Harnessing pain heterogeneity and RNA transcriptome to identify blood‐based pain biomarkers: a novel correlational study design and bioinformatics approach in a graded chronic constriction injury model

Abstract

A quantitative, peripherally accessible biomarker for neuropathic pain has great potential to improve clinical outcomes. Based on the premise that peripheral and central immunity contribute to neuropathic pain mechanisms, we hypothesized that biomarkers could be identified from the whole blood of adult male rats, by integrating graded chronic constriction injury (CCI), ipsilateral lumbar dorsal quadrant (iLDQ) and whole blood transcriptomes, and pathway analysis with pain behavior. Correlational bioinformatics identified a range of putative biomarker genes for allodynia intensity, many encoding for proteins with a recognized role in immune/nociceptive mechanisms. A selection of these genes was validated in a separate replication study. Pathway analysis of the iLDQ transcriptome identified Fcγ and Fcε signaling pathways, among others. This study is the first to employ the whole blood transcriptome to identify pain biomarker panels. The novel correlational bioinformatics, developed here, selected such putative biomarkers based on a correlation with pain behavior and formation of signaling pathways with iLDQ genes. Future studies may demonstrate the predictive ability of these biomarker genes across other models and additional variables.

Pathological pain and the neuroimmune interface

“…However, clinical translation of such therapies may be limited by potential disruption of the beneficial neuroprotective and neuroregenerative effects of TNF and IL-1, and by the inability of such molecules to penetrate the blood–CNS barrier. Although the beneficial effects of pro-inflammatory mediators could be left intact by selectively targeting receptor subtypes that mediate damaging pro-inflammatory processes (for example, TNFR1 or IL-1R1), such approaches have not yet been demonstrated for pain, but are likely to be too specific to address the widespread adaptations and possible redundancy of cytokines and pain processing pathways 33 . Hence, the first two cellular approaches present the greatest potential for clinical translation and are focused on below (summarized in TABLE 1).…”

Chronic nerve injury-induced Mas receptor expression in dorsal root ganglion neurons alleviates neuropathic pain

“…Neuropathic pain can arise as a consequence of a lesion or disease affecting the somatosensory system (1). Symptoms may include hypersensitivity to noxious (hyperalgesia) and non-noxious (allodynia) stimuli, as well as spontaneous pain (2). An estimated 7-8% of the general population suffers from mild to moderate forms of neuropathic pain, and 5% may be severely affected by it (3).…”

“…An estimated 7-8% of the general population suffers from mild to moderate forms of neuropathic pain, and 5% may be severely affected by it (3). Such pain is a major health problem that substantially reduces quality of life for the afflicted individuals and poses a significant economic burden to the health system and society (2). Understanding the pathophysiological process of neuropathic pain and the underlying molecular mechanisms will facilitate the development of novel therapies for neuropathic pain.…”

Peripheral Nerve Injury is Accompanied by Chronic Transcriptome-Wide Changes in the Mouse Prefrontal Cortex

“…It is therefore not surprising that injury is often accompanied by local or systemic alterations in gene expression. To date, several reports have identified strong links between injury and transcriptional changes in the peripheral nervous system [2], blood [3] and in the brain [4]. However, the full profile of transcriptional changes that accompany chronic pain in response to peripheral injury is unknown.…”