Formaldehyde (chemical formula HCHO) is one of the few organic compounds known to exist in outer space. Many a laboratory rat no doubt wishes it would stay out there. Formalin is formaldehyde’s acqueous/methanolic solution. A strong irritant, its label warns: “Avoid skin contact.”
Neuroscientists who trace the pathways of pain in the brain use formalin in a standard test for measuring nociception pain perception in rats. They inject the irritant into an animal’s foot pad, and count low long it keeps its paw gingerly up in the air.
“In in vivo rat experiments,” observed neuroscientist Lisa Teather, at Boston-based Massachusetts Institute of Technology, ”the formalin test is a commonly used model for rodent pain. It’s broken down into two responses: The initial one is an acute form of pain. That’s when we put the formalin in their paw and they say ouch!’ It’s the touching-the-hot-stove response. When there’s a 5-minute delay, the inflammatory reaction kicks in. This is a model for persistent or chronic pain. A lot of nociception out there induced by cancer or rheumatoid arthritis, say is based on the inflammatory system gone awry.
“So what we have,” Teather continued, “is a way of testing how certain drugs affect, first, the initial pain reaction which we really don’t want to influence. It’s needed for propagation of the species. If you put a hand on the stove, you want to know right way you’ve put it on the stove.
“But after the brain feels that heat,” she went on, “you don’t want it to stay on that hot surface. We don’t want the system to be sensitized, which is what happens in a lot of inflammatory-based diseases. The cells are always exuding stuff that makes us feel pain. That’s called Phase Two the late or chronic phase of pain.”
Teather, a postdoctoral fellow in MIT’s department of brain and cognitive sciences, is lead author of a paper in the journal Psychopharmacology, released online. Its title: “Platelet activating factor [PAF] antagonists decrease the inflammatory nociceptive response in rats.”
“Our overall finding in this article,” she told BioWorld Today, “was that we can at least alleviate pain sensation in rats. We administered these PAF antagonists, and completely prevented them from feeling inflammatory-induced nociception. Both antagonists worked at all three graduated doses and the animals feel little pain, if any.”
PAF Knows All Usual Suspects Of Pain
“PAF platelet-activating factor is a pro-inflammatory molecule,” she explained, “which regulates such things in the body as NFkB, tumor necrosis factor-alpha and prostaglandins all the usual suspects in inflammation. So by using these PAF antagonists we were, we think, preventing PAF from provoking these other pro-inflammatory factors, which might be why these rats were not feeling inflammation-induced pain.”
Teather noted that “there are two antagonists specific to PAF. The ones we used were developed from the ginko biloba tree one of these thousands of extracts from ginkolide B called BN52021. So it is a naturally occurring herbal substance. A lot of chemists showed PAF’s physiological role during the 1980s and 1990s,” she went on. “They found that this ginko molecule has a lot to do with attenuating pathologies inflammation, ischemia, seizures as well as memory processes. When they realized that this agent was obviously important in many situations, they made derivatives similar to the various PAF antagonists already in existence. So that’s where the two synthetic molecules came from. Biomeasure Inc. [of Milford, Mass.] gave us one of them, BN50730. So it binds the microsomal intracellular organelle membrane rather that binding external cell surface membranes.”
She described her team’s animal-pain experiment with PAF-antagonist treatment:
“We selected 60 rats by weight and randomly assigned them to four cohorts: three drug doses and one placebo control. Then we did the same for the second PAF antagonist. All three dosage regimens completely abolished the rats from displaying nociceptive responses. The formalin was injected into the hind-limb paw pad and produced two pain stages acute and delayed. The second stage was completely dampened in all of the animals. The controls received saline injections, and carried on typical rat behavior.”
Following up on those positive results, the co-authors are now “putting the drugs into rat brains. What we want to know,” Teather said, “is whether PAF is acting at the spinal cord level, or are these antagonists getting into the brain, which they both have capacity to do, and affecting processing. The second phase of pain, the chronic one, is greatly affected by the central nervous system,” she pointed out, “particularly from the hippocampus. The PAF receptors are really concentrated in that region. So we’re putting the drugs directly into the hippocampus to see what happens. Theoretically we’re hoping they will alleviate pain and show a role for the hippocampus in pain processing, and that we’re preventing endogenous PAF activity by putting these antagonists into this cerebral site.”
Does It Hurt Or Do You Just Think It Hurts?
“The hippocampus is a learning structure,” Teather observed, “so a lot of pain theory says that we learn something hurts. It is a positive feedback loop, as when you go to the dentist you just expect pain. Expectations affect how much you really feel. I think behavior modification and drug use will be the most successful combined treatments for pain relief eventually. Obviously, behavioral modification will be even better, because you don’t have to take any drugs.
“People with chronic pain from cancer need analgesic treatment,” Teather continued. “But morphine doesn’t last because it’s well tolerated. So our idea would be to use PAF antagonists with morphine, and have drug holidays’ from both. If a cancer patient takes morphine for a long period of time, during a terminal stage for two years, he must keep upping the dose because morphine is tolerated so quickly.
“And because PAF is acting on a different level, at different signal transduction systems, what you would do sometimes is give patients a morphine holiday. Wean them down and let their bodies recover from tolerating the morphine. That’s hell,” she allowed. “You’re basically taking somebody who’s in chronic pain and because the doses of morphine are getting too high, you almost make them do without treatment for three months say, so the body can get back to normal.”