by Allison Barry and colleagues. Published in PAIN journal, link here.
Brief summary on the PainStorm webpage here.
Transcriptomic Profiling of Murine DRG Subtypes: Summary and Clinical Implications
1. Background: The Cellular Complexity of Neuropathic Pain
Chronic neuropathic pain, a debilitating condition resulting from nervous system damage, affects approximately 8% of the global population. Its prevalence is increasing due to longer lifespans, diabetes and decreases in cancer mortality. Current treatments are often inadequate, leaving many patients with a significantly reduced quality of life.
Addressing chronic neuropathic pain requires a change from symptomatic relief to precision medicines. A deeper understanding of the molecular mechanisms driving new cases of longterm pain will be crucial for identifying new medicines.
Before nerves enter the spine, their primary sensory neurons (which provide information from the skin and internal organs into the central nervous system) group together in the dorsal root ganglia (DRGs) close to each vertebra. Many studies have shown that these cells are important in pain processing, but gaps remain about how different types of sensory neurons (e.g. “subtypes”) contribute to neuropathic pain, as well as how they may differ between sexes. This study was designed to fill these gaps by looking at the neurons sampled from DRGs. This study was designed to provide a highly detailed view of the different genes acting in different subtypes using mice that had received a nerve injury.
2. Study Aims and Objectives: Deep Sequencing and Sexual Dimorphism
. The primary objectives were:
• To describe the actions of genes in five specific mouse sensory neuron subtypes following injury, using a well established nerve injury model called Spared Nerve Injury (SNI).
• To evaluate sex differences in nerve injury.
3. Study Results and Conclusions: Stereotyped Responses vs. Subtype Uniqueness
The study compared the 5 different types of nerve cells and found that genetic changes were similar after the nerve injury. Despite showing similar changes after injury, the different subtypes kept their individual identities (the marker genes/proteins found in each cell, which correspond to their unique functions). If the different subtypes of cell remain distinct, then there it might be possible to target each of them with new drugs.
Recovery from injury: Most subtypes of nerve cell showed a response to the injury for many weeks. Distinct changes were also found in1 subtype (Aβ-RA/Aδ-LTMRs), while two subtypes (called non-peptidergic (NP) nociceptors and C-LTMRs) showed a molecular signal returning to normal by the 4-week mark. A complementary study with collaborators in Glasgow (led by Andy Cooper and Greg Weir) suggests that injured NP and C-LTMR neurons may die in mice soon after injury (doi: 10.1097/j.pain.0000000000003321), leaving only healthy cells from these populations in the DRG by this 4 week timepoint.
• Precise genetic changes were found in the nerve subtypes. They included ion channels that control the nerve signalling as well as signs of increased nerve cell activity.
• Sex and nerves: The researchers found that the genetic response to injury was similar between sexes. However, before injury there were interesting differences in the neurons between the sexes. Because the “starting point” is different, the injured neurons were distinct between males and female mice.
4. Recommendations for Researchers and Healthcare Professionals
Researchers are able to access the genetic data from this study through academic websites. This should enhance the rate of progress for future studies.
Healthcare Professionals should recognise that there might be sex-specific pain experiences. Future medicines or treatments could account for these underlying differences.