length of lesion and the length of spinal cord devoid of VMN increased in a time-dependent manner. The extent of VMN loss at specified distances rostral and caudal to the injury epicenter progressed symmetrically with time. Neuronal loss was accompanied by a loss of glial cells in ventral white matter that was significant at the epicenter by 4 h after injury. Oligodendrocyte loss followed the same temporal pattern as that of VMN while astrocyte loss was delayed. This information on the temporal-spatial pattern of cell loss can be used to investigate mechanisms involved in secondary injury of neurons and glia after SCI.  相似文献   

4.
Prior work has demonstrated that spinal cord neurons, isolated from the brain through a spinal transection, can support learning. Spinally transected rats given legshock whenever one hindlimb is extended learn to maintain the shocked leg in a flexed position, minimizing net shock exposure. This capacity for learning is inhibited by prior exposure to an uncontrollable stimulus (e.g., intermittent tailshock). The present experiments examined whether spinal cord neurons are more vulnerable to the adverse effects of uncontrollable stimulation after spinal cord injury. Experiment 1 confirmed that uncontrollable shock inhibits subsequent learning in transected rats. Rats that received uncontrollable stimulation prior to transection did not exhibit this effect, suggesting that brain systems exert a protective effect. Experiment 2 showed that this protective effect was removed if subjects received a dorsolateral funiculus lesion prior to shock exposure. Subsequent experiments were designed to determine the identity of the neurochemical systems that protect spinal plasticity. Intrathecal application of serotonin (5-HT) or a 5-HT 1A/7 agonist (8-OH DPAT) in transected rats had a protective effect that blocked the adverse effect of uncontrollable stimulation (Experiment 3). The alpha-2 noradrenergic agonist, clonidine, also protected plasticity (Experiment 4), but this effect was linked to cross-reactivity at the 5-HT 1A receptor (Experiment 5). Microinjection of a 5HT 1A antagonist (WAY 100635) into the spinal cord before intact rats received uncontrollable stimulation blocked the brain-dependent protection of spinal cord neurons. The findings indicate that serotonergic systems normally protect spinal cord plasticity from the deleterious effects of uncontrollable stimulation.  相似文献   

5.
Glial activation: a driving force for pathological pain   总被引:48,自引:0,他引:48  
Pain is classically viewed as being mediated solely by neurons, as are other sensory phenomena. The discovery that spinal cord glia (microglia and astrocytes) amplify pain requires a change in this view. These glia express characteristics in common with immune cells in that they respond to viruses and bacteria, releasing proinflammatory cytokines, which create pathological pain. These spinal cord glia also become activated by certain sensory signals arriving from the periphery. Similar to spinal infection, these signals cause release of proinflammatory cytokines, thus creating pathological pain. Taken together, these findings suggest a new, dramatically different approach to pain control, as all clinical therapies are focused exclusively on altering neuronal, rather than glial, function.  相似文献   

6.
This review examines recently recognized roles of immunological processes in pain modulation and explores the potential implications of these immunologically derived phenomena for human chronic pain control. The focus is an examination of how activation of immune-like glial cells within the spinal cord can amplify pain by modulating the excitability of spinal neurons. Such glially driven enhancement of pain can be physiological, as occurs in response to peripheral infection or inflammation. Here, immune-to-brain-to-spinal cord communication leads to pain enhancement (hyperalgesia) as one component of the well-characterized sickness response. This sickness-induced hyperalgesia, like many sickness responses, is mediated by the activation of glia and the consequent release of proinflammatory cytokines. However, glially driven pain can also occur under pathological conditions, such as occurs following peripheral nerve inflammation or trauma. Here, immune- and trauma-induced alterations in peripheral nerve function lead to the release of substances within the spinal cord that trigger the activation of glia. Evidence is reviewed that such pathologically driven glial activation is associated with enhanced pain states of diverse etiologies and that such pain facilitation is driven by glial release of proinflammatory cytokines and other neuroexcitatory substances. This recently recognized role of spinal cord glia and glially derived proinflammatory cytokines as powerful modulators of pain is exciting as it may provide novel approaches for controlling human chronic pain states that are poorly controlled by currently available therapies.  相似文献   

7.
Glial cells of an insect ganglion   总被引:1,自引:0,他引:1  
The rapid development of the study of insect neurobiology, which is currently occurring principally because individual neurons can be re-identified and because their activities can be recorded in situ and related to behavior, is generating a demand for more knowledge concerning insect glial cells and their functional relationships with neurons. This study examines the ultrastructure of glial cells in locust metathoracic ganglia in relation to general locale within the ganglion and also to specific identified neurons and neuron types. Seven major types of glial cell form are recognized, with subdivisions, requiring a new scheme for classification. Glial invaginations into neurons are of four different kinds: regular, chunky, filigree, and ridge (found only at axon hillocks). They also range from only intrusive to fully reciprocal. In addition, some neurons make projections of various lengths into surrounding glia and between neighboring neuron somata, and some glia make long, branched projections into other glial cells. The differences show that insect glial cells develop highly specific functional specializations; they may not be interchangeable. The complexity and intimacy of relationships of glia with neurons suggest that some glial cells may have roles other than that of nursemaids, possibly in modulation of behavior-determining neural activity, and in learning and other adaptive acts.  相似文献   

8.
Activated glial cells in the dorsal spinal cord take an important part in the development of pain after peripheral nerve injury. Our understanding of mechanisms involved in functional changes of spinal glia remains incomplete. Excepting drugs that completely disrupt glial function, pharmacological studies fail to target glia and to modify locally its function in order to really discriminate the role of neuronal versus glial cells in chronic pain. We developed an intraspinal gene transfer approach using pseudotyped lentiviral-derived vector targeting highly preferentially glial cells. Single microinjection of vector expressing EGFP under a CMV promoter control (LV-EGFP) allowed vector diffusion along a rostro-caudal axis but strictly restricted to the grey matter of the ipsilateral dorsal spinal cord. EGFP transgene was mainly expressed in astrocytes and microglial cells whereas less than 9% of cells containing EGFP were neurons. Notably, LV-EGFP administration and EGFP overexpression in glial cells did neither modify glial activity, nor alter animal's nociceptive or locomotor behaviors. Targeted modulation of the expression of gene of interest in glial cells, closely restricted to a particular region of the spinal cord, may thus represent an interesting approach to refine the understanding of mechanisms by which spinal glial cells participate in pain processing.  相似文献   

9.
The olfactory bulb (OB) is a structure of the central nervous system (CNS) in which axonal growth occurs throughout the lifetime of the organism. A major difference between the OB and the remaining CNS is the presence of ensheathing glia in the first two layers of the OB. Ensheathing glia display properties that might be involved in the process of regeneration and they appear to be responsible for the permissibility of the adult OB to axonal growth. In fact, transplants of ensheathing glia can be used as promoters of axonal regeneration within the adult CNS. The axonal growth-promoting properties of ensheathing glia make the study of this cell type interesting for understanding the mechanisms underlying axonal regeneration. Several groups have studied OB ensheathing cells extensively in an attempt to classify them within any of the known glial groups. However, this cell type does not exhibit the phenotypic features of any glial population described thus far. In this article we review the characteristics that differentiate ensheathing glia from other peripheral and central glial populations as well as the properties that involve them in axonal regeneration. The evidence suggests that ensheathing glia are unique, have their own identity, and do not belong to any previously described glial type. © 1995 Wiley-Liss, Inc.  相似文献   

10.
Although activation of spinal glia has been implicated in the development of pathological pain, the mechanisms underlying glial activation are not fully understood. One such mechanism may be triggered by reaction to neuroactive substances released from central axons of sensory afferents. The vanilloid receptor TRPV1, a nonselective cation channel in nociceptive sensory afferents, mediates the release of neurotransmitters, such as glutamate and CGRP in the dorsal horn, which can subsequently activate glia. To test the hypothesis that activation of spinal glia is mediated, at least in part, by TRPV1, we studied the expression of markers for microglia (ionized calcium-binding adapter molecule 1, Iba1) and astrocytes (glial fibrillary acidic protein, GFAP) in the spinal cord of TRPV1 knockout mice (KO) vs. wild-type mice (WT) in models of acute (intraplantar capsaicin), inflammatory (adjuvant-induced arthritis, AIA), and neuropathic pain (partial sciatic nerve ligation, PSNL). We found that (i) naïve KO mice had denser immunostaining for both Iba1 and GFAP than naive WT mice; (ii) the immunostaining for Iba1 increased significantly in treated mice, compared to naïve mice, 3 days after capsaicin and 7–14 days after AIA or PSNL, and was significantly greater in WT than in KO mice 3 days after capsaicin, 7–14 days after AIA, and 7 days after PSNL; and iii) the immunostaining for GFAP increased significantly in treated mice, compared to naïve mice, 3 days after capsaicin and 14–21 days after AIA or PSNL, and was significantly greater in WT than in KO mice 14 days after AIA or PSNL. Our results suggest that TRPV1 plays a role in the activation of spinal glia in mice with nociceptive, inflammatory, and neuropathic pain.  相似文献   

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