Neural mobilization reverses behavioral and cellular changes that characterize neuropathic pain in rats (original) (raw)
Related papers
Cellular and Molecular Neurobiology, 2010
Nerve growth factor (NGF), an essential peptide for sensory neurons, seems to have opposite effects when administered peripherally or directly to the central nervous system. We investigated the effects of 7-days intrathecal (i.t.) infusion of NGF on neuronal and glial spinal markers relevant to neuropathic behavior induced by chronic constriction injury (CCI) of the sciatic nerve. Allodynic and hyperalgesic behaviors were investigated by Von Frey and thermal Plantar tests, respectively. NGF-treated animals showed reduced allodynia and thermal hyperalgesia, compared to control animals. We evaluated on lumbar spinal cord the expression of microglial (ED-1), astrocytic (GFAP and S-100β), and C- and Aδ-fibers (SubP, IB-4 and Cb) markers. I.t. NGF treatment reduced reactive astrocytosis and the density of SubP, IB4 and Cb positive fibers in the dorsal horn of injured animals. Morphometric parameters of proximal sciatic nerve stump fibers and cells in DRG were also analyzed in CCI rats: myelin thickness was reduced and DRG neurons and satellite cells appeared hypertrophic. I.t. NGF treatment showed a beneficial effect in reversing these molecular and morphological alterations. Finally, we analyzed by immunohistochemistry the expression pattern of neurotrophin receptors TrkA, pTrkA, TrkB and p75NTR. Substantial alterations in neurotrophin receptors expression were observed in the spinal cord of CCI and NGF-treated animals. Our results indicate that i.t. NGF administration reverses the neuro-glial morphomolecular changes occurring in neuropathic animals paralleled by alterations in neurotrophin receptors ratio, and suggest that NGF is effective in restoring homeostatic conditions in the spinal cord and maintaining analgesia in neuropathic pain.
PAIN, 2010
The transcription factor nuclear factor kappa B (NF-κB) is a key regulator of inflammatory processes in reactive glial cells. We utilized a transgenic mouse model (GFAP-IκBα-dn) where the classical NF-κB pathway is inactivated by overexpression of a dominant negative (dn) form of the inhibitor of kappa B (IκBα) in glial fibrillary acidic protein (GFAP) expressing cells, which include astrocytes, Schwann cells, and satellite cells of the dorsal root ganglion (DRG) and sought to determine whether glial NF-κB inhibition leads to a reduction in pain behavior and inflammation following chronic constriction injury (CCI) of the sciatic nerve. As expected, following CCI nuclear translocation, and hence activation, of NF-κB was detected only in the in the sciatic nerve of wild type (WT) mice, and not in GFAP-IκBα-dn mice, while upregulation of GFAP was observed in the in sciatic nerve and DRGs of both WT and GFAP-IκBα-dn mice, indicative of glial activation. Following CCI, mechanical and thermal hyperalgesia were reduced in GFAP-IκBα-dn mice compared to WT, as well as gene and protein expression of CCL2, CCR2 and CXCL10 in the sciatic nerve. Additionally, gene expression of TNF, CCL2, and CCR2 was reduced in the DRGs of transgenic mice compared to WT after CCI. We can therefore conclude that transgenic inhibition of NF-κB in GFAP expressing glial cells attenuated pain and inflammation after peripheral nerve injury. These findings suggest that targeting the inflammatory response in Schwann cells and satellite cells may be important in treating neuropathic pain.
Neuroscience, 2009
Satellite glial cells in the dorsal root ganglion (DRG), like the better-studied glia cells in the spinal cord, react to peripheral nerve injury or inflammation by activation, proliferation, and release of messengers that contribute importantly to pathological pain. It is not known how information about nerve injury or peripheral inflammation is conveyed to the satellite glial cells. Abnormal spontaneous activity of sensory neurons, observed in the very early phase of many pain models, is one plausible mechanism by which injured sensory neurons could activate neighboring satellite glial cells. We tested effects of locally inhibiting sensory neuron activity with sodium channel blockers on satellite glial cell activation in a rat spinal nerve ligation (SNL) model. SNL caused extensive satellite glial cell activation (as defined by GFAP immunoreactivity) which peaked on day 1 and was still observed on day 10. Perfusion of the axotomized DRG with the Na channel blocker tetrodotoxin (TTX) significantly reduced this activation at all time points. Similar findings were made with a more distal injury (spared nerve injury model), using a different sodium channel blocker (bupivacaine depot) at the injury site. Local DRG perfusion with TTX also reduced levels of nerve growth factor (NGF) in the SNL model on day 3 (when activated glia are an important source of NGF), without affecting the initial drop of NGF on day 1 (which has been attributed to loss of transport from target tissues). Local perfusion in the SNL model also significantly reduced microglia activation (OX-42 immunoreactivity) on day 3 and astrocyte activation (GFAP immunoreactivity) on day 10 in the corresponding dorsal spinal cord. The results indicate that early spontaneous activity in injured sensory neurons may play important roles in glia activation and pathological pain.
BMC Neuroscience, 2014
Background: Altered hypothalamo-pituitary-adrenal (HPA) axis activity may be accompanied by a modulation of pain sensitivity. In a model of neuropathic pain (chronic constriction injury, CCI) we investigated the onset and maintenance of mechanical allodynia/hyperalgesia and the expression of biochemical mediators potentially involved in spinal cell modulation in two rat strains displaying either hypo-(Lewis-LEW) or hyper-(Fischer 344-FIS) reactivity of the HPA axis.
Glial NF-kappa B inhibition alters neuropeptide expression after sciatic nerve injury in mice
Brain Research, 2011
We utilized a transgenic mouse model where nuclear factor kappa B (NF-κB) is selectively inhibited in glial fibrillary acidic protein (GFAP) expressing cells. The transgene, GFAP-IκBαdn, overexpresses a dominant negative form of the inhibitor of NF-κB (IκBα) under the control of the GFAP promoter. In the present work, we sought to understand the impact of glial NF-κB inhibition on the expression of pain mediating sensory neuropeptides galanin and calcitonin gene related peptide (CGRP) in a model of neuropathic pain in mice. Chronic constriction injury (CCI) of the left sciatic nerve was performed on wild type (WT) and GFAP-IκBα-dn transgenic mice. RT-PCR and immunohistological staining were performed in sciatic nerve and/or L4-L5 DRG tissue for galanin, CGRP and macrophage marker CD11b.
Brain Research, 2000
Inhibition of proinflammatory cytokines reduces hyperalgesia in animal models of painful neuropathy. We set out to investigate the consequences of this treatment for nerve regeneration. Here we examined the sequels of epineurial application of neutralizing antibodies to tumor necrosis factor-alpha (TNF) in chronic constriction injury (CCI) of the sciatic nerve in C57 / BL 6 mice. The mice were tested behaviorally for manifestations of thermal hyperalgesia and mechanical allodynia. Nerve regeneration was assessed by morphometry of myelinated nerve fibers in the sciatic nerve and of the epidermal innervation density in the glabrous skin of the hindpaws. Antibodies to TNF reduced thermal hyperalgesia and mechanical allodynia after CCI. Myelinated fiber density in the sciatic nerve was reduced to 30% of normal on day 7 after surgery, and reached 60% on day 45, with no difference between antibody-treated and untreated animals. Epidermal innervation density as shown by PGP 9.5 and CGRP immunohistochemistry was reduced to 25-47% at both time points after CCI, again without differences between antibody treated and untreated mice. Myelinated fiber density but not epidermal innervation density was correlated to thermal and mechanical withdrawal thresholds. We conclude that neutralization of endoneurial TNF attenuates pain related behavior but has no effect on nerve regeneration. Furthermore, the number of epidermal nerve fibers is not relevant to the magnitude of behavioral hyperalgesia in CCI.
Neuroscience Letters, 1998
Adrenergic sprouts within axotomized dorsal root ganglia (DRG) may contribute to neuropathic pain, and may arise under the influence of nerve growth factor (NGF). We investigated effects of chronic constriction injury (CCI) on behavior and sprouting in mice in which NGF overexpression is driven by a glial protein (GFAP) promotor. GFAP-NGF mice were naturally hyperresponsive to radiant heat, and had enhanced ipsilateral responses to thermal and mechanical stimulation following CCI compared to wild-type mice. Sympathetic axons were already present in intact DRG of GFAP-NGF mice. Following CCI, sprouting in ipsilateral and to a lesser extent contralateral DRG occurred in both genotypes, but the sprout density 2 weeks post-lesion was much greater in GFAP-NGF mice. These results demonstrate a connection between the endogenous ectopic overexpression of NGF and (1) neuropathic pain behaviour and (2) sympathetic sprouting in the DRG.
Pain, 2011
An important issue in physical rehabilitation is how to protect from or to reduce the effects of peripheral nerve injury. In the present study, we examined whether ankle joint mobilization (AJM) would reduce neuropathic pain and enhance motor functional recovery after nerve injury. In the axonotmesis model, AJM during 15 sessions every other day was conducted in rats. Mechanical and thermal hyperalgesia and motor performance deficit were measured for 5 weeks. After 5 weeks, we performed morphological analysis and quantified the immunoreactivity for CD11b/c and glial fibrillary acidic protein (GFAP), markers of glial activation, in the lumbar spinal cord. Mechanical and thermal hyperalgesia and motor performance deficit were found in the Crush + Anesthesia (Anes) group (P < 0.001), which was significantly decreased after AJM (P < 0.001). In the morphological analysis, the Crush + Anes group presented reduced myelin sheath thickness (P < 0.05), but the AJM group presented enhanced myelin sheath thickness (P < 0.05). Peripheral nerve injury increased the immunoreactivity for CD11b/c and GFAP in the spinal cord (P < 0.05), and AJM markedly reduced CD11b/c and GFAP immunoreactivity (P < 0.01). These results show that AJM in rats produces an antihyperalgesic effect and peripheral nerve regeneration through the inhibition of glial activation in the dorsal horn of the spinal cord. These findings suggest new approaches for physical rehabilitation to protect from or reduce the effects of nerve injury. Ó
PloS one, 2015
The NF-κB pathway and chemokine (C-C motif) ligand 5 (CCL5) are involved in pain modulation; however, the precise mechanisms of their interactions in chronic neuropathic pain have yet to be established. The present study examined the roles of spinal NF-κB and CCL5 in a neuropathic pain model after chronic constriction injury (CCI) surgery. CCI-induced pain facilitation was evaluated using the Plantar and von Frey tests. The changes in NF-κB and CCL5 expression were analyzed by immunohistochemistry and Western blot analyses. Spinal NF-κB and CCL5 expression increased after CCI surgery. Repeated intrathecal infusions of pyrrolidine dithiocarbamate (PDTC, a NF-κB inhibitor) decreased CCL5 expression, inhibited the activation of microglia and astrocytes, and attenuated CCI-induced allodynia and hyperalgesia. Intrathecal injection of a CCL5-neutralizing antibody attenuated CCI-induced pain facilitation and also suppressed spinal glial cell activation after CCI surgery. However, the CCL5-...