Glia have emerged as key contributors to pathological and chronic pain mechanisms. On activation, both astrocytes and microglia respond to and release a number of signalling molecules, which have protective and/or pathological functions. Here we review the current understanding of the contribution of glia to pathological pain and neuroprotection, and how the protective, antiinflammatory actions of glia are being harnessed to develop new drug targets for neuropathic pain control. Given the prevalence of chronic pain and the partial efficacy of current drugs, which exclusively target neuronal mechanisms, new strategies to manipulate neuron-glia interactions in pain processing hold considerable promise.Under normal conditions, in otherwise healthy subjects, acute-pain processing consists of a chain of events that begins with stimuli that activate specialized receptive endings on peripheral sensory nerve fibres. Following such activation, excitatory impulses carried by the sensory afferent axons induce excitatory postsynaptic potentials in pain-transmission neurons located in the dorsal horn of the spinal cord, with the final synaptic relay occurring in the cortex. However, pain processing is not simply a relay of signals from the body to the brain, it is a redundant, multi-pathway and dynamic system in which profound pain suppression or enhancement can occur at any level of synaptic communication. When dysfunctional pain signalling (for example, pain signalling in the absence of tissue damage) occurs, pathological pain ensues. Lesions of the nervous system can produce a form of pathological pain, neuropathic pain, which is characterized by unexplainable widespread pain, a sensory deficit, a burning sensation, pain caused by light touch (allodynia), or acute pain in the absence of a noxious stimulus 1 . Furthermore, chronic neuropathic pain can persist for months, without the underlying cause being treatable or identifiable.Our understanding of pathological pain has primarily revolved around neuronal mechanisms. However, neighbouring astrocytes and microglia have recently been recognized as powerful modulators of pain and are emerging as a new target for drug development. Although glia are well known for having a number of housekeeping functions that are necessary for healthy neuronal communication, on strong activation they act as immunoresponsive cells or exert a neuroprotective effect. Glia can contribute to neuropathic-pain processing by releasing a number of glial and neuronal signalling molecules. These include, among others, the classic immune signals: cytokines and chemokines. There is substantial evidence that both astrocyte and microglia activation lead to pro-inflammatory responses with pathological effects, such as neuronal hyperexcitability, neurotoxicity and chronic inflammation. However, the notion that
Activated glial cells (microglia and astroglia) in the spinal cord play a major role in mediating enhanced pain states by releasing proinflammatory cytokines and other substances thought to facilitate pain transmission. In the present study, we report that intrathecal administration of minocycline, a selective inhibitor of microglial cell activation, inhibits low threshold mechanical allodynia, as measured by the von Frey test, in two models of pain facilitation. In a rat model of neuropathic pain induced by sciatic nerve inflammation (sciatic inflammatory neuropathy, SIN), minocycline delayed the induction of allodynia in both acute and persistent paradigms. Moreover, minocycline was able to attenuate established SIN-induced allodynia 1 day, but not 1 week later, suggesting a limited role of microglial activation in more perseverative pain states. Our data are consistent with a crucial role for microglial cells in initiating, rather than maintaining, enhanced pain responses. In a model of spinal immune activation by intrathecal HIV-1 gp120, we show that the anti-allodynic effects of minocycline are associated with decreased microglial activation, attenuated mRNA expression of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-1beta-converting enzyme, TNF-alpha-converting enzyme, IL-1 receptor antagonist and IL-10 in lumbar dorsal spinal cord, and reduced IL-1beta and TNF-alpha levels in the CSF. In contrast, no significant effects of minocycline were observed on gp120-induced IL-6 and cyclooxygenase-2 expression in spinal cord or CSF IL-6 levels. Taken together these data highlight the importance of microglial activation in the development of exaggerated pain states.
Mirror-image allodynia is a mysterious phenomenon that occurs in association with many clinical pain syndromes. Allodynia refers to pain in response to light touch/pressure stimuli, which normally are perceived as innocuous. Mirror-image allodynia arises from the healthy body region contralateral to the actual site of trauma/inflammation. Virtually nothing is known about the mechanisms underlying such pain. A recently developed animal model of inflammatory neuropathy reliably produces mirror-image allodynia, thus allowing this pain phenomenon to be analyzed. In this sciatic inflammatory neuropathy (SIN) model, decreased response threshold to tactile stimuli (mechanical allodynia) develops in rats after microinjection of immune activators around one healthy sciatic nerve at mid-thigh level. Low level immune activation produces unilateral allodynia ipsilateral to the site of sciatic inflammation; more intense immune activation produces bilateral (ipsilateral ϩ mirror image) allodynia. The present studies demonstrate that both ipsilateral and mirrorimage SIN-induced allodynias are (1) reversed by intrathecal (peri-spinal) delivery of fluorocitrate, a glial metabolic inhibitor; (2) prevented and reversed by intrathecal CNI-1493, an inhibitor of p38 mitogen-activated kinases implicated in proinflammatory cytokine production and signaling; and (3) prevented or reversed by intrathecal proinflammatory cytokine antagonists specific for interleukin-1, tumor necrosis factor, or interleukin-6. Reversal of ipsilateral and mirror-image allodynias was rapid and complete even when SIN was maintained constantly for 2 weeks before proinflammatory cytokine antagonist administration. These results provide the first evidence that ipsilateral and mirror-image inflammatory neuropathy pain are created both acutely and chronically through glial and proinflammatory cytokine actions.
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