Trauma, infection, and diseases such as diabetes can damage nerves, causing pain that persists long after the acute condition has been resolved. Such chronic pain, called neuropathic to signify that it is caused by injuries to nerves themselves rather than to surrounding tissues, is difficult to treat. The strongest analgesics, the opioids, such as morphine and fentanyl, often only partially control it. Moreover, the opioids' side effects, which include constipation, nausea, anxiety, sedation, and respiratory depression, make long-term dosing to control persistent, intractable pain problematic. The opioids' potential for physical dependence and addiction places additional constraints on long-term use.
AM1241 Reverses Pain Responses in Sensitized Rats. Following surgery that increased rats' sensitivity to painful stimuli, the animals' ability to tolerate pressure from a probe (A) or heat from a lamp (B) increased proportionally with increases in AM1241, a cannabinoid agonist. Higher doses increased their ability to tolerate heat well beyond levels established before the surgery.Better relief may be on the way, however, for patients with chronic neuropathic pain as well as others. NIDA-funded researchers recently created and tested a new experimental analgesic compound that reduced pain caused by nerve damage in mice and rats without apparent undesirable side effects. Further, the compound also showed efficacy in inflammatory pain. If these preliminary findings hold up, the compound could fulfill a longstanding need for controlling pain due to neuropathy and also to conditions, such as cancer, that can cause pain through multiple mechanisms.
Minimizing Side Effects
Dr. Alexandros Makriyannis, of the University of Connecticut in Storrs, developed the compound, a new synthetic molecule belonging to the class of chemicals called cannabinoids. The cannabinoids, which are similar to THC, the active ingredient in marijuana, have analgesic effects; however, like opioids, most also produce sedation, anxiety, and other side effects that preclude their administration in doses high enough to manage severe pain.
Dr. Makriyannis's molecule, however, called AM1241, possesses an unusual feature that distinguishes it from most other cannabinoids. While the others activate two types of cellular receptors, called CB1 and CB2, AM1241 activates only the latter. While CB1 receptors are concentrated on nerve cells in the brain and spinal cord (central nervous system, CNS), CB2 receptors primarily occupy various types of cells in the rest of the .
Dr. Makriyannis's rationale in creating AM1241 was that the cannabinoids' side effects appeared to reflect their activity in the CNS, while at least some of their pain relief might derive from their stimulation of the CB2 receptors. If so, AM1241 might relieve pain without the usual cannabinoid side effects. To test whether it would, Dr. Makriyannis teamed with Dr. T. Philip Malan, Jr., of the University of Arizona in Tucson.
The researchers first demonstrated that AM1241 reduced rats' sensitivity to acute pain induced by heat. In a subsequent study, they surgically increased pain sensitivity in nerves adjacent to the spinal cord, a procedure that mirrors human chronic neuropathic pain conditions. They then established baseline tactile and heat pain thresholds in the sensitized rats by timing how long it took for the animals to withdraw a paw when the researchers applied a probe or focused a lamp on it.
"Using the animals' pain thresholds to measure their responses to painful stimuli means they can free themselves from whatever we are doing to them as soon they are uncomfortable enough to want to move," Dr. Malan explains. "They simply lift their paw and the stimulus is withdrawn."
When the hypersensitized rats were given AM1241, they withstood more pressure from the probe or heat from the lamp before withdrawing their paws than they had before being given the compound. Furthermore, the animals' tolerance for pressure or heat increased proportionally with larger doses of AM1241. "We were even able to increase the rats' pain sensitivity thresholds beyond levels established before the chronic pain condition was induced," Dr. Malan says.
"AM1241 provides pain relief equal to that seen with opioids, which is the fullest we're capable of producing in animal models," says Dr. Malan. In addition, the compound did not produce any of the sedative effects seen with broader cannabinoid agonists. "We looked at the dose that produced maximum pain relief, then we went as high as 10 times that dose and still did not see any CNS effects," he says. "While we haven't done real toxicology studies pushing doses super high, we have used doses in other tests that are as much as a hundredfold the doses required to relieve pain and we haven't seen any untoward effects from that."
Goals of Further Research
"While AM1241 is looking very good in terms of being effective, it is a big step to go from a successful animal model to treating humans in pain," Dr. Malan cautions. Before that can occur, the researchers need to answer many questions about the compound, such as how it works to relieve pain. "We know that CB2 receptors, where AM1241 works, are at their highest concentration in the immune cells," he says. "And the fact that AM1241 can block acute pain caused by a brief application of heat that doesn't damage tissue makes us think whatever we are blocking or stimulating is coming from cells that are there all the time," as opposed to cells that migrate to sites of tissue inflammation or nerve injury.
Mast cells, one class of immune cells distributed throughout the , are particularly intriguing candidates. They are always present and tend to sit next to nerve endings, suggesting that AM1241 might affect mast cells in ways that indirectly alter the pain sensitivity of nearby nerve cells. "However, we have evidence for a number of possibilities and are not ready to say what the mechanism is," says Dr. Malan.
In addition to trying to nail down AM1241's mechanism of action, the researchers are continuing to study its ability to reduce various types of pain. In a just-completed study, Dr. Malan and his team showed that AM1241 can reduce inflammatory pain in rats. In humans, inflammatory pain can be acute when it results from injury or surgery, or chronic when it stems from diseases such as arthritis. "It is difficult to put some pains into one classification or another," Dr. Malan says, adding, "one source, such as cancer, can cause pain by a variety of mechanisms." Currently, no single medication can relieve acute pain caused by stimulation of localized receptors, chronic neuropathic pain, and inflammatory pain. "Thus far, AM1241 looks promising for doing that," he says. Noting again that it is difficult to predict how well the findings will hold up in pilot studies with human subjects, Dr. Malan adds, "I think this compound has as much potential to treat chronic and acute pain, based on what we see in animals, as anything that's come along at this stage of development."
Sources
- Ibrahim, M.M.; Deng, H.; Zvonok, A.; Cockayne, D.A.; Kwan, J.; Mata, H.P.; Vanderah, T.W.; Lai, J.; Porreca, F.; Makriyannis, A.; and Malan, T.P., Jr. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS. Proceedings of the National Academy of Sciences 100(18):10529-10533, 2003. [Abstract]
- Quartilho, A.; Mata, H.P.; Ibrahim, M.M.; Vanderah, T.W.; Porreca, F.; Makriyannis, A.; and Malan, T.P., Jr. Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors. Anesthesiology 99(4):955-960, 2003. [Abstract]