Microglial Modulation as a Target for Chronic Pain: From the Bench to the Bedside and Back

Haight, Elena S.; Forman, Thomas E.; Cordonnier, Stephanie A.; James, Michelle L.; Tawfik, Vivianne L.

doi:10.1213/ane.0000000000004033

Cited by 52 publications

(48 citation statements)

References 123 publications

(141 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 1 , 20 , 54 Attenuation of neuroinflammation, through inhibition of microglial activation, targeting of specific microglial genes, or selective depletion of spinal microglia, relatively consistently reverses pain hypersensitivity. 25 , 35 …”

Section: Introductionmentioning

confidence: 99%

Differential expression of cerebrospinal fluid neuroinflammatory mediators depending on osteoarthritis pain phenotype

Bjurström

Bodelsson

Montgomery

et al. 2020

Pain

View full text Add to dashboard Cite

Neuroinflammation is implicated in the development and maintenance of persistent pain states, but there are limited data linking cerebrospinal fluid (CSF) inflammatory mediators with neurophysiological pain processes in humans. In a prospective observational study, CSF inflammatory mediators were compared between patients with osteoarthritis (OA) who were undergoing total hip arthroplasty due to disabling pain symptoms (n = 52) and pain-free comparison controls (n = 30). In OA patients only, detailed clinical examination and quantitative sensory testing were completed. Cerebrospinal fluid samples were analyzed for 10 proinflammatory mediators using Meso Scale Discovery platform. Compared to controls, OA patients had higher CSF levels of interleukin 8 (IL-8) (P = 0.002), intercellular adhesion molecule 1 (P = 0.007), and vascular cell adhesion molecule 1 (P = 0.006). Osteoarthritis patients with central sensitization possibly indicated by arm pressure pain detection threshold <250 kPa showed significantly higher CSF levels of Fms-related tyrosine kinase 1 (Flt-1) (P = 0.044) and interferon gamma-induced protein 10 (IP-10) (P = 0.024), as compared to subjects with PPDT above that threshold. In patients reporting pain numerical rating scale score ≥3/10 during peripheral venous cannulation, Flt-1 was elevated (P = 0.025), and in patients with punctate stimulus wind-up ratio ≥2, CSF monocyte chemoattractant protein 1 was higher (P = 0.011). Multiple logistic regression models showed that increased Flt-1 was associated with central sensitization, assessed by remote-site PPDT and peripheral venous cannulation pain, and monocyte chemoattractant protein-1 with temporal summation in the area of maximum pain. Multiple proinflammatory mediators measured in CSF are associated with persistent hip OA-related pain. Pain phenotype may be influenced by specific CSF neuroinflammatory profiles.

show abstract

Section: Introductionmentioning

confidence: 99%

Differential expression of cerebrospinal fluid neuroinflammatory mediators depending on osteoarthritis pain phenotype

Bjurström

Bodelsson

Montgomery

et al. 2020

Pain

View full text Add to dashboard Cite

show abstract

“…involved in the pathogenesis of chronic pain due to their contributions to neuroinflammation and the resulting alternations in neuronal functions. [4][5][6] Following stimulation, ascending somatosensory signals are generally transmitted from periphery, via the spinal cord, to higher brain regions such as thalamus and cortex. The spinal cord dorsal horn acts as the first relay for ascending somatosensory transmission.…”

mentioning

confidence: 99%

Spinal microglia-neuron interactions in chronic pain

Chan

et al. 2020

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Current deficiency in our understanding of acute-to-chronic pain transition remains a hurdle for developing effective treatments against chronic pain. Whereas neurocentric mechanisms alone are insufficient to provide satisfactory explanation for such transition, neuro-immune crosstalk has attracted attention in recent pain research. In contrast to brain microglia, spinal microglia are activated immediately in various pain states. The fast-responsive enrichment and activation of spinal microglia among different pain conditions have highlighted the crucial role of neuroinflammation caused by microglia-neuron crosstalk in pain initiation. Recent studies have revealed spinal microglia-neuron interactions are also involved in chronic pain maintenance, albeit, with different anatomic distribution, cellular and molecular mechanisms, and biologic functions. Delineating the exact temporal discrepancies of spinal microglia distribution and functions along acute-to-chronic pain transition may provide additional mechanistic insights for drug development to prevent deterioration of acute pain into the chronic state. This narrative review summerizes the longitudinal alterations of spinal microglia-neuron interactions in the initiation of pain hypersensitivity, acuteto-chronic pain progression, and chronic pain maintenance, followed by an overview of current clinical translation of preclinical studies on spinal microglia. This review highlights the crucial role of the interaction between spinal microglia and neighboring neurons in the initiation and maintenance of pain hypersensitivity, in relation to the release of cytokines, chemokines, and neuroactive substances, as well as the modulation of synaptic plasticity. Further exploration of the uncharted functions of spinal microglia-neuron crosstalk may lead to the design of novel drugs for preventing acute-to-chronic pain transition.

show abstract

“…Studies in animal models of neuropathic pain have demonstrated that activated spinal microglia (Tsuda et al, 2008) release pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and lead to phosphorylation of the mitogen-activated protein kinases (MAPKs) including p38-MAPK, extracellular signal-regulated protein kinase (ERK), and c-Jun N-terminal kinase (JNK), which are known to participate in central sensitization and generation of pain hypersensitivity (Obata and Noguchi, 2004; Wang et al, 2014). A recently emerging approach in drug discovery, for diseases characterized by underlying neuroinflammation, is therefore the modulation of microglial polarization and selective regulation of the release of pro-/anti-inflammatory molecules (Haight et al, 2019). This could represent a promising new pharmacological strategy for treatment of chronic pain but also of other disorders such as chronic pain-associated affective disorders and depression (Benatti et al, 2016; Pena-Altamira et al, 2016; Du et al, 2017; Barcelon et al, 2019).…”

Section: Neuroinflammation and Microglial Activation In The Pathophysmentioning

confidence: 99%

Rescue of Noradrenergic System as a Novel Pharmacological Strategy in the Treatment of Chronic Pain: Focus on Microglia Activation

et al. 2019

View full text Add to dashboard Cite

Different types of pain can evolve toward a chronic condition characterized by hyperalgesia and allodynia, with an abnormal response to normal or even innocuous stimuli, respectively. A key role in endogenous analgesia is recognized to descending noradrenergic pathways that originate from the locus coeruleus and project to the dorsal horn of the spinal cord. Impairment of this system is associated with pain chronicization. More recently, activation of glial cells, in particular microglia, toward a pro-inflammatory state has also been implicated in the transition from acute to chronic pain. Both α2- and β2-adrenergic receptors are expressed in microglia, and their activation leads to acquisition of an anti-inflammatory phenotype. This review analyses in more detail the interconnection between descending noradrenergic system and neuroinflammation, focusing on drugs that, by rescuing the noradrenergic control, exert also an anti-inflammatory effect, ultimately leading to analgesia. More specifically, the potential efficacy in the treatment of neuropathic pain of different drugs will be analyzed. On one side, drugs acting as inhibitors of the reuptake of serotonin and noradrenaline, such as duloxetine and venlafaxine, and on the other, tapentadol, inhibitor of the reuptake of noradrenaline, and agonist of the µ-opioid receptor.

show abstract

Microglial Modulation as a Target for Chronic Pain: From the Bench to the Bedside and Back

Cited by 52 publications

References 123 publications

Differential expression of cerebrospinal fluid neuroinflammatory mediators depending on osteoarthritis pain phenotype

Differential expression of cerebrospinal fluid neuroinflammatory mediators depending on osteoarthritis pain phenotype

Spinal microglia-neuron interactions in chronic pain

Rescue of Noradrenergic System as a Novel Pharmacological Strategy in the Treatment of Chronic Pain: Focus on Microglia Activation

Contact Info

Product

Resources

About