scholarly journals Dual leucine zipper kinase is required for mechanical allodynia and microgliosis after nerve injury

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Josette J Wlaschin ◽  
Jacob M Gluski ◽  
Eileen Nguyen ◽  
Hanna Silberberg ◽  
James H Thompson ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Mechanical Allodynia ◽  
Leucine Zipper ◽  
Early Event ◽  
Immune Gene ◽  
Molecular Signaling ◽  
Transcriptional Program ◽  
Somatosensory Neurons ◽  
Neuronal Stress

Neuropathic pain resulting from nerve injury can become persistent and difficult to treat but the molecular signaling responsible for its development remains poorly described. Here, we identify the neuronal stress sensor dual leucine zipper kinase (DLK; Map3k12) as a key molecule controlling the maladaptive pathways that lead to pain following injury. Genetic or pharmacological inhibition of DLK reduces mechanical hypersensitivity in a mouse model of neuropathic pain. Furthermore, DLK inhibition also prevents the spinal cord microgliosis that results from nerve injury and arises distant from the injury site. These striking phenotypes result from the control by DLK of a transcriptional program in somatosensory neurons regulating the expression of numerous genes implicated in pain pathogenesis, including the immune gene Csf1. Thus, activation of DLK is an early event, or even the master regulator, controlling a wide variety of pathways downstream of nerve injury that ultimately lead to chronic pain.

scholarly journals Plasticity-Related PKMζSignaling in the Insular Cortex Is Involved in the Modulation of Neuropathic Pain after Nerve Injury

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Jeongsoo Han ◽  
Minjee Kwon ◽  
Myeounghoon Cha ◽  
Motomasa Tanioka ◽  
Seong-Karp Hong ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Neural Plasticity ◽  
Mechanical Allodynia ◽  
Insular Cortex ◽  
Long Term Potentiation ◽  
Inhibitory Peptide ◽  
Term Potentiation ◽  
Potential Applications

The insular cortex (IC) is associated with important functions linked with pain and emotions. According to recent reports, neural plasticity in the brain including the IC can be induced by nerve injury and may contribute to chronic pain. Continuous active kinase, protein kinase Mζ(PKMζ), has been known to maintain the long-term potentiation. This study was conducted to determine the role of PKMζin the IC, which may be involved in the modulation of neuropathic pain. Mechanical allodynia test and immunohistochemistry (IHC) of zif268, an activity-dependent transcription factor required for neuronal plasticity, were performed after nerve injury. Afterζ-pseudosubstrate inhibitory peptide (ZIP, a selective inhibitor of PKMζ) injection, mechanical allodynia test and immunoblotting of PKMζ, phospho-PKMζ(p-PKMζ), and GluR1 and GluR2 were observed. IHC demonstrated that zif268 expression significantly increased in the IC after nerve injury. Mechanical allodynia was significantly decreased by ZIP microinjection into the IC. The analgesic effect lasted for 12 hours. Moreover, the levels of GluR1, GluR2, and p-PKMζwere decreased after ZIP microinjection. These results suggest that peripheral nerve injury induces neural plasticity related to PKMζand that ZIP has potential applications for relieving chronic pain.

Sortilins in neuropathic pain

2012 ◽  
Vol 3 (3) ◽  
pp. 183-184
Author(s):  
M. Richner ◽  
O.J. Bjerrum ◽  
Y. De Koninck ◽  
A. Nykjaer ◽  
C.B. Vaegter
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Peripheral Nerve ◽  
Nerve Injury ◽  
Peripheral Nerve Injury ◽  
Mechanical Allodynia ◽  
Molecular Mechanisms ◽  
Intrathecal Injection ◽  
Ion Concentration ◽  
Down Regulation

AbstractBackground/aimsThe molecular mechanisms underlying neuropathic pain are incompletely understood, but recent data suggest that down-regulation of the chloride extruding co-transporter KCC2 in spinal cord sensory neurons is critical: Following peripheral nerve injury, activated microglia in the spinal cord release BDNF, which stimulates neuronal TrkB receptors and ultimately results in the reduction of KCC2 levels. Consequently, neuronal intracellular chloride ion concentration increases, impairing GABAA-receptor mediated inhibition. We have previously described how the receptor sortilin modulates neurotrophin signaling by facilitating anterograde transport of Trk receptors. Unpublished data further link SorCS2, another member of the Sortilins family of sorting receptors (sortilin, SorLA and SorCS1–3) to BDNF signaling by regulating presynaptic TrkB trafficking. The purpose of this study is to explore the involvement of Sortilins in neuropathic pain.MethodsWe subjected wild-type (wt), sortilin knockout (Sort1-/-) and SorCS2 knockout (SorCS2-/-) mice to the Spared Nerve Injury (SNI) model of peripheral nerve injury. Mechanical allodynia was measured by von Frey filaments using the up-down-up method and a 3-out-of-5 thresshold.ResultsAs previously described by several groups, wt mice developed significant mechanical allodynia following SNI. Interestingly however, mice lacking sortilin or SorCS2 were fully protected from development of allodynia and did not display KCC2 down-regulation following injury. In addition, a single intrathecal injection of antibodies against sortilin or SorCS2 could delay or rescue mechanical allodynia in wt SNI mice for 2-3 days. Finally, neither sortilin nor SorCS2 deficient mice responded to intrathecal injection of BDNF, in contrast to wt mice which developed transient mechanical allodynia.ConclusionWe hypothesize that sortilin and SorCS2 are involved in neuropathic pain development by regulating TrkB signaling. Alternatively, Sortilins may directly influence the regulation of KCC2 membrane levels following injury. Both hypotheses are currently being investigated by our group.

Comprehensive analysis of neurobehavior associated with histomorphological alterations in a chronic constrictive nerve injury model through use of the CatWalk XT system

2014 ◽  
Vol 120 (1) ◽  
pp. 250-262 ◽  
Author(s):  
Chien-Yi Chiang ◽  
Meei-Ling Sheu ◽  
Fu-Chou Cheng ◽  
Chun-Jung Chen ◽  
Hong-Lin Su ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Nerve Injury ◽  
Mechanical Allodynia ◽  
S100 Protein ◽  
Thermal Hyperalgesia ◽  
Nerve Damage ◽  
Dorsal Spinal Cord ◽  
Sensory Evoked ◽  
Dorsal Spinal

Object Neuropathic pain is debilitating, and when chronic, it significantly affects the patient physically, psychologically, and socially. The neurobehavior of animals used as a model for chronic constriction injury seems analogous to the neurobehavior of humans with neuropathic pain. However, no data depicting the severity of histomorphological alterations of the nervous system associated with graded changes in neurobehavior are available. To determine the severity of histomorphological alteration related to neurobehavior, the authors created a model of chronic constrictive injury of varying intensity in rats and used the CatWalk XT system to evaluate neurobehavior. Methods A total of 60 Sprague-Dawley rats, weighing 250–300 g each, were randomly assigned to 1 of 5 groups that would receive sham surgery or 1, 2, 3, or 4 ligatures of 3-0 chromic gut loosely ligated around the left sciatic nerve. Neurobehavior was assessed by CatWalk XT, thermal hyperalgesia, and mechanic allodynia before injury and periodically after injury. The nerve tissue from skin to dorsal spinal cord was obtained for histomorphological analysis 1 week after injury, and brain evoked potentials were analyzed 4 weeks after injury. Results. Significant differences in expression of nerve growth factor existed in skin, and the differences were associated with the intensity of nerve injury. After injury, expression of cluster of differentiation 68 and tumor necrosis factor–α was increased, and expression of S100 protein in the middle of the injured nerve was decreased. Increased expression of synaptophysin in the dorsal root ganglion and dorsal spinal cord correlated with the intensity of injury. The amplitude of sensory evoked potential increased with greater severity of nerve damage. Mechanical allodynia and thermal hyperalgesia did not differ significantly among treatment groups at various time points. CatWalk XT gait analysis indicated significant differences for print areas, maximum contact maximum intensity, stand phase, swing phase, single stance, and regular index, with sham and/or intragroup comparisons. Conclusions. Histomorphological and electrophysiological alterations were associated with severity of nerve damage. Subtle neurobehavioral differences were detected by the CatWalk XT system but not by mechanical allodynia or thermal hyperalgesia. Thus, the CatWalk XT system should be a useful tool for monitoring changes in neuropathic pain, especially subtle alterations.

scholarly journals Resveratrol Mediates Mechanical Allodynia Through Modulating Inflammatory Response via the TREM2-autophagy Axis in SNI Rat Model

2020 ◽  
Author(s):  
Yaping Wang ◽  
Yu Shi ◽  
Yongquan Huang ◽  
Wei Liu ◽  
Guiyuan Cai ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Inflammatory Response ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Rat Model ◽  
Mechanical Allodynia ◽  
Spinal Dorsal Horn ◽  
Intrathecal Administration ◽  
Spared Nerve Injury ◽  
Spinal Dorsal

Abstract Background Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms. Methods A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanism allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, Lentivirus coding TREM2 was intrathecal injected into SNI rats to activate TREM2 and the pain behavior was detected by the Von Frey test. Furthermore, 3-Methyladenine (3-MA, an autophagy inhibitor) was performed to analyze the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, immunofluorescence. Results The TREM2 expression and number of the microglial cell was significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-methyladenine in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia. Conclusions Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.

scholarly journals Behavioral, Biochemical and Electrophysiological Changes in Spared Nerve Injury Model of Neuropathic Pain

2020 ◽  
Vol 21 (9) ◽  
pp. 3396 ◽  
Author(s):  
Francesca Guida ◽  
Danilo De Gregorio ◽  
Enza Palazzo ◽  
Flavia Ricciardi ◽  
Serena Boccella ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Pathological Condition ◽  
Somatosensory System ◽  
Neuronal Firing ◽  
Molecular Signaling ◽  
Spared Nerve Injury ◽  
Preclinical Research ◽  
Pathophysiological Mechanisms ◽  
Advanced Phase

Neuropathic pain is a pathological condition induced by a lesion or disease affecting the somatosensory system, with symptoms like allodynia and hyperalgesia. It has a multifaceted pathogenesis as it implicates several molecular signaling pathways involving peripheral and central nervous systems. Affective and cognitive dysfunctions have been reported as comorbidities of neuropathic pain states, supporting the notion that pain and mood disorders share some common pathogenetic mechanisms. The understanding of these pathophysiological mechanisms requires the development of animal models mimicking, as far as possible, clinical neuropathic pain symptoms. Among them, the Spared Nerve Injury (SNI) model has been largely characterized in terms of behavioral and functional alterations. This model is associated with changes in neuronal firing activity at spinal and supraspinal levels, and induces late neuropsychiatric disorders (such as anxious-like and depressive-like behaviors, and cognitive impairments) comparable to an advanced phase of neuropathy. The goal of this review is to summarize current findings in preclinical research, employing the SNI model as a tool for identifying pathophysiological mechanisms of neuropathic pain and testing pharmacological agent.

scholarly journals Suppressive Effects of Bee Venom-Derived Phospholipase A2 on Mechanical Allodynia in a Rat Model of Neuropathic Pain

Toxins ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 477
Author(s):  
Seunghui Woo ◽  
Geehoon Chung ◽  
Hyunsu Bae ◽  
Sun Kwang Kim
Keyword(s):  
Neuropathic Pain ◽  
Phospholipase A2 ◽  
Nerve Injury ◽  
Mechanical Allodynia ◽  
Spinal Nerve ◽  
Bee Venom ◽  
Sprague Dawley ◽  
Relieve Pain ◽  
Adrenergic Antagonist ◽  
History Of

Bee venom (BV) has a long history of being used in traditional Korean medicine to relieve pain. Here, we investigated the effect of BV-derived phospholipase A2 (bvPLA2), a major component of BV, on peripheral nerve injury-induced neuropathic pain in rats. Spinal nerve ligation (SNL) was performed in Sprague Dawley rats to induce neuropathic pain, and paw withdrawal thresholds were measured using von Frey test. Mechanical allodynia, the representative symptom of neuropathic pain, was manifested following SNL and persisted for several weeks. The repetitive bvPLA2 treatment (0.2 mg/kg/day, i.p.) for two days significantly relieved the SNL-induced mechanical allodynia. The antiallodynic effect of bvPLA2 was blocked by spinal pretreatment with α1-adrenergic antagonist prazosin (30 μg, i.t.) but not with α2-adrenergic antagonist idazoxan (50 μg, i.t.). Also, the spinal application of α1-adrenergic agonist phenylephrine (50 μg, i.t.) reduced mechanical allodynia. These results indicate that bvPLA2 could relieve nerve injury-induced neuropathic mechanical allodynia through the activation of spinal α1-adrenergic receptors.

scholarly journals Author response: Dual leucine zipper kinase is required for mechanical allodynia and microgliosis after nerve injury

2018 ◽  
Author(s):  
Josette J Wlaschin ◽  
Jacob M Gluski ◽  
Eileen Nguyen ◽  
Hanna Silberberg ◽  
James H Thompson ◽  
...  
Keyword(s):  
Nerve Injury ◽  
Mechanical Allodynia ◽  
Leucine Zipper ◽  
Author Response

scholarly journals Control of mechanical pain hypersensitivity through ligand-targeted photoablation of TrkB positive sensory neurons

2017 ◽  
Author(s):  
Rahul Dhandapani ◽  
Cynthia Mary Arokiaraj ◽  
Francisco J. Taberner ◽  
Paola Pacifico ◽  
Sruthi Raja ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Sensory Neurons ◽  
Mechanical Allodynia ◽  
List Type ◽  
Light Touch ◽  
Peripheral Neurons ◽  
Necessary And Sufficient ◽  
Peripheral Sensory

SummaryMechanical allodynia is a major symptom of neuropathic pain whereby innocuous touch evokes severe pain. Here we identify a population of peripheral sensory neurons expressing TrkB that are both necessary and sufficient for producing pain from light touch after nerve injury. Mice in which TrkB-Cre expressing neurons are ablated are less sensitive to the lightest touch under basal conditions, and fail to develop mechanical allodynia in a model of neuropathic pain. Moreover, selective optogenetic activation of these neurons after nerve injury evokes marked nociceptive behavior. Using a phototherapeutic approach based upon BDNF, the ligand for TrkB, we perform molecule-guided laser ablation of these neurons and achieve long-term retraction of TrkB positive neurons from the skin and pronounced reversal of mechanical allodynia across multiple types of neuropathic pain. Thus we identify the peripheral neurons which transmit pain from light touch and uncover a novel pharmacological strategy for its treatment.HighlightsTrkB+ neurons detect light touch under basal conditionsTrkB+ neurons convey mechanical allodynia in neuropathic pain statesA photosensitizing derivative of BDNF allows for photoablation of TrkB+ neuronsBDNF-guided photoablation reverses allodynia in multiple types of neuropathic pain

scholarly journals Intravenous Administration of Substance P Attenuates Mechanical Allodynia Following Nerve Injury by Regulating Neuropathic Pain-Related Factors

2017 ◽  
Vol 25 (3) ◽  
pp. 259-265 ◽  
Author(s):  
Eunkyung Chung ◽  
Tae Gyoon Yoon ◽  
Sumin Kim ◽  
Moonkyu Kang ◽  
Hyun Jeong Kim ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Substance P ◽  
Nerve Injury ◽  
Intravenous Administration ◽  
Mechanical Allodynia ◽  
Related Factors
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