Chronic pain is an unmitigated, well, pain.

If acute pain is the body's fire alarm, chronic pain is the fire alarm that goes off whenever dinner is cooked. It serves no function, but it won't go away. Even worse, chronic pain can lead to a hypersensitive state where formerly innocuous stimuli are suddenly perceived as painful.

But despite the fact that tens of millions of Americans live with chronic pain, the treatment options are limited.

"Existing therapy for chronic pain lacks sufficient efficacy and produces too many side effects. This creates a situation of enormous unmet clinical need which has not been satisfied by the pharmaceutical industry," Clifford Woolf told BioWorld Today. Add to that the problems that COX-2 inhibitors have had in recent years, and for most patients, treatment options remain extremely limited: opioid-based drugs for extreme pain and, still, variants of the old "take two aspirin and call me in the morning" for less serious cases.

Boston-based Solace Pharmaceuticals hopes to change that. The start-up, founded in March, is focusing on chronic pain.

Solace was co-founded by Boston Venture Capital firm PureTech Ventures, and pain experts that PureTech sought out. Co-founder and managing partner Daphne Zohar, who also is interim CEO of Solace, told BioWorld Today that this proactive approach is unusual. "PureTech's model is different from other venture funds - we are sort of an entrepreneurial venture fund," she said. "We will start with an unmet need/focus area and then gather leading experts in that field," deciding on the exact drug development programs it will pursue only later in the game. Solace's founding team looked at more than 50 potential opportunities, and ultimately decided to pursue three.

One of Solace's earlier-stage programs is based on an approach published in the November 2006 issue of Nature Medicine, now available online. Woolf is the senior author, and in the paper, researchers reported on a gene that appears to have a role in determining susceptibility to chronic, as well as acute pain. From their data, they concluded that "we have identified both a previously unknown pathway involved in the production and modulation of pain and a genetic marker of pain sensitivity."

The researchers began with a gene screen and found that in rats, two of the three genes necessary for making tetrahydrobiopterin, or BH4, were up-regulated after the scientists injured the animals' sciatic nerve. In another experimental protocol that induces hypersensitivity, all three enzymes were up-regulated, with the rate-limiting enzyme, GTP cyclohydrolase, showing a much larger increase; levels of BH4 also were increased. A few days later, blocking GCH1, the gene that encodes for GTP cyclohydrolase, reversed the animals' hypersensitivity to stimuli, and reduced the levels of tetrahydrobiopterin.

In animals, reducing levels of BH4 brought effective pain relief for both neuropathic and inflammatory pain; Solace founding team member and PureTech senior associate Kevin Pojasek said that BH4 may be exerting its effects upstream of several enzymes that are important for neurotransmitter synthesis, "so the hope is that there is a broader effect going on."

BH4 is necessary for the synthesis of a number of neurotransmitters including dopamine, serotonin and nitric oxide. Cell culture studies suggested that the effects of increased BH4 during pain states are partly due to effects on nitric oxide, and it is possible that such an increase also disrupts regulation by upsetting the balance between BH4 and a protein that regulates GCH1 under normal circumstances.

The researchers also tested whether specific alleles of human genes involved in the regulation of BH4 might be associated with different responses to pain. Searching for alterations in the gene for GCH1, they genotyped tissues from patients who had participated in an earlier study of patients who had had back surgery. One specific GCH1 haplotype was more common in study participants who reported less neuropathic pain in the year after their surgery.

In a study of several hundred healthy volunteers, participants with the protective version of GCH1 also reported less pain in response to slightly painful stimuli. Volunteers with two copies of the protective sequence were less sensitive to pain than those with only one protective allele, suggesting that less BH4 causes decreased sensitivity to pain. Pojasek called the haplotype findings "a really nice validation" for the program: "Usually, in an early stage program like this, you are years away from validating it in people," he told BioWorld Today.

The white blood cells of less pain-sensitive individuals also were less sensitive to GCH1-up-regulating stimuli in cell culture, giving researchers a peripheral biomarker - and possibly, clinicians a simple way to identify individuals at risk for chronic pain.

The Nature Medicine paper was co-authored by researchers from Massachusetts General Hospital and Harvard Medical School in Charlestown, Mass.; Johann Wolfgang Goethe-Universitaet in Frankfurt, Germany; the National Institutes on Alcohol Abuse and Alcoholism and on Dental and Craniofacial Research, both of the National Institutes of Health in Bethesda, Md.; the University of North Carolina at Chapel Hill; and the University of Florida in Gainesville.