One immune system plays many parts: The dynamic role of the immune system in chronic pain and opioid pharmacology

Mustafa, Sanam; Bajic, Juliana Esma; Barry, Benjamin; Evans, Susan; Siemens, Kariel R.; Hutchinson, Mark R.; Grace, Peter M.

doi:10.1016/j.neuropharm.2023.109459

Cited by 10 publications

(9 citation statements)

References 143 publications

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“…Neuroimmune interactions contribute to the development or maintenance of chronic pain 50,51,52 . Macrophages and T cells enhance pain via proinflammatory mediators and resolve pain via anti-inflammatory mediators such as IL-10 and endogenous opioids 53. Immune cells can also stimulate the release of endogenous opioid peptides or enhance their synthesis 43 , which can then bind opioid receptors on these cells and modulate their function 54 .…”

Section: Discussionmentioning

confidence: 99%

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Inflammatory pain resolution by mouse serum-derived small extracellular vesicles

Lin,

Luo,

Wickman

et al. 2024

Preprint

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Chronic pain is a significant public health issue. Current treatments have limited efficacy and significant side effects, warranting research on alternative strategies for pain management. One approach involves using small extracellular vesicles (sEVs) to transport beneficial biomolecular cargo to aid pain resolution. Exosomes are 30-150 nm sEVs that can carry RNAs, proteins, and lipid mediators to recipient cells via circulation. sEVs can be beneficial or harmful depending on their source and contents. To investigate the short and long-term effects of mouse serum-derived sEVs in pain modulation, sEVs from naive control or spared nerve injury (SNI) model donor mice were injected intrathecally into naive recipient mice. Basal mechanical thresholds transiently increased in recipient mice. This effect was mediated by opioid signaling as this outcome was blocked by naltrexone. Mass Spectrometry of sEVs detected endogenous opioid peptide leu-enkephalin. A single prophylactic intrathecal injection of sEVs two weeks prior to induction of the pain model in recipient mice delayed mechanical allodynia in SNI model mice and accelerated recovery from inflammatory pain after complete Freund's adjuvant (CFA) injection. ChipCytometry of spinal cord and dorsal root ganglion (DRG) from sEV treated mice showed that prophylactic sEV treatment reduced the number of natural killer (NK) and NKT cells in spinal cord and increased CD206+ anti-inflammatory macrophages in (DRG) after CFA injection. Further characterization of sEVs showed the presence of immune markers suggesting that sEVs can exert immunomodulatory effects in recipient mice to promote the resolution of inflammatory pain. Collectively, these studies demonstrate multiple mechanisms by which sEVs can attenuate pain.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inflammatory pain resolution by mouse serum-derived small extracellular vesicles

Lin,

Luo,

Wickman

et al. 2024

Preprint

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“…As mentioned earlier, macrophages and microglia are crucial to the process of repairing nerve injury, but inflammatory mediators generated by these cells at the same time contrib-ute to the etiology of chronic pain by sustaining and potentiating the increased sensitivity of pain-sensing neurons. 19 Macrophages can be tagged with iron nanoparticles and followed using MRI, given that iron has superparamagnetic characteristics. MRI can thus be used to follow the migration of iron oxide nanoparticles after intravenous administration into the body.…”

Section: Magnetic Resonance Imaging Of Macrophage Traffickingmentioning

confidence: 99%

“…The nociceptive nerve's excitability is affected by a host of modulatory events, such as neuroimmune mediators, ion channel dysregulation, inflammatory mediators, and macrophage interactions. 19 Closely following these processes are the phenomena of microglial cell activation, central sensitization, and changes in synaptic plasticity, just a few of the maladaptive changes that occur in the brain and spinal cord centers that lead to an environment where pain sensitivity is increased. 20 …”

Section: Pathophysiology Of Chronic Painmentioning

confidence: 99%

“…Numerous molecular mechanisms are involved in chronic pain that act in parallel. 19 A paradigm for molecular imaging techniques targeting this multitude of receptors and inflammatory mediators involved in pain was previously proposed dividing mechanisms into four categories ( Fig. 1 ): cellular response, inflammatory mediators and receptors, ion channel expression, and metabolic response.…”

Section: Molecular Imaging For Chronic Painmentioning

confidence: 99%

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Up-and-coming Radiotracers for Imaging Pain Generators

van der Heijden,

Biswal

2023

Semin Musculoskelet Radiol

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Chronic musculoskeletal pain is among the most highly prevalent diseases worldwide. Managing patients with chronic pain remains very challenging because current imaging techniques focus on morphological causes of pain that can be inaccurate and misleading. Moving away from anatomical constructs of disease, molecular imaging has emerged as a method to identify diseases according to their molecular, physiologic, or cellular signatures that can be applied to the variety of biomolecular changes that occur in nociception and pain processing and therefore have tremendous potential for precisely pinpointing the source of a patient's pain. Several molecular imaging approaches to image the painful process are now available, including imaging of voltage-gated sodium channels, calcium channels, hypermetabolic processes, the substance P receptor, the sigma-1 receptor, and imaging of macrophage trafficking. This article provides an overview of promising molecular imaging approaches for the imaging of musculoskeletal pain with a focus on preclinical methods.

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Genetic impact of blood C-reactive protein levels on chronic spinal & widespread pain

et al. 2023

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Purpose Causal mechanisms underlying systemic inflammation in spinal & widespread pain remain an intractable experimental challenge. Here we examined whether: (i) associations between blood C-reactive protein (CRP) and chronic back, neck/shoulder & widespread pain can be explained by shared underlying genetic variants; and (ii) higher CRP levels causally contribute to these conditions. Methods Using genome-wide association studies (GWAS) of chronic back, neck/shoulder & widespread pain (N = 6063–79,089 cases; N = 239,125 controls) and GWAS summary statistics for blood CRP (Pan-UK Biobank N = 400,094 & PAGE consortium N = 28,520), we employed cross-trait bivariate linkage disequilibrium score regression to determine genetic correlations (rG) between these chronic pain phenotypes and CRP levels (FDR < 5%). Latent causal variable (LCV) and generalised summary data-based Mendelian randomisation (GSMR) analyses examined putative causal associations between chronic pain & CRP (FDR < 5%). Results Higher CRP levels were genetically correlated with chronic back, neck/shoulder & widespread pain (rG range 0.26–0.36; P ≤ 8.07E-9; 3/6 trait pairs). Although genetic causal proportions (GCP) did not explain this finding (GCP range − 0.32–0.08; P ≥ 0.02), GSMR demonstrated putative causal effects of higher CRP levels contributing to each pain type (beta range 0.027–0.166; P ≤ 9.82E-03; 3 trait pairs) as well as neck/shoulder pain effects on CRP levels (beta [S.E.] 0.030 [0.021]; P = 6.97E-04). Conclusion This genetic evidence for higher CRP levels in chronic spinal (back, neck/shoulder) & widespread pain warrants further large-scale multimodal & prospective longitudinal studies to accelerate the identification of novel translational targets and more effective therapeutic strategies.

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One immune system plays many parts: The dynamic role of the immune system in chronic pain and opioid pharmacology

Cited by 10 publications

References 143 publications

Inflammatory pain resolution by mouse serum-derived small extracellular vesicles

Inflammatory pain resolution by mouse serum-derived small extracellular vesicles

Up-and-coming Radiotracers for Imaging Pain Generators

Genetic impact of blood C-reactive protein levels on chronic spinal & widespread pain

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