Detailed characterization of neuro-immune responses following neuropathic injury in mice (original) (raw)
Related papers
Journal of Neuroimmunology, 2010
In a large proportion of individuals nervous system damage may lead to a debilitating chronic neuropathic pain. Such pain may now be considered a neuro-immune disorder, since recent data indicate a critical involvement of innate and adaptive immune responses following nerve injury. Activation of immune and immune-like glial cells in the injured nerve, dorsal root ganglia and spinal cord results in the release of both pro-and anti-inflammatory cytokines, as well as algesic and analgesic mediators, the balance of which determines whether pain chronicity is established. This review will critically examine the role of the immune system in modulating chronic pain in animal models of nervous system injury, and highlight the possible therapeutic opportunities to intervene in the development and maintenance of neuropathic pain.
The neuropathic pain triad: neurons, immune cells and glia
Nature Neuroscience, 2007
Nociceptive pain results from the detection of intense or noxious stimuli by specialized high-threshold sensory neurons (nociceptors), a transfer of action potentials to the spinal cord, and onward transmission of the warning signal to the brain. In contrast, clinical pain such as pain after nerve injury (neuropathic pain) is characterized by pain in the absence of a stimulus and reduced nociceptive thresholds so that normally innocuous stimuli produce pain. The development of neuropathic pain involves not only neuronal pathways, but also Schwann cells, satellite cells in the dorsal root ganglia, components of the peripheral immune system, spinal microglia and astrocytes. As we increasingly appreciate that neuropathic pain has many features of a neuroimmune disorder, immunosuppression and blockade of the reciprocal signaling pathways between neuronal and non-neuronal cells offer new opportunities for disease modification and more successful management of pain.
Encoding of inflammatory hyperalgesia in mice spinal cord
2021
Inflammation modifies the input-output properties of peripheral nociceptive neurons, thus leading to hyperalgesia, i.e., changes in the perception of noxious heat stimuli such that the same stimulus produces enhanced pain. The increased nociceptive output enters the superficial dorsal spinal cord (SDH), which comprises the first CNS network integrating the noxious information. Here we used in vivo calcium imaging and a computational approach to investigate how the SDH network in mice encodes the injury-mediated abnormal input from peripheral nociceptive neurons. We show the application of noxious heat stimuli to the mice hind paw in naive conditions before induction of injury affects the activity of 70% of recorded neurons by either increasing or suppressing it. Application of the same noxious heat stimuli to hyperalgesic skin leads to activation of previously non-responded cells and de-suppression of the "suppressed" neurons. We demonstrate that reduction in synaptic inhi...
Role of spinal microglia in rat models of peripheral nerve injury and inflammation
European Journal of Pain, 2007
Mounting evidence supports the hypothesis that spinal microglia modulate the development and maintenance of some chronic pain states. Here we examined the role of spinal microglia following both peripheral inflammatory insult and peripheral nerve injury. We observed significant ipsilateral dorsal horn microglia activation 2 weeks after injury and bilateral activation 50 days following nerve injury as well as 24 h following intraplantar zymosan but not intraplantar complete Freund's adjuvant (CFA). Ipsilateral but not contralateral microglia activation was associated with hind paw mechanical hyperalgesia. Spinal injection of the glial metabolic inactivator fluorocitrate attenuated ipsilateral hyperalgesia and bilateral spinal microglia activation after peripheral nerve injury. Intrathecal fluorocitrate reversed hyperalgesia after intraplantar zymosan and produced no reversal of CFA-induced hyperalgesia. These data suggest a role for spinal glia in the persistence of mechanical hyperalgesia following peripheral nerve injury. However, activation of spinal microglia contralaterally did not correlate to nociception. Furthermore, it would appear that the time course of microglia activation and their contribution to inflammatory pain is dependent on the inflammatory stimulus administered.
Journal of neurochemistry, 2017
Neuropathic pain is a debilitating chronic pain condition occurring after damage in the nervous system and is refractory to the currently available treatments. Major challenges include elucidating its mechanisms and developing new medications to treat it. Nerve injury-induced pain hypersensitivity involves aberrant excitability in spinal dorsal horn (SDH) neurons as a consequence of dysfunction of inhibitory interneurons and of hyperactivity of glial cells, especially microglia, the immune cells of the central nervous system. Evidence of this is found using animal models to investigate the molecular and cellular mechanisms of neuropathic pain. The pathologically altered somatosensory signals in the SDH then convey to the brain regions, including the anterior cingulate cortex (ACC). In these regions, nerve injury produces pre- and postsynaptic long-term plasticity, which contributes to negative emotions and anxiety associated with chronic pain conditions. Furthermore, recent evidence...
Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003
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 + mirror image) allodynia....
Neuroscience, 2006
We investigated the role and mechanisms of inflammatory responses within the dorsal root ganglion (DRG) in the development of chemogenic pathological pain. DRG inflammation was induced by a single deposit of the immune activator zymosan in incomplete Freund's adjuvant in the epidural space near the L5 DRG via a small hole drilled through the transverse process. After a single zymosan injection, rats developed bilateral mechanical hyperalgesia and allodynia which began by day 1 after surgery, peaked at days 3-7, and lasted up to 28 days. The number of macrophages in ipsilateral and contralateral DRGs increased significantly, lasting over 14 days. Robust glial activation was observed in inflamed ganglia. Cytokine profile analysis using a multiplexing protein array system showed that, in normal DRG, all but IL-5, IL-10 and GM-CSF were detectable with concentrations of up to 180 pg/mg protein. Local inflammatory irritation selectively increased IL-1β, IL-6, IL-18, MCP-1, and GRO/KC up to 17 fold, and decreased IL-2 and IL-12 (p70) up to 3 fold. Inflaming the DRG also remarkably increased the incidence of spontaneous activity of A-and C-fibers recorded in the dorsal root. Many of the spontaneously active A-fibers exhibited a short-bursting discharge pattern. Changes in cytokines and spontaneous activity correlated with the time course of pain behaviors, especially light stroke-evoked tactile allodynia. Finally, local inflammation induced extensive sprouting of sympathetic fibers, extending from vascular processes within the inflamed DRG. These results demonstrate the feasibility of inducing chronic localized inflammatory responses in the DRG in the absence of traumatic nerve damage, and highlight the possible contribution of several inflammatory cytokines/chemokines to the generation of spontaneous activity and development and persistence of chemogenic pathologic pain.
European Journal of Pharmacology, 2009
The pharmacological attenuation of glial activation represents a novel approach for controlling neuropathic pain, but the role of microglial and astroglial cells is not well established. To better understand the potential role of two types of glial cells, microglia and astrocytes, in the pathogenesis of neuropathic pain, we examined markers associated with them by quantitative RT-PCR, western blot and immunohistochemical analyses in the dorsal horn of the lumbar spinal cord 7 days after chronic constriction injury (CCI) to the sciatic nerve in mice. The mRNA and protein of microglial cells were labeled with C1q and OX42(CD11b/c), respectively. The mRNA and protein of astrocytes were labeled with GFAP. The RT-PCR results indicated an increase in C1q mRNA that was more pronounced than the increased expression of GFAP mRNA ipsilateral to the injury in the dorsal spinal cord. Similarly, western blot and immunohistochemical analyses demonstrated an ipsilateral upregulation of OX42-positive cells (72 and 20%, respectively) and no or little (8% upregulation) change in GFAP-positive cells in the ipsilateral dorsal lumbar spinal cord. We also found that chronic intraperitoneal injection of the minocycline (microglial inhibitor) and pentoxifylline (cytokine inhibitor) attenuated CCI-induced activation of microglia, and both, but not fluorocitrate (astroglial inhibitor), diminished neuropathic pain symptoms and tactile and cold sensitivity. Our findings indicate that spinal microglia are more activated than astrocytes in peripheral injury-induced neuropathic pain. These findings implicate a glial regulation of the pain response and suggest that pharmacologically targeting microglia could effectively prevent clinical pain syndromes in programmed and/or anticipated injury.
Neuronal and microglial mechanisms of neuropathic pain
Molecular Brain, 2011
Neuropathic pain is generally defined as a chronic pain state resulting from peripheral and/or central nerve injury. Effective treatment for neuropathic pain is still lacking, due in part to poor understanding of pathological mechanisms at the molecular level. Neuronal mechanisms of neuropathic pain, especially synaptic plasticity, are the major focus of many investigators. N-methyl-D-aspartate (NMDA) receptor dependent synaptic plasticity at the spinal and cortical levels is believed to contribute to enhanced sensory responses after injury. Glial cells, including astrocytes and microglia, have recently been implicated in neuropathic pain. These glial cells form close interactions with neurons and thus may modulate nociceptive transmission under pathological conditions. In this review, we present recent progress in the study of neuronal and microglial mechanisms underlying neuropathic pain. We propose that activity-dependent neuronal plasticity is a key target for treatment in neuropathic pain.
Initial Phase of Neuropathic Pain within a Few Hours after Nerve Injury in Mice
Journal of Neuroscience, 2011
We tested a hypothesis that the spinal plasticity induced within a few hours after nerve injury may produce changes in cortical activities and an initial phase of neuropathic pain. Somatosensory cortical responses elicited by vibratory stimulation were visualized by transcranial flavoprotein fluorescence imaging in mice. These responses were reduced immediately after cutting the sensory nerves. However, the remaining cortical responses mediated by nearby nerves were potentiated within a few hours after nerve cutting. Nerve injury induces neuropathic pain. In the present study, mice exhibited tactile allodynia 1-2 weeks after nerve injury. Lesioning of the ipsilateral dorsal column, mediating tactile cortical responses, abolished somatic cortical responses to tactile stimuli. However, nontactile cortical responses appeared in response to the same tactile stimuli within a few hours after nerve injury, indicating that tactile allodynia was acutely initiated. propanoic acid], a specific antagonist of group II metabotropic glutamate receptors (mGluRs), on to the surface of the spinal cord also induced the potentiation of nontactile cortical responses. Together, it is suggested that low-frequency afferent firing produced by GDNF in touch-sensitive nerve fibers continuously activated spinal group II mGluRs and that failure of this activation triggered tactile allodynia.