Pain comes in all shapes and sizes, from a trivial paper cut or a stubbed toe to phantom pain (severe illusory discomfort felt by an amputee in the area of the missing limb). However, the ultimate anguish is CNS neuropathic pain (CNS/NP).

"It's been known for many years," observed pain pharmacologist Philip Malan, at the University of Arizona at Tucson. "It's not really common, but neither is it really rare," he noted. "Probably 1 percent of the population has some kind of neuropathic pain."

Malan ran down his mental short list of the most prominent CNS/NP diseases: "Some patients who get shingles (herpes zoster) have enduring pain - post-herpetic neuralgia - long after the shingles subsided. Then there's the facial pain of trigeminal neuralgia. It's marked by severe paroxysmal bursts of pain in one or more branches of the trigeminal nerve. Diabetics can incur diabetic neuropathy," Malan continued, "which is the nerve disease associated with diabetes pain in the limbs."

Malan is senior author of a paper in the Proceedings of the National Academy of Sciences (PNAS), released online Aug. 11, 2003. Its title: "Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS."

"There are two findings," Malan observed. "One is what we focused upon when we wrote the paper. Neuropathic pain is a difficult clinical problem to treat. One reason is that strictly all of the therapies we use have significant side effects. That decreases the dosage of the drugs that we can administer. The side effects are bothersome to the patients.

"These adverse effects," he continued, "all tend to be based in the central nervous system, causing effects like sedation. If we found a drug target that was outside the CNS and relieves pain, then we should be able to relieve this neuropathic pain without these CNS side effects.

"Second, cannabinoids for pain relief are drugs related to tetracannabinol, the active ingredient in marijuana. There are two classes of cannabinoid receptors, CB1 and CB2. CB1 is found in the brain and central nervous system, whereas CB2 isn't. It does occur in peripheral tissues and is mostly identified on immune cells. We found that it's activating CB2 receptors with this AM1241 drug producing pain relief."

Malan paused to remark that AM1241 was synthesized and acronymically named by the PNAS paper's co-senior author, medicinal chemist Alex Makriyannis, who specializes in cannabinoids.

Patients Worry Too Much Over Cannabis Pain Ease

"One thing that limits the utility of marijuana or tetracannabinoid for treating pain," Malan went on, "is that they have significant side effects that cause acute sedation or anxiety. CNS/NP patients worry about their abuse potential. But if we target cannabinoid receptors outside the CNS and get beneficial effects, then we can employ cannabinoid drugs without these troubling side effects.

"Patients with diabetes can get diabetic neuropathy," Malan noted, "which is the nerve disease associated with diabetes - pain in the extremities. Patients with HIV can get neuropathic pain from their disease or its treatment.

"I don't think the molecular mechanism is really known," Malan told BioWorld Today. "The underlying theme is that neuropathic pain requires injury to the nerves. When these neurons get injured they go haywire and do funny things. And one of the things they seem to do is fire excessively. That sets up a series of changes in the CNS that amplifies the pain and makes them more sensitive to things like touch.

"Side effects of currently used drugs that seem to trouble patients are sedation," Malan pointed out, "especially affecting people who haven't used marijuana before. They often get anxious when they use marijuana or drugs derived from marijuana. Sometimes CNS/NP patients choose not to take the drugs because they don't like the side effects. They limit these analgesics because the more they take the more severe the side effects.

"I understand that patients who smoke marijuana to treat their pain learn to smoke just enough to the point where they start to get side effects; then they stop," Malan said. "But that self limitation may prevent the drug from getting into the effective therapeutic range for easing pain.

"We have a model of neuropathic pain that we use for in vivo experiments," Malan recounted. "It involves doing a surgical operation and putting sutures around a couple of the nerves as they exit the spinal column. That made the rats more sensitive to normal temperature and to touch.

"Then we gave the animals the AM1241 drug," he went on, "and saw that their pain sensitivity was blocked. It went back to normal, or in the case of temperature even beyond normal. So really what we were looking at was pain threshold - in this instance, heat resistance. Its source was a projector bulb that we placed near their paw. When the rats got to a point where they felt uncomfortably hot they lifted up their paws. We measured the times it took for them to withdraw their paws from the heat.

"Rats and mice are similar," Malan added. "We did the experiments on mice because we wanted to confirm that the receptor still worked in CB1 knockout mice. We aimed at showing that it wasn't necessary for the action of AM1241."

Too-Hot Rats, KO Mice, Test Synthetic Painkiller

Malan summed up his ongoing research plan.

"We really don't know exactly how AM1241 produces its effects, because it seems to block pain, which is carried by nerve cells, without being present on those cells," Malan said. "So we're doing experiments to try and figure out how it might act. One idea is that immune cells release products that make nerve cells more sensitive. Our drug might be blocking the release of those things that sensitize nerve cells, thereby increasing the pain threshold.

"We're looking at the mechanism. For it to go forward, it needs to be tested for toxic effect, and then it can start to be tested in humans.

"I would say that would occur probably within five years. The toxicology studies should be much sooner than that," he concluded, "only a year or two."