Shown is the image of a tissue section from the brain of a rat that received perispinal injection of a TNF-antibody (labeled green). The white and yellow arrows indicate where the TNF-antibody (green) has reached the brain, in the lateral ventricle and the brain’s blood vessels. The image was created using a type of microscopy called multispectral fluorescence, which uses lasers to detect different fluorescent labels.

Treatment to Block Chronic Pain Developed by Ignatowski

Tracey A. Ignatowski, PhD

Published December 3, 2019

Tracey A. Ignatowski, PhD, assistant professor of pathology and anatomical sciences, has developed a treatment for chronic pain that could have an impact in dealing with the opioid crisis.

“Our preclinical research findings suggest an entirely new procedure and novel target in the brain to alleviate chronic pain in humans.”
Assistant professor of pathology and anatomical sciences

Research Builds on Previous Jacobs School Work

Ignatowski and Robert Spengler had previously discovered how chronic neuropathic pain arises in the brain, and the new treatment is designed to block that pain.

The new findings were published online July 31 in the journal Brain, Behavior, and Immunity.

“Our preclinical research findings suggest an entirely new procedure and novel target in the brain to alleviate chronic pain in humans,” says Ignatowski, corresponding author on the paper. “The findings are particularly important given the current national opioid epidemic and the imminent need for new methods for treating chronic pain.”

Targets Tumor Necrosis Factor-Alpha

The new, minimally invasive procedure utilizes delivery of an antibody that targets and thus blocks the pro-inflammatory protein called tumor necrosis factor (TNF)-alpha, specifically in the brain.

Unlike acute pain that occurs in response to a sudden injury, chronic neuropathic pain can develop slowly in response to nerve damage that occurs over time. It is a growing global problem seen increasingly among patients suffering from diabetes, stroke, traumatic brain injury, multiple sclerosis or cancer.

Increase in TNF Inhibits Norepinephrine Release

The possibility of an effective and safe new treatment method for chronic neuropathic pain would be welcome news, since treatments have thus far proven to have side effects — including addiction — and result in limited relief of pain.

“We previously showed that in neuropathic pain, the accumulation of TNF in the brain — specifically the hippocampus — causes the dysregulation of the normal analgesic response,” Ignatowski says. “We propose that enhanced levels of TNF in the brain inhibit the release of norepinephrine. Normally, norepinephrine would activate the descending inhibitory pain pathway that projects to the spinal cord, thereby alleviating pain. But when activation of this inhibitory pathway is lost, pain may transition to a chronic state.”

The new method originated with Jacobs School of Medicine and Biomedical Sciences researchers’ discovery in 1999 of TNF, a novel therapeutic target, specifically in the brain. They previously demonstrated that peripheral nerve injury — injury to the nerves connecting the spinal cord to the rest of the body — boosts levels of this protein in the hippocampus, a part of the brain responsible for learning and memory, and which they have recently found to be involved in the experience of chronic pain.

“We previously established that in order for chronic pain to develop, there must be enhanced TNF production in the brain,” says Ignatowski, who is also a faculty member in the neuroscience program. “Our current work demonstrates that treatments that selectively block brain-TNF reduce pain in animal models.”

Alternative to Surgery or Spinal Tap

The research is groundbreaking because it demonstrates a way to get to the root of chronic neuropathic pain in the brain in a minimally invasive way.

“Previously, brain delivery was thought to require either brain surgery or a spinal tap,” Ignatowski says. “We have shown — for the first time — that effective pain relief in an animal model could be achieved by direct brain delivery accomplished with a simple peripheral (outside of the brain and spinal cord) subcutaneous injection of an anti-TNF drug into the neck.”

“This is the first time that perispinal delivery of a drug has ever been demonstrated to provide rapid, sustained pain relief in an animal model,” Ignatowski adds.

Studies Being Done on Additional Pain Models

She is now studying how blocking TNF activity in the brain produces analgesia, relief from pain — including determining the receptor and signaling pathways — and which cell types and brain regions are involved.

“Ultimately, we predict that any type of chronic pain that involves altered neuron functioning (neuroplasticity) would be susceptible to this treatment,” Ignatowski says.

The research team has initiated studies using additional diverse pain models — such as a persistent pain model — as well as a chemotherapy-induced neuropathic pain model.

“Based upon our preclinical data, perispinal administration, as a novel injection method to noninvasively enhance delivery of large molecules to the brain, has enormous potential to increase our understanding of brain pathophysiology,” says Spengler, a co-author of the study. Spengler is currently co-director of research and development in the neuroscience division of NanoAxis LLC and a former faculty member in the Department of Pathology and Anatomical Sciences.

Other co-authors associated with the Jacobs School are:

  • Asif Abidi, MBBS, research instructor of pathology and anatomical sciences
  • Tariq Ahmed, MD, family medicine resident
  • Muhammad Jaffari, master’s student of biological sciences; currently a medical student at Touro College of Osteopathic Medicine
  • Zach M. LaMacchia, first-year medical student and research instructor of pathology and anatomical sciences
  • Natasha Singh, third-year medical student

Edward L. Tobinick, MD, of the Institute of Neurological Recovery, is also a co-author.