A previously undiscovered mechanism of cellular communication, between neurons and immune cells in neuropathic pain, has been revealed in new research from King’s College London. Researchers identified a new method of treating neuropathic pain in mice, which could be more safe and effective than current treatments comprising of opioids and anti-epileptic drugs.
Neuropathic pain is a type of chronic pain that is usually caused by an injury to nerves, but the pain persists long after the injury has healed. Neuropathic pain may occur after surgery or a car accident, or in some cases when a limb has been amputated.
Currently the only available drugs for neuropathic pain are either opioids or antiepileptic medication. Opioids, like morphine and tramadol, are highly addictive and the NHS have recently raised concerns about prescription of these drugs, due to opioid overdoses more than doubling in the last decade.
This makes finding novel mechanisms and therapeutic targets a pressing issue.
Using cellular and mouse models of neuropathic pain, the scientists studied a cluster of neurons in the dorsal root ganglion (DRG), which are part of the sensory neurons that play an important role in communicating pain information to the brain.
They found that after nerve injury, pain neurons in this area released very small biological particles (exosome cargo) containing microRNA-21. These particles were then taken up by surrounding immune cells, ultimately leading to local inflammation and neuropathic pain.
[caption id=“attachment_93369” align=“aligncenter” width=“680”] Expression of miR-21 is increased in DRG neurons following spared nerve injury.
a–d) Upregulation of miR-21 expression detected by fluorescence in situ hybridization (FISH) in ipsilateral L5 DRG neurons 7 days after SNI compared to sham injury and contralateral DRG neurons. Scale bar = 100 μm.
e) Quantification of miR-21+ neurons in L4/5 DRG.
f, g) Immunostaining for large-diameter DRG neurons (NF-200, red) and FISH for miR-21 (green) in sham and SNI ipsilateral L5 DRG. Scale bar = 100 μm.
h) Quantification of large cell bodies NF-200+ neurons that also express miR-21 in L4/5 DRG.
i, j) Immunostaining of small-diameter DRG neurons (CGRP, red) and FISH for miR-21 (green) in sham and SNI ipsilateral L5 DRG. Scale bar = 100 μm.
k) Quantification of CGRP+ neurons that also express miR-21 in L4/5 DRG.
l–o) Immunostaining of macrophages (F4/80+ cells, red), FISH for miR-21 (green), and nuclei (4',6-diamidino-2-phenylindole (DAPI), blue) in sham and SNI DRG. Scale bar = 100 μm.
m, o) Representative example of high-magnification merge (×63), a puncta (yellow) can be seen in macrophages (F4/80+ red cells), scale bar = 10 μm.
Credit: Raffaele Simeoli et al. CC-BY[/caption]
At the site of injury and in the DRG, monocytes/macrophages infiltrate in response to chemokines produced by Schwann cells and satellite cells.
The authors showed that when they blocked dorsal root ganglion pain neurons from releasing microRNA-21 in particles, this had an anti-inflammatory effect at a cellular level, which prevented neuropathic pain from occurring in mice. The advantage of this method is that these particles, containing agents that block microRNA-21, do not infiltrate the brain and lead to side effects.
Blocks Neuropathic Pain
A similar method could be applied in humans to block pain neurons from releasing microRNA-21 in particles, which would prevent neuropathic pain from occurring. If successful, this would be the first drug to target neuropathic pain in specific areas without side effects, which is in stark contrast to the non-specific painkillers currently available.
Fortunately, similar treatments are already being trialled in cancer patients receiving immunotherapy, making the application to other conditions like neuropathic pain highly feasible.
The authors write that “preparations of exosomes derived from dendritic cells have entered clinical trials for immunotherapy in cancer patients and both production and characterization of clinical-grade exosome products are being actively pursued.”
The study was supported by a grant from the European Commission.
Raffaele Simeoli, Karli Montague, Hefin R. Jones, Laura Castaldi, David Chambers, Jayne H. Kelleher, Valentina Vacca, Thomas Pitcher, John Grist, Hadil Al-Ahdal, Liang-Fong Wong, Mauro Perretti, Johnathan Lai, Peter Mouritzen, Paul Heppenstall & Marzia Malcangio Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma Nature Communications 8, Article number: 1778 (2017) doi:10.1038/s41467-017-01841-5
Top Image: Prof. Bill Harris, Wellcome Images