By David N. Leff

Pain perception comes in two persuasions ¿ acute and chronic ¿ colloquially denoted as the ¿ouch¿ and ¿agony¿ factors, respectively.

The ouch of acute pain persuades its recipient that he or she has incurred an immediate injury and should do something about it. Victims of chronic pain suffer repeated or unremitting agony, ranging typically from arthritis to migraine to backache to cancer and other debilitating diseases, not to mention the phantom, imagined pangs of an amputated limb ¿ as if the nerves and brain ¿remember¿ that agonizing affront to the body. Then there is fibromyalgia, a diffuse, achy, tender pain in fibrous tissues ¿ muscles, tendons, ligaments ¿ of unknown etiology. It afflicts primarily women and girls.

The Society of Neuroscience estimates that 97 million Americans suffer headaches, back pain and arthritic pain each year.

In all its forms, chronic pain seems to result from faulty signaling by a small group of neurons in the spinal cord. These inappropriate messages can make patients hypersensitive to stimuli that are minimally painful, such as a pinprick. Conversely, they may elicit pain in stimuli that are not painful at all ¿ such as a warm shower.

For unbearable throes of agony, as in end-stage cancer, arthritis or neurodegenerative diseases, physicians often prescribe morphine, which is only partially effective and has serious side effects.

Many neuroscientists, seeking the neuronal wellsprings of chronic, intractable pain, are focusing on a perpetrator peptide called substance P (SP). This 11-amino-acid neurotransmitter carries pain signals from its causal point of stimulus to a central relay station in the dorsal horn of the spinal cord. This mission control center forwards the neuroelectrical messages of hurt onward, via wire-like axons, to areas in the brain that ultimately feel the pain.

Those nociception-signaling neurons make up less than 5 percent of the nerve cells in the spinal cord. Neuroscientist and pain expert Patrick Mantyh and his colleagues at the University of Minnesota, Minneapolis, reasoned that if this small number of trouble-making cells could be silenced or terminated, chronic pain might be stopped in its neuronal tracks.

SP Receptor Drags SAP Killer Into Doomed Cells

Mantyh¿s paper in the current issue of Science, dated Nov. 19, reports the implementation and outcome of this rationale. Its title: ¿Transmission of chronic nociception by spinal neurons expressing the substance P receptor.¿

The co-authors hitched SP to a powerful neurotoxin, saporin (SAP), which kills cells by irreversibly blocking their ribosomal function. When injected into the spinal cord¿s dorsal horn, the SP receptor, which studs the surfaces of their pain-perceiving target neurons, lured the hybrid molecule into the interior of those cells, where the saporin component promptly laid them low.

This targeted toxin was developed by Advanced Targeting Systems, based in San Diego. Its president and senior scientist is biochemist Douglas Lappi, a co-author of the Science paper.

¿The beautiful thing about this technique,¿ Mantyh pointed out, ¿is that we can pick out the neurons expressing substance P receptors and leave the normal pain-transmitting neurons intact.

¿This selectivity,¿ he added, ¿doesn¿t interfere with the mechanism by which morphine works. Physicians who want to administer this type of analgesic to their patients should therefore find it reassuring that they could still use morphine as a standby.¿ What makes this possible is that morphine works by an entirely different pain pathway, based on opiate receptors in the brain.

¿It¿s important,¿ Mantyh pointed out, ¿as morphine remains the bedrock of the pharmacological treatment for severe chronic pain.¿

The Minnesota team subjected rats to a variety of standard, measurable pain stimuli, which they watered down 30 days in advance by intrathecal infusions of their SP-SAP conjugate. One month after administering this pain-abolishing SP-SAP treatment, they daubed the paw pads of rats with capsaicin, the active ingredient of red-hot peppers. Normal rodents respond to this chemical heat treatment by cringing and flinching their paws to ward off the thermal pain. They also display allodynia, a syndrome in which ordinarily innocuous stimulus, for example, gentle stroking with a soft brush, evokes extreme pain responses such as biting, scratching and licking themselves in a head-to-tail direction.

In contrast, the Science paper reported, ¿Thirty days after infusion of SP-SAP, there was a distinct concentration-related reduction in these behaviors.¿

Subcutaneous injection of formalin, a painful inflammatory irritant, into hind paws elicited a two-phase, hour-long reaction. ¿SP-SAP did not significantly affect the first phase [0 to 10 minutes],¿ Science reported. ¿However, in the second phase [20 to 50 minutes], the paw-flinching behavior was significantly reduced.¿

In a separate test of neuropathic pain (caused by the neural signaling itself going awry with no tissue damage required), the co-authors tightly tied two spinal nerves, resulting in long-lasting allodynia seven days later. But instead of pretreatment with SP-SAP 30 days beforehand, this test dosed the rats after they had experienced pain transmission and achieved ¿significant reduction¿ in that response.

Follow-up as late as 200 days after the experiments indicated that the rats¿ loss of pain sensitivity appeared to be permanent, and with no side effects.

Next: A Kinder, Gentler Chronic Pain Fix

¿So far,¿ Mantyh observed, ¿This method kills the pain-signaling neurons, so its uses may be limited to stopping the extreme pain of terminally ill patients. However, designing a less drastic variation that would temporarily silence the neurons, should now be a very doable thing.¿ One possible candidate for such a moderating approach, he surmised, might be a molecule known to temporarily shut down the neurons¿ energy sources, namely, the cells¿ mitochondria.

At present, the co-authors are planning a toxicology study to see whether the saporin neurotoxin used in their rats would be safe in treating terminally ill humans desperate for pain relief. Lappi foresees that ¿limited clinical trials could begin within two years.¿

The team¿s findings also afford the opportunity to investigate what causes chronic pain in the first place. n