Neuroimmune-glial cells interactions elevate the kynurenine metabolic pathway to sustain neuropathic pain

Neuropathic pain is triggered by injury to the somatosensory system, and is one of the most important types of chronic pain. Nevertheless, critical pathophysiological mechanisms that maintain neuropathic pain are poorly understood. Here, we show that neuropathic pain is abrogated when the kynurenine metabolic pathway (KYNPATH) initiated by the enzyme indoleamine 2,3-dioxygenase (IDO) is ablated pharmacologically or genetically. Mechanistically, it was found that IDO upregulation in dendritic cells that accumulate in the dorsal root leptomeninges led to increased levels of kynurenine (Kyn) in the spinal cord, where Kyn is metabolized by astrocytes-expressed kynurenine-3-monooxygenase into a pro-nociceptive metabolite 3-hydroxykynurenine. Ultimately, 3-hydroxyanthranilate 3,4-dioxygenase-derived quinolinic acid, the final step of the canonical KYNPATH, is also involved in neuropathic pain development through the activation of glutamatergic NMDA receptor. In conclusion, these data reveal a novel role for KYNPATH as an important factor maintaining neuropathic pain during neuroimmune-glia cell interactions. This novel paradigm offers potential new targets for drug development against this type of chronic pain.

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Quantitative Sensory Testing of Spinal Cord and Dorsal Root Ganglion Stimulation in Chronic Pain Patients

Neuromodulation Technology at the Neural Interface ◽

10.1111/ner.13329 ◽

2021 ◽

Author(s):

Vishwanath Sankarasubramanian ◽

Srinivas Chiravuri ◽

Ehsan Mirzakhalili ◽

Carlos J. Anaya ◽

John Ryan Scott ◽

...

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Dorsal Root Ganglion ◽

Dorsal Root ◽

Quantitative Sensory Testing ◽

Sensory Testing ◽

Chronic Pain Patients ◽

Pain Patients

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Role of the immune system in neuropathic pain

Scandinavian Journal of Pain ◽

10.1515/sjpain-2019-0138 ◽

2019 ◽

Vol 20 (1) ◽

pp. 33-37 ◽

Cited By ~ 16

Author(s):

Marzia Malcangio

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Nervous System ◽

Neuropathic Pain ◽

Immune System ◽

Peripheral Nerve ◽

Dorsal Horn ◽

Nerve Injury ◽

Immune Cells ◽

Peripheral Nerve Injury

AbstractBackgroundAcute pain is a warning mechanism that exists to prevent tissue damage, however pain can outlast its protective purpose and persist beyond injury, becoming chronic. Chronic Pain is maladaptive and needs addressing as available medicines are only partially effective and cause severe side effects. There are profound differences between acute and chronic pain. Dramatic changes occur in both peripheral and central pathways resulting in the pain system being sensitised, thereby leading to exaggerated responses to noxious stimuli (hyperalgesia) and responses to non-noxious stimuli (allodynia).Critical role for immune system cells in chronic painPreclinical models of neuropathic pain provide evidence for a critical mechanistic role for immune cells in the chronicity of pain. Importantly, human imaging studies are consistent with preclinical findings, with glial activation evident in the brain of patients experiencing chronic pain. Indeed, immune cells are no longer considered to be passive bystanders in the nervous system; a consensus is emerging that, through their communication with neurons, they can both propagate and maintain disease states, including neuropathic pain. The focus of this review is on the plastic changes that occur under neuropathic pain conditions at the site of nerve injury, the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord. At these sites both endothelial damage and increased neuronal activity result in recruitment of monocytes/macrophages (peripherally) and activation of microglia (centrally), which release mediators that lead to sensitisation of neurons thereby enabling positive feedback that sustains chronic pain.Immune system reactions to peripheral nerve injuriesAt the site of peripheral nerve injury following chemotherapy treatment for cancer for example, the occurrence of endothelial activation results in recruitment of CX3C chemokine receptor 1 (CX3CR1)-expressing monocytes/macrophages, which sensitise nociceptive neurons through the release of reactive oxygen species (ROS) that activate transient receptor potential ankyrin 1 (TRPA1) channels to evoke a pain response. In the DRG, neuro-immune cross talk following peripheral nerve injury is accomplished through the release of extracellular vesicles by neurons, which are engulfed by nearby macrophages. These vesicles deliver several determinants including microRNAs (miRs), with the potential to afford long-term alterations in macrophages that impact pain mechanisms. On one hand the delivery of neuron-derived miR-21 to macrophages for example, polarises these cells towards a pro-inflammatory/pro-nociceptive phenotype; on the other hand, silencing miR-21 expression in sensory neurons prevents both development of neuropathic allodynia and recruitment of macrophages in the DRG.Immune system mechanisms in the central nervous systemIn the dorsal horn of the spinal cord, growing evidence over the last two decades has delineated signalling pathways that mediate neuron-microglia communication such as P2X4/BDNF/GABAA, P2X7/Cathepsin S/Fractalkine/CX3CR1, and CSF-1/CSF-1R/DAP12 pathway-dependent mechanisms.Conclusions and implicationsDefinition of the modalities by which neuron and immune cells communicate at different locations of the pain pathway under neuropathic pain states constitutes innovative biology that takes the pain field in a different direction and provides opportunities for novel approaches for the treatment of chronic pain.

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Dorsal root ganglion stimulation lead fractures: potential mechanisms and ways to avoid

BMJ Case Reports ◽

10.1136/bcr-2020-241353 ◽

2021 ◽

Vol 14 (5) ◽

pp. e241353

Author(s):

Gaurav Chauhan ◽

Brandon I Roth ◽

Nagy Mekhail

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Case Report ◽

Dorsal Root Ganglion ◽

Dorsal Root ◽

Unusual Case ◽

Pain Syndrome ◽

Structural Instability ◽

Probable Mechanism ◽

Lead Fracture

Dorsal root ganglion stimulation (DRGS) therapy is a rapidly emerging tool being used by pain physicians in the treatment of chronic pain. Complex regional pain syndrome (CRPS), a debilitating disease whose mechanism is still has yet to be fully elucidated, is a common pathology targeted by DRGS therapy, often better results than traditional spinal cord stimulation. DRGS therapy, however, is not bereft of complications. Lead migration and fracture are two examples in particular that are among the most common of these complications. The authors report an unusual case of lost efficacy due to lead fractures in patients with CRPS treated with DRGS. The case report narrates identification, management and probable mechanism of DRGS lead fracture. The structural instability of DRGS leads can yield distressing symptoms at any point during the therapy, and physicians should be cognisant of the complications of DRGS therapy.

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The N-methyl-D-aspartate (NMDA) receptor in skin, dorsal root ganglion and spinal cord: an ideal target gene for RNA interference therapy for pain relief

Neuropsychiatry ◽

10.4172/neuropsychiatry.1000209 ◽

2017 ◽

Vol 07 (03) ◽

Author(s):

Chia Chih Alex Tseng ◽

Yuan Yi Chia ◽

Chien Cheng Liu ◽

Kuan Ming Feng ◽

Ping Heng Tan

Keyword(s):

Spinal Cord ◽

Rna Interference ◽

Nmda Receptor ◽

Pain Relief ◽

Dorsal Root Ganglion ◽

Dorsal Root ◽

Target Gene

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Microglial BDNF, PI3K, and p-ERK in the Spinal Cord Are Suppressed by Pulsed Radiofrequency on Dorsal Root Ganglion to Ease SNI-Induced Neuropathic Pain in Rats

Pain Research and Management ◽

10.1155/2019/5948686 ◽

2019 ◽

Vol 2019 ◽

pp. 1-15 ◽

Cited By ~ 3

Author(s):

Xueru Xu ◽

Shaoxiong Fu ◽

Xiaomei Shi ◽

Rongguo Liu

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Dorsal Root Ganglion ◽

Nerve Injury ◽

Calcium Binding ◽

Dorsal Root ◽

Intrathecal Injection ◽

Pulsed Radiofrequency ◽

Erk Phosphorylation ◽

Extracellular Signal

Background. Pulsed radiofrequency (PRF) on the dorsal root ganglion (DRG) has been applied to alleviate neuropathic pain effectively, yet the mechanisms underlying pain reduction owing to this treatment are not clarified completely. The activated microglia, brain-derived neurotrophic factor (BDNF), phosphatidylinositol 3-kinase (PI3K), and phosphorylated extracellular signal-regulated kinase (p-ERK) in the spinal cord were demonstrated to be involved in developing neuropathic pain. Also, it has been just known that PRF on DRG inhibits the microglial activation in nerve injury rats. Here, we aim to investigate whether PRF treatment could regulate the levels of BDNF, PI3K, and p-ERK in the spinal cord of rats with spared nerve injury (SNI) via suppressing the spinal microglia activation to ease neuropathic pain. Methods. The rats with SNI were intrathecally treated with minocycline (specific microglia inhibitor) or same volume of dimethyl sulfoxide once daily, beginning from 1 h before nerve transection to 7 days. PRF was applied adjacent to the L4-L5 DRG of rats with SNI at 45 V for 6 min on the seventh postoperative day, whereas the free-PRF rats were treated without PRF. The withdrawal thresholds were studied, and the spinal levels of ionized calcium-binding adapter molecule 1 (Iba1), BDNF, PI3K, and p-ERK were calculated by western blot analysis, reverse transcription-polymerase chain reaction, and immunofluorescence. Results. The paw withdrawal mechanical threshold and paw withdrawal thermal latency decreased in the ipsilateral hind paws after SNI, and the spinal levels of Iba1, BDNF, PI3K, and p-ERK increased on day 21 after SNI compared with baseline (P<0.01). An intrathecal injection of minocycline led to the reversal of SNI-induced allodynia and increase in levels of Iba1, BDNF, PI3K, and p-ERK. Withdrawal thresholds recovered partially after a single PRF treatment for 14 days, and SNI-induced microglia hyperactivity, BDNF upregulation, and PI3K and ERK phosphorylation in the spinal cord reduced on D14 due to the PRF procedure. Conclusion. Microglial BDNF, PI3K, and p-ERK in the spinal cord are suppressed by the therapy of PRF on DRG to ease SNI-induced neuropathic pain in rats.

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Elevated Expression of Fractalkine (CX3CL1) and Fractalkine Receptor (CX3CR1) in the Dorsal Root Ganglia and Spinal Cord in Experimental Autoimmune Encephalomyelitis: Implications in Multiple Sclerosis-Induced Neuropathic Pain

BioMed Research International ◽

10.1155/2013/480702 ◽

2013 ◽

Vol 2013 ◽

pp. 1-14 ◽

Cited By ~ 19

Author(s):

Wenjun Zhu ◽

Crystal Acosta ◽

Brian MacNeil ◽

Claudia Cortes ◽

Howard Intrater ◽

...

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Neuropathic Pain ◽

Experimental Autoimmune Encephalomyelitis ◽

Protein Expression ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Autoimmune Encephalomyelitis ◽

Receptor Cx3cr1 ◽

Experimental Autoimmune

Multiple sclerosis (MS) is a central nervous system (CNS) disease resulting from a targeted autoimmune-mediated attack on myelin proteins in the CNS. The release of Th1 inflammatory mediators in the CNS activates macrophages, antibodies, and microglia resulting in myelin damage and the induction of neuropathic pain (NPP). Molecular signaling through fractalkine (CX3CL1), a nociceptive chemokine, via its receptor (CX3CR1) is thought to be associated with MS-induced NPP. An experimental autoimmune encephalomyelitis (EAE) model of MS was utilized to assess time dependent gene and protein expression changes of CX3CL1 and CX3CR1. Results revealed significant increases in mRNA and the protein expression of CX3CL1 and CX3CR1 in the dorsal root ganglia (DRG) and spinal cord (SC) 12 days after EAE induction compared to controls. This increased expression correlated with behavioural thermal sensory abnormalities consistent with NPP. Furthermore, this increased expression correlated with the peak neurological disability caused by EAE induction. This is the first study to identify CX3CL1 signaling through CX3CR1 via the DRG /SC anatomical connection that represents a critical pathway involved in NPP induction in an EAE model of MS.

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Contralateral Neuropathic Pain and Neuropathology in Dorsal Root Ganglion and Spinal Cord Following Hemilateral Nerve Injury in Rats

Spine ◽

10.1097/brs.0b013e3181733188 ◽

2008 ◽

Vol 33 (12) ◽

pp. 1344-1351 ◽

Cited By ~ 58

Author(s):

Satoshi Hatashita ◽

Miho Sekiguchi ◽

Hideo Kobayashi ◽

Shin-ichi Konno ◽

Shin-ichi Kikuchi

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Dorsal Root Ganglion ◽

Nerve Injury ◽

Dorsal Root

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Perspectives in Pain Research 2014: Neuroinflammation and glial cell activation: The cause of transition from acute to chronic pain?

Scandinavian Journal of Pain ◽

10.1016/j.sjpain.2014.10.002 ◽

2015 ◽

Vol 6 (1) ◽

pp. 3-6 ◽

Cited By ~ 21

Author(s):

Brian E. Cairns ◽

Lars Arendt-Nielsen ◽

Paola Sacerdote

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Dorsal Root Ganglion ◽

Glial Cell ◽

Schwann Cells ◽

Glial Cells ◽

Proinflammatory Cytokines ◽

Immune Cells ◽

Dorsal Root ◽

Satellite Glial Cells

AbstractBackgroundIt is unknown why an acute pain condition under various circumstances can transition into a chronic pain condition.There has been a shift towards neuroinflammation and hence glial cell activations specifically in the dorsal root ganglion and spinal cord as a mechanism possibly driving the transition to chronic pain. This has led to a focus on non-neuronal cells in the peripheral and central nervous system. Besides infiltrating macrophages, Schwann cells and satellite glial cells release cytokines and therefore important mechanisms in the maintenance of pain. Activated Schwann cells, satellite glial cells, microglia, and astrocytes may contribute to pain sensitivity by releasing cytokines leading to altered neuronal function in the direction of sensitisation.Aims of this perspective paper1) Highlight the complex but important recent achievement in the area of neuroinflammation and pain at spinal cord level and in the dorsal root ganglion.2) Encourage further research which hopefully may provide better understanding of new key elements driving the transition from acute to chronic pain.Recent results in the area of neuroinflammation and painFollowing a sciatic nerve injury, local macrophages, and Schwann cells trigger an immune response immediately followed by recruitment of blood-derived immune cells. Schwann cells, active resident, and infiltrating macrophages release proinflammatory cytokines. Proinflammatory cytokines contribute to axonal damage and also stimulate spontaneous nociceptor activity. This results in activation of satellite glial cells leading to an immune response in the dorsal root ganglia driven by macrophages, lymphocytes and satellite cells. The anterograde signalling progresses centrally to activate spinal microglia with possible up regulation of glial-derived proinflammatory/pronociceptive mediators.An important aspect is extrasegmental spreading sensitisation where bilateral elevations in TNF-α, IL-6, and IL-10 are found in dorsal root ganglion in neuropathic models. Similarly in inflammatory pain models, bilateral up regulation occurs for TNF-α, IL-1 β, and p38 MAPK. Bilateral alterations in cytokine levels in the DRG and spinal cord may underlie the spread of pain to the uninjured side.An important aspect is how the opioids may interact with immune cells as opioid receptors are expressed by peripheral immune cells and thus can induce immune signaling changes. Furthermore, opioids may stimulate microglia cells to produce proinflammatory cytokines such as IL-1.ConclusionsThe present perspective paper indicates that neuroinflammation and the associated release of pro-inflammatory cytokines in dorsal root ganglion and at the spinal cord contribute to the transition from acute to chronic pain. Neuroinflammatory changes have not only been identified in the spinal cord and brainstem, but more recently, in the sensory ganglia and in the nerves as well. The glial cell activation may be responsible for contralateral spreading and possible widespread sensitisation.ImplicationsCommunication between glia and neurons is proposed to be a critical component of neuroinflammatory changes that may lead to chronic pain. Sensory ganglia neurons are surrounded by satellite glial cells but how communication between the cells contributes to altered pain sensitivity is still unknown. Better understanding may lead to new possibilities for (1) preventing development of chronic pain and (2) better pain management.

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