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Killing the Messenger

Other basic questions about the effectiveness of blocking specific ion channels remain unanswered. For one thing, no one is certain that blocking one type of ion channel will be enough; other kinds of channels-there are dozens-might open and cause a spike anyway. “The real question is, will one drug do it?” says Basbaum. He thinks that ion channel blockers may work well for specific kinds of pain, but that no single drug will work for everything. “Is there a magic bullet?” he asks. “The answer is, it may very well be that [drug] cocktails are the way to go.”

Still, ziconotide holds out the tantalizing possibility that a single drug might be enough. Nerve impulses traverse the body through a vast system of neurons laid out end to end, not quite touching. The gaps between neurons are called synapses, and certain calcium ion channels are essential to conveying impulses across the gaps. While capsaicin and sodium channel blockers prevent pain-sensing neurons from firing, ziconotide keeps the impulse from crossing the synapse by blocking these calcium channels. So it doesn’t matter if the other channels are stuck wide open, causing the first nerve in a pathway to fire violently and endlessly. If the impulse can’t cross the synapse, no pain is felt. The first neuron “is firing as fast as it can, but it’s not telling the next neuron that anything’s going on,” explains Bruce Morimoto, director of drug development for NeuroMed, a Vancouver, British Columbia, biotech company.

Ziconotide is too toxic and too hard to deliver ever to be widely used; its side effects include confusion, memory loss, dizziness, and tremors. It fogs the brain the same way it stops pain, by preventing neurons from communicating. But NeuroMed and Ionix are developing next-generation versions of ziconotide. These drugs can be taken as pills and-their developers hope-will avoid ziconotide’s worst side effects. The key is to target only nerves that are sending pain impulses. “Under pain conditions, those neurons are firing at a very rapid rate compared to normal’ neurons,” explains Morimoto. “If our compounds are blocking the channel with this very rapid, high-frequency stimulation, [then] we are more likely to hit only the channels involved in pain transmission, and not other ones in the body.”

Scientists at NeuroMed identified such compounds by applying tiny electrical shocks to nerve cells. They used minuscule glass electrodes clamped onto single neurons to measure the current generated by the opening of individual ion channels as the neurons fired. The company’s compounds were tested, one by one, for their effects on these individual channels. Only those compounds that closed the channels while the nerve fired vigorously became drug candidates.

NeuroMed hopes its lead drug candidate will enter human trials later this year. Ionix anticipates starting tests of its drug candidate by the end of 2004. Only then will we begin to know if ziconotide’s spectacular but erratic analgesia can be bettered.

A Bell in Your Brain

There is one more cautionary footnote to the tale of the new pain drugs. All the approaches, and the billions of dollars the drug industry has invested in them, teeter on an untested assumption: that blocking nerve impulses in the body’s periphery, before the signals reach the spinal cord, is the best way to block pain. This seems self-evident but in fact may be wrong.

In the 17th century, Descartes postulated that injury generates pain by sending a message via nerves to the brain, as if pulling at the end of a rope to ring a bell. You bash your shin, the rope rings the bell in your brain, and you feel pain. It follows that cutting the rope-blocking the peripheral nerves-should prevent the pain from ever reaching the brain.

But it’s not that simple. It’s now clear that the sensation of pain doesn’t match up consistently with stimulation of pain-sensing nerves. The same injury can produce intense pain in some people and nothing in others, depending on the person’s immediate circumstances, past experiences, and state of mind. Soldiers, for instance, may not realize they have been shot until a battle is over. On the other hand, many amputees suffer “phantom limb” pain, in which, say, a missing hand and fingers are felt in every detail.

“There is no such thing as a painful sensation; there are only sensations that get interpreted as pain,” says Tito Serafini, a neuroscientist at the South San Francisco biotech company Renovis. The brain’s role is central. “Looking at the periphery, simply because we can do it, is going off in the wrong direction,” argues John Loeser, a neurosurgeon at the University of Washington. “The processing of information in the brain is probably far more important than what happens in the periphery.”

In fact, neuroscientists now know that pain messages do not flow unchecked from the body to the brain. Instead, “gates” in the spinal cord alter the level and intensity of nerve impulses. And impulses descending from the brain can open and close these pain gates.

“Pain is in the brain,” Basbaum concedes. Unfortunately, he says, we have no idea how to find a drug that will attack pain via the brain, still the most mysterious organ. “We know the brain is an essential part of the pain experience,” he says, “but we just don’t know anything about circuitry or the chemistry.”

Until neuroscientists begin to figure out how the brain controls pain, blocking ion channels could prove the best way to find highly potent painkillers with few side effects. These drugs may not be the last word in analgesia, but if human tests confirm the drugmakers’ theories, they will finally make morphine and its cousins obsolete. That’s good news for Vicki Wiltshire, Elaine Casanova, and the millions like them who suffer from devastating pain.

Target: Ion Channels
Company Target Status
Elan Pharmaceuticals (Dublin, Ireland) Select calcium channels In human trials
GlaxoSmithKline (Brentford, England) Capsaicin receptors Preclinical development
Select sodium channels In human trials
Ionix Pharmaceuticals (Cambridge, England) Select calcium channels Human trials scheduled for 2004
Select sodium channels Human trials scheduled for 2005
Merck (Whitehouse Station, NJ) Capsaicin receptors and select sodium channels Basic research
Neurogen (Branford, CT) Capsaicin receptors Human trials scheduled for 2004
NeuroMed (Vancouver, British Columbia) Select calcium channels Human trials scheduled for 2003
Novartis (Basel, Switzerland) Capsaicin receptors Preclinical development

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