Researchers Describe Potential New Painkiller

In mice, enzyme is 8 times more potent than morphine

by Jim Schnabel

November 24, 2008

Researchers have discovered that an enzyme once used to label spinal neurons in laboratory tests also appears to function as a potent and long-lasting treatment for chronic pain, at least in animal tests. Although it is too early to tell whether the same strategy will work in humans, the finding could open up a new approach to pain therapy.

“The magnitude of its effect is similar to that of morphine, but it lasts longer,” says Mark Zylka, the University of North Carolina pain researcher who led the study, published Oct. 9 in Neuron.

The discovery originated from a series of experiments involving thiamine monophosphatase (TMPase), an enzyme once commonly used to label pain-sensing neurons in the spine. TMPase was supplanted by better labeling molecules in the 1990s, but the fact that it bound so reliably and extensively to so many pain-sensing neurons made it an interesting target for further research. But the gene that coded for it was never discovered, and researchers moved on to other targets.

Zylka and his students recently returned to investigating TMPase, and found that the enzyme was identical to another known enzyme, prostate acid phosphatase (PAP). PAP’s function in the body is unclear, although levels of PAP are elevated in prostate cancer and evidence suggests that it plays a tumor-suppressing role in the disease.

Zylka found that Pirkko Vikho and her colleagues at the University of Helsinki had been studying PAP’s function in prostate cancer using one of the classic tools of modern biology—“knockout mice” genetically engineered to not express the gene for PAP. Zylka’s lab found that these PAP-knockout mice were normally sensitive to acute pain but extraordinarily sensitive to experimentally induced chronic pain, both from inflammation and from nerve damage.

To see whether they could reverse this chronic pain by replacing PAP, Zylka and his colleagues injected it into the spinal columns of the mice, near the neurons causing the pain. It worked, and with surprising potency. The dose of morphine required to produce the same effect would have brought unwanted side effects such as sedation and would have had to have been repeated every few hours. PAP’s painkilling effect didn’t seem to sedate the mice, and it lasted more than three days.

This effect “is presumably not going to be tapping into the reward pathways, so you’re not going to be getting addiction, as you would with opiates,” Zylka says.

A drug based on PAP might be used in epidural injections and implantable pumps for postoperative pain, during and after childbirth and for other longer-term pain conditions. With a UNC colleague who has experience in the pharmaceutical industry, Zylka also is trying to develop a PAP-mimicking molecule that can survive the digestive process so that it could be taken in pill form.

What side effects such a pill would have are unknown, and Zylka emphasizes that the development of any such drug would take many years at best. Indeed, James Eisenach, a Wake Forest University pain researcher and editor in chief of the journal Anesthesiology, notes that the rationale behind a PAP-mimicking drug remains to be proved in humans.

PAP appears to work in rodents by breaking down a chemical known as adenosine monophosphate, which is produced by neurons, into adenosine. The adenosine molecules in turn activate adenosine A1 receptors on spinal pain-sensing neurons, quieting their activity and, in effect, quieting the sensation of pain.

In a study published in 2003, Eisenach and his colleagues showed that “the spinal injection of adenosine, which causes the same degree of [apparent pain reduction] in rats and mice as PAP, fails to reduce pain in patients with chronic neuropathic pain,” he says. Partly because of this finding, researchers have begun to doubt some of the results of pain studies in rodents, he says.

“There are clinical trials with centrally acting adenosine receptor enhancers under way by King Pharmaceuticals, and the results of those studies will be crucial to validating this [adenosine receptor] target,” Eisenach says.