"Mice are smart," avers neuroscientist Anthony Basile at the NIH's National Institute of Diabetes and Digestive and Kidney Diseases. "When you give mice something that feels good," he pointed out, "they'll tend to hang out in the same environment to get more of that feel-good stuff."

Are people smart? "Why do people overeat?" Basile asks rhetorically, and replies, "Because it makes them feel good. Why do people gamble? Because it makes them feel good. Why do people smoke cigarettes? They feel good. You can potentially have an impact on a lot of these behaviors," he continued, "and remove or reduce that feel-good aspect that makes people over-use or abuse these feel-good substances."

Basile is first author of a paper in the Proceedings of the National Academy of Sciences (PNAS) online Early Edition released July 29, 2002. Its title: "Deletion of the M₅ muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia." The paper's senior author is molecular pharmacologist Jürgen Wess. Both authors are in the Neurosciences Group at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Md.

"We found that M₅ receptors regulate neurons that project to the brain's ventral tegument, a region that plays an important role in the feel-good reward effects of drugs of abuse," Basile told BioWorld Today. "Blocking the receptors one could potentially take opiates and become less likely to get addicted. And even if you were to become addicted, the withdrawal symptoms - behaviors marked by that addiction - would be significantly reduced.

"What we found in particular in appetitive reward testing in M₅ receptor-minus knockout mice," Basile continued, "was that we not only got significant reduction in rewards and withdrawal behavior but it didn't alter the analgesia mediated by, in this case, morphine. And we don't have it published here, but it reduced withdrawal with cocaine, too. However, if M₅ receptor antagonists were developed, this pathway is so specific both in the periphery and in the central nervous system that the development of drugs to block these receptors would have a high probability of having reduced side-effect profiles. That's the kicker here. A good drug would knock that pathway out, and potentially reduce addiction and withdrawal, without interfering with some of the positive attributes of such drugs."

Morphine itself is an analgesic. It relieves chronic intractable pain. Besides hospital settings, Basile pointed out, "People can take morphine pills at home. Opiates in general are administered by oral route for a number of severe pains such as are associated with orthopedic surgery, cancer or severe back pain. Sometimes patients with legitimate medical needs may become addicted to opiates, such as morphine therapy. But opiates," Basile continued, "are extraordinarily valuable analgesics. There's really nothing coming down the pike to replace them. And while people who are in genuine pain need these, and are probably not likely to abuse them, those individuals who do divert them for their own use - or use illegal opiates - could potentially be treated by these M₅ receptor antagonists, if such were to be developed to help them get off their addiction."

Does It Hurt Or Do You Only Think It Hurts?

"Or potentially," he went on, "these compounds could be co-administered with opiates to prevent people from becoming addicted to them in the first place. It involves a number of aspects of the quality of the pain. Is it really a sharp stabbing pain, a long-term sort of throbbing anguish, or a pain that is so burdensome it causes depression? There are a number of psychological aspects of pain that are mediated by upper cortical brain levels, which are not understood. The fortunate thing is that opiates can help modify a person's perception of how severe the pain is."

Basile described the mouse experiments that he and his co-authors conducted: "The most important for this paper was the reward experiment. The environment we created was two plexiglass boxes stuck end to end and connected by a little door. One box was very bright and white; the other nice and dark. Mice don't like the light; they like the dark. So we trained the mice to recognize the space they're going to get that makes them feel good. We habituated them to defy their native behavior and hang out in the white box. And when they did, they also got an injection of morphine. When they hung out in the dark area, they only get a shot of saline.

"After we've trained them up to recognize under what conditions they were going to get morphine injections, no matter how long they spent in the white box, even under the test conditions, we didn't give them any more morphine. They were learning that that environment is associated with the administration of a substance that makes them feel good. In the case of the M₅-recetpor knockouts, those mice didn't care. They never learned to associate that environment with the administration of opiates or cocaine or some other things we looked at. That was an indication that the reward effect was blunted."

Do Mice Develop Addictions?

"There's a number of ways you can addict animals," Basile observed. "One is to let them take drugs until they get themselves addicted. But that's a pretty hard thing to do, because animals don't like to abuse drugs. It's not evolutionarily in their favor. What we had to do with these mice, which don't get any bang out of taking opiates, was to implant a pellet of morphine under their skin. That gave them a high level of opiate for a long period of time. So they would get addicted whether they wanted to or not.

"Then we administered an antagonist to the opiate receptor, which precipitated the withdrawal symptoms. They shook like wet dogs, they jumped around, flicked their paws, chattered their teeth. It's an uncomfortable thing for a mouse. But when we did the same thing to the M₅ receptor knockout mice that had also been addicted to morphine, the severity of these behaviors was dramatically reduced. The ones that seemed most salient for the human condition, the jumping and the wet-dog shakes, were almost completely eliminated, reduced by about 90 percent - a significant decrease," Basile concluded.