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Feb 21, 2008
 |  BC Innovations  |  Targets & Mechanisms

Hitting pain where it hurts

The molecular mechanisms of neuropathic pain are not well understood, and existing treatments typically provide only temporary relief-often with significant side effects-by blocking pain signaling instead of stopping pain at the source. Now, Boston-area researchers have shed new light on the mechanisms of acute and chronic neuropathic pain, offering potential new targets for both indications.

In a Nature Medicine article published online Feb. 10, researchers from Brigham and Women's Hospital, Harvard Medical School, Children's Hospital Boston and Massachusetts General Hospitalreported that two matrix metalloproteinases (MMPs) play distinct roles in different types of glial cells in the development of neuropathic pain in mice.

The team found that nerve trauma induced rapid and short-lived neuropathic pain by upregulating MMP9 in dorsal root ganglia (DRG), which then activated a feedback loop between p38 mitogen-activated protein kinase (p38 MAPK) and interleukin-1b (IL-1b) in microglial cells.

They also found that nerve trauma induced delayed, longer-lasting neuropathic pain by upregulating MMP2 in both DRG and astrocytes. In DRG, MMP2 upregulated IL-1b expression. In astrocytes, MMP2 activated a feedback loop between IL-1b and MAP kinases ERK-1 and ERK-2. (See "MMP-mediated mechanisms for early- and late-phase neuropathic pain.")

As a result, the researchers suggest that MMP9 and MMP2 are potential therapeutic targets for acute and chronic neuropathic pain, respectively.1

"Current treatments for neuropathic pain, such as opioids and neuro-transmitter inhibitors, are mostly ineffective and can have severe side effects," said Ru-Rong Ji, assistant professor of anesthesiology at Brigham and Women's Hospital and leader of the research team that published the Nature Medicinepaper. "For instance, drugs like Lyrica only mask the pain temporarily without addressing the underlying pathology."

He noted that annual sales of Lyrica pregabalin, which came in at $1.8 billion in 2007, underscore patients' need for pain relief, temporary or otherwise. Pfizer Inc. markets Lyrica for neurological pain, epilepsy and fibromyalgia syndrome. The drug is an analog of g-aminobutyric acid, which is an inhibitory neurotransmitter that blocks transmission of pain signals to the brain.

Companies contacted by SciBX agreed that the pathways described in the Nature Medicine paper hold potential for improving neuropathic pain treatments, but they said that MMP9 and MMP2 might not be the best targets in those pathways.

Eliot Forster, CEO of Solace Pharmaceuticals Inc., said the results were consistent with the company's working hypotheses about the central role glial cells play in neuropathic pain. Solace's SLC022 modulator...

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