Epigenetic Changes in Post-Surgical vs Chronic Pain

Distinct Sets of Genes are Activated in Post-Surgical and Chronic Pain Conditions– Clincial Pain Advisor – Florence Chaverneff, Ph.D. – December 02, 2016

The locations of epigenetic changes brought on by pain show how long-term pain affects numerous areas of our physical functioning, including:

• neurodevelopment,
• cell-mediated immune response,
• amino acid metabolism,
• humoral response (involves substances found in the humors, or body fluids), and
• cell cycle.

Such epigenetic changes could be ameliorated if  the pain stimulation is blocked long enough (with opioids or whatever means necessary) to allow the changes to reverse themselves (as they do with acute pain). 

This shows that epigenetics are involved in the development of chronic pain, whether as the “cause” or as a “correlation” indicating another underlying “cause”.

The involvement of such fundamental epigenetic changes with chronic pain cast some doubt on the many popular psychological theories of pain.

The molecular mechanisms underlying chronic joint pain associated with osteoarthritis (OA) are largely unknown.

In order to study those mechanisms, researchers have developed a mouse model for OA. In this model, animals undergo surgical intervention to sever the anterior medial meniscotibial ligament, thus producing destabilization of the medial meniscus (DMM).

Control mice undergo a sham surgery, in which their ligament is kept intact

Following surgery, mice present with mechanical allodynia that develops shortly after the intervention (4 weeks). This allodynia  appeared to be maintained for 16 weeks, as indicated by lower force thresholds required to trigger paw withdrawal in the von Frey test, in DMM- vs sham-operated animal

Lower performance in these behavioral tests in DMM- vs sham-operated mice are indicative of activity-induced, pain-related behaviors.

Previous results indicated that these pain-related behaviors were associated with molecular changes in the dorsal root ganglia (DRG), namely, a temporary upregulation of monocyte chemoattractant protein (MCP)-1 and its receptor, chemokine receptor 2 (CCR2), 8 weeks following surgery.

Two different microarray studies were conducted:

1. one 4 weeks post-surgery to investigate “early pain” gene expression in post-surgical pain conditions;
2. one at 8 and 16 weeks following surgery to identify “late pain” genes in chronic or persistent pain conditions

comparing samples from naïve animals to those from sham- and DMM-operated mice.

Microarray analysis of samples investigating “early pain” revealed that 345 genes were upregulated in the DRGs of both sham- and DMM-operated animals, compared with naïve mice.

This would be the acute pain from the surgery itself as it heals.

These genes are involved in 3 main functions:

• cellular function, cell morphology and protein synthesis;
• inflammatory response ; and
• cell cycle and apoptosis

There were 227 genes that were found to be upregulated in the DRG of DMM mice relative to both the sham-operated and naïve animals.

This would be the chronic pain of the “knee-destablilized” mice.

Those genes were generally involved in

• neurodevelopment,
• cell-mediated immune response,
• amino acid metabolism,
• humoral response, and
• cell cycle.

Only 10 genes were found to be upregulated both in the early and late pain samples, validating the experimental design  

The authors concluded that results from this study investigating gene expression in an animal model of chronic OA pain “support behavioral data suggesting that distinct phases exist in the pain developing after DMM surgery.”