By David N. Leff

Does it hurt, or do you only think it hurts?

This is not a whimsical or semantic question. A person who loses a limb to trauma or surgical amputation may go through life "feeling" severe anguish in the arm or leg that isn't there any more.

A contrary case is that of the infantryman who, oblivious to pain, goes right on firing his machine-gun, after both his legs have been blown away.

Just how pain travels from its source in an injury or insulted tissue to its perception in the brain is a puzzling area of neurological research. Here is how neurobiologist and anesthesiologist Min Zhuo, at Washington University, in St. Louis, traces that tricky pathway.

"Actually, it's quite interesting," Zhuo observed. "A lot of the ascending pain pathway mechanism is not completely understood.

"Say, for example," he recounted, "you've suffered a burn injury to your skin. This is going to activate nociceptors, [which are] pain-sensing nerve terminals under the skin. Of course, the heat will also release chemicals. So the burn activates this nociceptive nerve fiber, and that fiber is going to fire action potentials — electrical impulses that will enter the spinal cord's dorsal horn.

"There are many many cells in that area of the spinal column," Zhuo continued. "They have ascending projections all the way through the spinal cord to a structure in the brain called the thalamus.

"Because the signals cross synapses (junctions) on their way to the brain, they can be modified en route — which is what opioids do, for example.

"In the brain, the thalamus will then send diffusible projections to various areas of the cortex. There these will cause all kinds of emotional responses, as well as motor responses — such as you wanting to remove your hand from the fire."

This natural unthinking reflex can bypass the brain, Zhuo pointed out.

"During evolution, humans developed some kinds of protective functions." he recounted. "So very often you see a lot of reflex actions that happen right away. Some of these responses don't really need the brain in order to react. So we call them spinal reflexes."

Zhuo is senior author of a paper in the current issue of Nature, dated June 18, 1998. Its title: "Silent glutamatergic synapses and nociception in mammalian spinal cord."

"Glutamate," he observed, "is the major excitatory neurotransmitter in our brain. Many times when you touch something, or remember something, we believe glutamate plays a key role in your entire brain system, in order to get this neuronal process going.

Meet Serotonin Jekyll, Serotonin Hyde

"One new thing about our Nature paper," Zhuo told BioWorld Today, "is that we were able to show that another neuromodulator — serotonin — produced a long-lasting modulation on a glutamate transmission.

"The serotonin in the spinal cord," Zhuo narrated, "is mainly released by descending projection fibers from the brainstem. These structures for many years were thought to be very important for opiate analgesic effect. So if a patient takes morphine, a major effect will be to activate these neurons, release serotonin as well as other transmitters, and produce an analgesic effect.

"Recently we found out that the human body is more complex. We showed that by stimulating the same nerve nuclei at different parameters, we were able to enhance pain, rather than relieve it. And interestingly, when we enhance pain in the spinal cord, it is also transmitted by the serotonin, which activates silent synapses."

How does Zhuo interpret that contrarian finding?

"My previous pharmacology studies," he observed, "have shown that even though these effects are all mediated by serotonin, they likely involve different kinds of receptors in the spinal cord's dorsal horn. So now we are calling the serotonin effect biphasic modulation. It does good things — stopping pain, but also bad things — causing more pain.

"When serotonin does what it does," he pointed out, "will depend on dose, where it's released, and what post-synaptic receptor is involved. This is very nicely demonstrated in our paper."

Zhuo made the point that "if you give a lot of serotonin, the total effect will be pain inhibition. But that inhibition is short-lasting, as when we take pain-killing medicine. When the medicinal effect goes away, you need more medicine, because inhibition disappears."

Remembering What You Forgot To Forget

But Zhuo has pinpointed a neuronal receptor on the far side of non-functional, or silent, synapses. "Using electrophysiological methods," he said, "our data show that when the silent receptor is recruited, pain transmission won't disappear again, even if we stop applying serotonin. That suggests a mechanism," he went on, "that may be very long-lasting, like the processes involved in learning and memory.

"That likely could be the mechanism," Zhuo speculated, "why chronic or persistent pain is hard to treat. As when you remember something that you can't really forget right away."

He cited one example: phantom limb pain.

"When a person undergoes amputation, it has been suggested that during or right after it, when local anesthetic at the stump may go away, there will be a lot of abnormal activity going on in a damaged nociceptive nerve terminal. There is evidence suggesting that this type of terminal could recruit many transmitters in the spinal cord, including those that activate these silent receptors. Maybe they could be contributing to the neuronal elements of the phantom pain."

The brain can "teach" cells in the spinal cord to feel pain, he proposed. Once receptors on these cells are activated, they continue to transmit pain signals, even if there is no injury any more.

"If this is the case," Zhuo suggested, "the clinical aspect of silent sensory transmission may serve as an important mechanism during persistent pain, caused by different kinds of injury. How to turn this silent receptor on and off will help the future design of chemicals for treating chronic pain."

Zhuo is presently seeking "a connection with industry," and looking forward "in a short period of time to even trying clinical trials." *

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