Rodent, Heal Thyself

by Megan Talkington on 5/19/2011

In animal models, measuring responses to evoked pain is relatively straightforward, but it is a formidable challenge to figure out whether an animal is in pain, and whether an analgesic is doing anything to alleviate that discomfort (Mogil, 2009). A new study lends credence to the idea that animals may be able to signal relief of spontaneous pain based on how they self-administer an analgesic.

In a paper published online on May 6 in Pain, Andrea Hohmann at Indiana University in Bloomington and her colleagues report that nerve-injured rats learned to self-medicate with a pain-relieving drug, an agonist of cannabinoid receptor 2 (CB₂). There was evidence that the animals were not abusing the drug; instead it appeared that it was alleviating their pain. “We believe that the drug self-administration paradigm is providing a window into what the animals think is attenuating their spontaneous pain,” said Hohmann. This method, which mimics patient-controlled analgesia, may offer a way to evaluate novel analgesics targeted at neuropathic or other types of ongoing pain.

Most previous work on analgesic self-administration in animals has looked at opioids (see Martin and Ewan, 2008; Clark, 2007), which have a strong abuse potential as well as CNS and other side effects. Hohmann and colleagues extend these methods to an analgesic compound that, they demonstrate, has neither.

In the study, rats were trained to self-administer the CB₂ agonist AM1241 intravenously by pressing a lever. In rats with a spared nerve injury model of neuropathic pain, self-administration of the drug alleviated mechanical allodynia at the site of the injury. That left open the question of whether the drug provided the kind of relief that would motivate the animals to self-administer it.

To find out, first author Tannia Gutierrez compared the behavior of nerve-injured and sham-operated rats. Initially she found that injured and control animals self-medicated with AM1241 to a similar extent. However, when she rigged the lever so that a rat had to press repeatedly to deliver the drug, the nerve-injured animals were more persistent than the sham-operated animals. In that way, Hohmann said, “We are able to show that under conditions in which the animals in the nerve-injured state self-medicated with the CB₂ agonists, naïve animals under the same conditions did not reliably self-administer the drug.”

Were the nerve-injured animals motivated to self-administer AM1241 because they were getting pain relief, or because they were getting a high? Cannabinoid CB₂receptors are favored as analgesic targets because—unlike CB₁—they are expressed in only low levels in the brain and are not associated with psychotropic effects. But it was not actually known whether CB₂agonists might have some abuse potential. To determine that, the researchers replaced the drug with saline, and found that injured animals then pressed the lever less frequently. “That’s quite different from drugs of abuse,” Hohmann said. “For drugs of abuse, when animals are switched over to vehicle, they’ll actually press the lever more, in an attempt to get the positive reinforcing drug.” As a result, Hohmann and her colleagues conclude that the reason that nerve-injured rats self-medicated with AM1241 is that it alleviated their pain. (For further discussion of this topic, see the comment from Thomas Martin below.)

Gutierrez also performed additional experiments demonstrating that AM1241 does not have side effects in the CNS. Now, Hohmann said, her group wants to examine whether rats will self-medicate with agents that are restricted to the periphery. “We are very interested in further validating the model to see that beyond a doubt, this model would be useful for identifying non-psychotropic analgesics that would lack abuse liability,” she said.

In an accompanying perspective, Kenneth Sufka of the University of Mississippi in Oxford writes, “One interesting aspect of this research, beyond that of showing that the CB2 receptor may be a viable target for analgesic drug development, is their use of a more clinically relevant analgesic screening procedure. Such advances in screening protocols may facilitate drug discovery efforts.”