Deconstructing neuropathic pain: Could it give clues to better drugs?

neuropathic pain

Neuropathic pain is chronic pain originating through some malfunction of the nervous system, often triggered by an injury. It causes hypersensitivity to innocuous stimuli and is often extremely debilitating. It doesn’t respond to existing painkillers — even opioids can’t reach it well.

New research in a mouse model, described last week in Cell Reports, deconstructed neuropathic pain and could offer new leads for treating it. The carefully done study showed that two major neuropathic pain symptoms in patients — extreme touch sensitivity and extreme cold sensitivity — operate through separate pathways.

“We think this separation will allow targeted drug-based therapies in the future,” says Michael Costigan, PhD, of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, who was the study’s senior investigator. “If our results stand experimental scrutiny by others, this will be profoundly important in our overall understanding of neuropathic pain.”

neuropathic painMany patients with neuropathic pain find the lightest touch excruciating, even when putting on clothes or taking a shower. The pain can create a vicious cycle that’s reinforced by fear.

Working with a mouse model of neuropathic pain, sparked by a partial nerve injury, Costigan and colleagues delved deep. They measured pain sensitivity daily over 10 days, observing the animals’ reactions to light touch (with fishing line) and cold (induced by a drop of acetone on their paws).

Concurrently, every 24 hours, they measured which genes were turned on and off in the dorsal root ganglia, a structure that contains the cell bodies of the sensory neurons and resident immune and support cells.

Then they looked for correlations between the two data sets.

Two distinct pain pathways

In all, the study implicated 1,704 genes, which fell into eight categories shown on this day-to-day “heat map” (red indicates increased gene expression; blue, reduced expression):

gene expression in neuropathic pain

Through a series of careful experiments, Costigan and colleagues concluded that:

  • Cold hypersensitivity (also known as cold allodynia) kicks in earlier than touch hypersensitivity (mechanical allodynia): In mice, onset was at 3 days and 5 days, respectively.
  • Based on multiple pathway-analysis algorithms, each pain modality correlates with a pattern of gene expression. Hypersensitivity to cold correlates with gene expression changes in cold-sensing neurons, while hypersensitivity to touch involves changes in both neurons and immune cells — macrophages and T cells.

neuropathic pain hypersensitivityNeuronal and immune components of pain

In experiments, touch hypersensitivity disappeared almost completely when macrophages were killed off, and was markedly reduced when T cells were knocked out genetically. In both cases, cold hypersensitivity remained. Conversely, when cold-sensing neurons were selectively killed off, mice did not have cold hypersensitivity, but painful touch sensitivity remained.

“The two different neuropathic pain symptoms have two different mechanisms,” says Costigan, also a member of the Department of Anesthesiology, Perioperative and Pain Medicine at Boston Children’s. “When we’re producing drugs, we need to know that. While people are focusing a lot on the immune system now, the immune system is only important for tactile allodynia, so blunting the neuro-immune axis will not help cold allodynia.”

A third important neuropathic pain symptom in humans — spontaneous, unprovoked pain — is difficult to study in mice, Costigan says. But in the meantime, based on their findings, the researchers suggest that targeting a particular set of neurons, known as TRPV1 lineage nociceptors, may be the best strategy for patients whose primary pain symptom is painful cold sensitivity. For people with extreme pain associated with touch, focusing on immune cells and neurons with mechanoreceptors may be the best plan.

Authors and funding

Enrique Cobos was the study’s first author. Coauthors were: Chelsea Nickerson, Rafael Gonzalez-Cano, Priscilla Riva, Nick Andrews, Alban Latremoliere, Corey Seehus, Michio Painter, Chi Him Eddie Ma,Takao Omura and Clifford Woolf of Boston Children’s Hospital’s Kirby Neurobiology Center; Fuying Gao, Vijayendran Chandran, Daniel Geschwind and Giovanni Coppola of the University of California, Los Angeles; Inmaculada Bravo-Caparros, Gloria Perazzoli, Francisco Nieto of the University Hospital Complex of Granada (Spain); Nicole Joller and Manu Rangachari of Brigham and Women’s Hospital (Boston) and  Elissa Chesler of the Jackson Laboratory (Bar Harbor, ME).

Supporters included the National Institutes of Health (R01NS074430, R01NS58870, R37NS039518); the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; the NINDS Informatics Center for Neurogenetics and Neurogenomics (P30 NS062691); the Boston Children’s Hospital IDDRC (1U54HD090255); the Spanish Ministry of Economy and Competitiveness (MINECO; SAF2013-47481P, SAF2016-80540-R) and the European Regional Development Fund (FEDER).

For a complete list of affiliations and supporters, see the paper.

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