Expression of IL-1� in supraspinal brain regions in rats with neuropathic pain (original) (raw)
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Expression of IL-1β in supraspinal brain regions in rats with neuropathic pain
Neuroscience Letters, 2006
We examined mRNA expression of the pro-inflammatory cytokine IL-1 in the brainstem, thalamus, and prefrontal cortex in two rat models of neuropathic pain. Rats received a neuropathic injury: spared nerve injury (SNI) or chronic constriction injury (CCI), sham injury, or were minimally handled (control). Neuropathic pain-like behavior was monitored by tracking tactile thresholds. SNI-injured animals showed a robust decrease in tactile thresholds of the injured foot, while CCI-injured animals did not show tactile threshold changes. Ten or 24 days after nerve injury, IL-1 gene expression in the brain was determined by RT-PCR. IL-1 expression changes were observed mainly at 10 days after injury in the SNI animals, contralateral to the injury side, with increased expression in the brainstem and prefrontal cortex. The results indicate that neuro-immune activation in neuropathic pain conditions includes supraspinal brain regions, suggesting cytokine modulation of supraspinal circuitry of pain in neuropathic conditions.
Chronic neuropathic pain-like behavior and brain-borne IL-1β
Annals of the New York Academy of Sciences, 2012
Neuropathic pain in animals results in increased IL-1 expression in the damaged nerve, the dorsal root ganglia, and the spinal cord. Here, we discuss our results showing that this cytokine is also overexpressed at supraspinal brain regions, in particular in the contralateral side of the hippocampus and prefrontal cortex and in the brainstem, in rats with neuropathic pain-like behavior. We show that neuropathic pain degree and development depend on the specific nerve injury model and rat strain studied, and that there is a correlation between hippocampal IL-1 expression and tactile sensitivity. Furthermore, the correlations between hippocampal IL-1 and IL-1ra or IL-6 observed in control animals, are disrupted in rats with increased pain sensitivity. The lateralization of increased cytokine expression indicates that this alteration may reflect nociception. The potential functional consequences of increased IL-1 expression in the brain during neuropathic pain are discussed.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011
IL-1β and TNF are potential targets in the management of neuropathic pain after injury. However, the importance of the IL-1 and TNF systems for peripheral nerve regeneration and the mechanisms by which these cytokines mediate effects are to be fully elucidated. Here, we demonstrate that mRNA and protein levels of IL-1β and TNF are rapidly upregulated in the injured mouse sciatic nerve. Mice lacking both IL-1β and TNF, or both IL-1 type 1 receptor (IL-1R1) and TNF type 1 receptor (TNFR1), showed reduced nociceptive sensitivity (mechanical allodynia) compared with wild-type littermates after injury. Microinjecting recombinant IL-1β or TNF at the site of sciatic nerve injury in IL-1β- and TNF-knock-out mice restored mechanical pain thresholds back to levels observed in injured wild-type mice. Importantly, recovery of sciatic nerve function was impaired in IL-1β-, TNF-, and IL-1β/TNF-knock-out mice. Notably, the infiltration of neutrophils was almost completely prevented in the sciatic ...
Experimental Neurology, 2001
Cytokines may be pathophysiologically involved in hyperalgesia. Uncertainty exists about the types of cytokines and their site of action. To study the role of key pro-and anti-inflammatory cytokines in a chronic constriction model of neuropathic pain, mRNA expression of TNF, IL-1, IL-6, and IL-10 was quantified using competitive RT-PCR. Each cytokine mRNA in rat sciatic nerve was examined at days 3, 7, 14, and 45 after chronic constriction injury (CCI). We also undertook behavioral testing of these rats. Thermal warming and touch thresholds were significantly reduced at days 3, 7, and 14 in the CCI group, compared with the shamoperated group. Cytokine gene expression in sciatic nerve was significantly increased at day 7 for IL-1 and IL-6 and at day 14 for TNF. Expression of IL-10 underwent a gradual and progressive increase, reaching statistical significance at day 45.
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.
Detailed characterization of neuro-immune responses following neuropathic injury in mice
Brain Research, 2011
Partial sciatic nerve injury is a common model of neuropathic pain in rodents, and produces both mechanical and thermal pain hypersensitivity. Several types of immune cells have been implicated in the pathogenesis of neuropathic pain due to nerve injury; however, the timing of their appearance has not been fully elucidated. Here, using immunohistochemistry, we characterized the time course and magnitude of inflammatory cell infiltration and resident immune cell activation in the sciatic nerves, L3-5 dorsal root ganglia (DRGs) and spinal segments following partial ligation of the sciatic nerve (PSNL) in C57BL/6J mice. PSNL markedly decreased paw withdrawal threshold to mechanical stimuli and paw withdrawal latency to thermal stimuli in the injured side. No changes were observed in the uninjured contralateral side. Mechanical allodynia persisted, and thermal hyperalgesia resolved by 2 weeks after injury. We found a significant increase in the numbers of infiltrating neutrophils,
Journal of Neuroinflammation, 2015
Background: Chronic neuropathic pain is a neuro-immune disorder, characterised by allodynia, hyperalgesia and spontaneous pain, as well as debilitating affective-motivational disturbances (e.g., reduced social interactions, sleep-wake cycle disruption, anhedonia, and depression). The role of the immune system in altered sensation following nerve injury is well documented. However, its role in the development of affective-motivational disturbances remains largely unknown. Here, we aimed to characterise changes in the immune response at peripheral and spinal sites in a rat model of neuropathic pain and disability. Methods: Sixty-two rats underwent sciatic nerve chronic constriction injury (CCI) and were characterised as either Pain and disability, Pain and transient disability or Pain alone on the basis of sensory threshold testing and changes in post-CCI dominance behaviour in resident-intruder interactions. Nerve ultrastructure was assessed and the number of T lymphocytes and macrophages were quantified at the site of injury on day six post-CCI. ATF3 expression was quantified in the dorsal root ganglia (DRG). Using a multiplex assay, eight cytokines were quantified in the sciatic nerve, DRG and spinal cord. Results: All CCI rats displayed equal levels of mechanical allodynia, structural nerve damage, and reorganisation. All CCI rats had significant infiltration of macrophages and T lymphocytes to both the injury site and the DRG. Pain and disability rats had significantly greater numbers of T lymphocytes. CCI increased IL-6 and MCP-1 in the sciatic nerve. Examination of disability subgroups revealed increases in IL-6 and MCP-1 were restricted to Pain and disability rats. Conversely, CCI led to a decrease in IL-17, which was restricted to Pain and transient disability and Pain alone rats. CCI significantly increased IL-6 and MCP-1 in the DRG, with IL-6 restricted to Pain and disability rats. CCI rats had increased IL-1β, IL-6 and MCP-1 in the spinal cord. Amongst subgroups, only Pain and disability rats had increased IL-1β. Conclusions: This study has defined individual differences in the immune response at peripheral and spinal sites following CCI in rats. These changes correlated with the degree of disability. Our data suggest that individual immune signatures play a significant role in the different behavioural trajectories following nerve injury, and in some cases may lead to persistent affective-motivational disturbances.
Possible role of inflammatory mediators in tactile hypersensitivity in rat models of mononeuropathy
PAIN, 2000
Peripheral hypersensitivity (hyperalgesia and allodynia) are common phenomena both in in¯ammatory and in neuropathic pain conditions. Several rat models of mononeuropathy (Bennett, Seltzer and Gazelius models) display such symptoms following partial injury to the sciatic nerve. Using immunohistochemistry and behavioral tests, we investigated in¯ammatory cell and cytokine responses in the sciatic nerve 14 days after injury created in these different models as well as after axotomy. Tactile hypersensitivity (`allodynia') was present in all Gazelius model rats whereas only 38 and 29% of the Bennett and Seltzer models, respectively, displayed this sign of neuropathy. The in¯ammatory reactions in rats with and without tactile allodynia were compared. Monocytes/macrophages (ED-1), natural killer cells, T lymphocytes, and the pro-in¯ammatory cytokines tumor necrosis factor-a (TNF-a ) and interleukin-6 (IL-6), were signi®cantly upregulated in all nerve injured rats in comparison to sham-operated controls. Interestingly, ED-1-, TNF-a -and IL-6-positive cells increased more markedly in allodynic Bennett and Seltzer rats than in non-allodynic ones. The magnitude of the in¯ammatory response does not seem to relate to the extent of damage to the nerve ®bers because axotomized rats displayed much lower upregulation. Our ®ndings indicate that the considerable increase in monocytes/macrophages induced by a nerve injury results in a very high release of IL-6 and TNF-a . This may relate to the generation of tactile allodynia/hyperalgesia, since there was a clear correlation between the number of ED-1 and IL-6-positive cells and the degree of allodynia. It is possible that measures to reduce monocyte/macrophage recruitment and the release of pro-in¯ammatory interleukins after nerve damage could in¯uence the development of neuropathic pain.
Behavioural Brain Research, 2006
The pro-inflammatory cytokine interleukin-1 (IL-1) has been implicated in both inflammatory processes and nociceptive neurotransmission. To further investigate the role of IL-1 in different pain states, gene-disrupted mice lacking both IL-1␣ and IL-1 genes (IL-1␣ (−/−)) were characterized in inflammatory, neuropathic, and post-operative pain models. IL-1␣ (−/−) mice showed normal sensorimotor function as measured by the rotorod assay compared to control mice (BALB/c). Acute and persistent formalin-induced nocifensive behaviors were reduced by 20% in IL-1␣ (−/−) mice as compared to control mice. IL-1␣ (−/−) mice also showed reduced inflammatory thermal and mechanical hyperalgesia compared to controls following the intraplantar administration of carrageenan or complete Freund's adjuvant (CFA). The duration of inflammatory hyperalgesia was shortened in IL-1␣ (−/−) mice versus controls in the CFA model. In contrast, deletion of IL-1␣ did not change the extent or the duration of post-operative pain developing after skin incision of the hind paw. Finally, time to onset, duration, and magnitude of mechanical allodynia were reduced in two models of neuropathic pain, spinal nerve L5-L6 ligation and chronic constriction injury of the sciatic nerve, in IL-1␣ (−/−) mice versus controls. These results demonstrate that IL-1␣ modulates both the generation and the maintenance of inflammatory and chronic neuropathic pain and that IL-1 may modulate nociceptive sensitivity to a greater extent in conditions of chronic as compared to acute pain.
European Journal of Pain, 2011
Neuropathic pain is a chronic pain state resulting from peripheral nerve injury, characterized by hyperalgesia and allodynia. We have reported that mice with genetic impairment of IL-1 signaling display attenuated neuropathic pain behavior and ectopic neuronal activity. In order to substantiate the role of IL-1 in neuropathic pain, WT mice were implanted subcutaneously with osmotic micropumps containing either IL-1ra or vehicle. Two days following the implantation, two models of neuropathic pain were used; partial nerve injury (spinal nerve transection, SNT), or complete nerve cut (spinal neuroma model). Mechanosensitivity was assessed seven consecutive days following SNT, and on day 7 recordings of spontaneous ectopic activity were performed. In the spinal nerve neuroma model, autotomy scores were recorded up to 35 days. Vehicle-treated mice developed significant allodynia and autotomy, and clear ectopic activity (4.1 ± 1.1% of the axons); whereas IL-1ra-treated mice did not display allodynic response, displayed delayed onset of autotomy and markedly reduced severity of autotomy scores, and displayed reduced spontaneous activity (0.8 ± 0.4% of the axons). To test whether IL-1 is involved in maintenance of mechanical allodynia, a separate group of WT mice was treated with a single injection of either saline or IL-1ra four days following SNT, after the allodynic response was already manifested. Whereas salinetreated mice displayed robust allodynia, acute IL-1ra treatment induced long-lasting attenuation of the allodynic response. The results support our hypothesis that IL-1 signaling plays an important role in neuropathic pain and in the ectopic neuronal activity that underling its development.