By Jean Tracy

The first-ever National Pain Strategy, commissioned by the Department of Health & Human Services and released in final form in March, is unequivocal on the need for a robust basic and translational research effort to reduce the current burden of pain. The Interagency Pain Research Coordinating Committee, which prepared the strategy, is now charged with creating an agenda to advance pain-related research.

In the College of Medicine's Department of Pharmacology & Physiology, a robust basic research effort has long been underway to find new molecular mechanisms involved in the development and maintenance of pain states. Further understanding of these mechanisms could lead to the identification of new targets for drugs that would be alternatives to anti-inflammatory drugs and opioids.

Melissa Manners, who successfully defended her doctoral thesis in March, has been studying the role of the epigenetic regulator methyl-CpG-binding protein 2 (MeCP2) in modulating pain. Mutations in MECP2 cause Rett syndrome, and it has been observed that people with Rett syndrome have reduced pain sensitivity. What Manners did was to show the molecular link between MeCP2 and pain.

Children with Rett syndrome (almost exclusively girls) have a number of severe neurological and physical disabilities; the lack of pain sensation has not been a particular focus of the Rett community, but it was of interest to the Drexel researchers. Manners explains: "A classic example is that young girls will chew on their fingers to the point of severe injury. They don't seem to have the ability to sense the pain normally. Where we would sense the pain and stop, they have a very delayed or reduced reaction."

Manners did her thesis research in the laboratory of Seena Ajit, PhD, assistant professor in the Department of Pharmacology & Physiology. The Ajit lab pursues various aspects of epigenetics including DNA methylation, histone modifications, and RNA-mediated gene silencing, all aimed at understanding the molecular mechanisms underlying pain.

Manners was specifically looking at microRNAs and MeCP2. MeCP2 binds differently after nerve injury. "What we've found is that after a nerve injury that causes neuropathic pain, microRNAs that repress MeCP2 are downregulated and MeCP2 is upregulated," Manners explains. "We were interested in investigating this regulatory mechanism, but also wanted to know what these changes in MeCP2 levels meant for gene expression.

We found that upregulation of MeCP2 ultimately leads to changes in MeCP2 binding to DNA, and this leads to the dysregulation of many downstream genes. We found many genes that were changed, but the one we focused on was microRNA-126." The researchers found that miR-126 was repressed by MeCP2 in a neuropathic pain model and that the repression of miR-126 led to upregulation of pain targets.

MeCP2 has been well studied in the brain, but the goal of Manners' research was to look at the periphery. The dorsal root ganglia convey noxious stimuli from the periphery to the central nervous system. Previous miRNA profiling of dorsal root ganglia in a neuropathic pain model showed decreased expression of multiple miRNAs predicted to target MeCP2. The researchers confirmed MeCP2 upregulation in the dorsal root ganglia following nerve injury and repression of MeCP2 by miRNAs in vitro.

There are just a handful of publications concerning MeCP2 in pain – and two of them are from the Ajit lab. "The link had been hypothesized, but it had not been empirically validated, and certainly not in the periphery," Manners says. Other studies that have been conducted have been in the brain, investigating the perception of pain. "But the periphery — the sensation of pain — hasn't really been explored till now."

Manners is headed for a postdoctoral fellowship at the University of Pennsylvania, where she will study epigenetic regulators and anxiety in the laboratory of Julie Blendy, PhD. In the Ajit lab, she studied the periphery and spinal cord. In her new lab, she will be studying the brain. "With both experiences, I will have covered the entire nervous system, and that is kind of awesome," she says with a grin.

In the process of finding a good fit, Manners looked at several epigenetics labs at Penn. "I was very fortunate to have a great experience with interviewing there, largely because I was so well prepared here at Drexel," she says.

"They were impressed by the research, even the work that was unpublished — they thought it was innovative, interesting — so it was really nice to give a seminar there." Manners was always interested in science. "My parents have a science background so I was raised with that in mind. I was interested in anything from the environment to planets." In college, she majored in biology. "I loved my labs, and I knew I wanted to be in the lab," she says. "When I found my first lab position, at Pfizer in Princeton, it solidified for me that I wanted to do the research end of science."

She was happily at Pfizer for almost three years and published two papers with her colleagues. Then the Pfizer site where she worked shut down. "I found another job right away, so that wasn't a problem, but from the layoff to the next job, I realized that having a PhD and being able to lead projects was really important to me," she says. "Instead of just participating in projects, I wanted to come up with the projects, and so I applied for the PhD."

Manners knows that she wants to stay in an active research role but finds it hard to say whether her future lies in industry or academia. "I have loved both environments, and I'm open to either. That position is unusual, I know, but I think because I've seen the good and bad in both, I'm more likely to go where there's a great opportunity. There's a great opportunity at Penn right now, and I'm going to go with that."

In the third year of her doctoral program, Manners gave birth to a daughter, and she is now expecting her second child. "In a few years I'll have to see what's out there and what makes sense," she says. "Being employed and work-life balance are both important to me."