People are not the only animals that become addicted to drugs of abuse. Withdrawal is the price that lab mice pay when they can no longer obtain a fix of some opiate, such as morphine. Folks, too, pay the behavioral price of a missing dose of the same.

When a mouse vents its chagrin at an absent charge of anticipated laboratory morphine, it reacts dramatically. Its severe opiate withdrawal symptoms range from diarrhea, jumping, wet-dog shakes, walking backward and paw and body tremors to weight loss and ptosis (drooping or prolapse of an organ, such as an eyelid).

Yale University neuroscientist Marina Picciotto contrasts the uncertain lot of laboratory mice to that of humans: "We can't smoke, drink or take drugs in our offices, obviously," she observed. "In a bar you can go in, light up and down a drink or two. So if you offer friends a choice of where they want to go, they'd probably choose to spend time in the bar.

"We offer the same choice to mice," Picciotto continued, "namely, a so-called place-preference setup. That is, we give them injections of placebo saline or vehicle in one compartment chamber of their cage, and injections of morphine in the second compartment. We do this over three days, or three repetitions of each treatment. Then we open the door between the two paired compartments and invite the animals to explore freely. What we found was that every time we injected morphine, plus preference-blocking molecules, the mice spent no more time exploring in the morphine-paired compartment than it did in the control saline-paired chamber. Meaning that it really had not felt those good feelings that normally allow an addict to go seek that drug."

Picciotto, an associate professor of psychiatry on the Yale faculty, is senior author of a paper in the Proceedings of the National Academy of Sciences (PNAS), dated June 31, 2003, and titled "The neuropeptide galanin modulates behavioral and neurochemical signs of opiate withdrawal."

"We found," she told BioWorld Today, "that in three experiments, galanin - which is a neuropeptide that is normally in the brain - signaling to modulate many kinds of behavior is protective against opiate signs of withdrawal. And we showed that first in a galanin knockout mouse that doesn't have galanin at all in its genes."

Galnon + Galanin = Novel Peptides

"That galanin KO rodent," she added, "had increased signs of opiate withdrawal. And one of the things we're interested in is that galanin protects us humans against addictive drug abuse and opiate withdrawal. Galanin seems to be one of those factors in the brain," she went on. "So we then asked the question: Is there a way to use this drug therapeutically?' Galanin is a neuropeptide so you can't actually administer it to a human patient either orally or by injection, and expect to get it into the brain. It's too big and bulky to cross the blood-brain barrier.

"But this much-smaller molecule, galnon, a galanin chemical mimic, can penetrate that barrier and decrease the activity of nerve cells in the brain that are normally highly activated by opiate withdrawal. So we gave galnon to mice that had been made dependent on morphine. It decreased those withdrawal signs and symptoms. Our co-authors generated a number of small molecules.

"So then we looked to see what happens if we put extra galanin in the brain. And those transgenic mice, with surplus galanin, had less withdrawal behavior - both genetically and pharmacologically. Galanin has some unique properties," Picciotto pointed out. "If you inject it directly into the spinal cord, as other groups have shown, it actually increases - potentiatiates - morphine analgesia. It makes that clinical pain-abating drug more effective for controlling unbearable pain, and can increase the effectiveness of morphine as a neuronal analgesic control while decreasing the addictive and dependence-like symptoms that are associated with chronic morphine treatment. So as an adjunct to opiates for pain treatment it would be really effective in promoting the good qualities of morphine while combating some of the bad properties. Those that make it liable for abuse.

"Galanin is normally found throughout the brain. It's a peptide, which means it's made up of 40 amino acids, and has three different types of receptors that are found both in the body and in the brain. Galanin was discovered 15 or 20 years ago in the gut. It was then found to have most of its important actions in the brain as well. Galnon is a small molecule first published a year ago, and shown to decrease seizure activity - because it decreases the excitability, the firing, of nerve cells. It is not used therapeutically yet."

Picciotto allowed that "our next step is to get the second generation of galanin agonists - small molecules that will penetrate into the brain and spinal cord more efficiently. And our group is interested in the molecular changes that occur. What do galanin and galnon do to signal inside nerve cells to combat opiate withdrawal?"

From Mice To Humans In A Few Years'

"At what point would we move from mice to people?" she asked rhetorically, and responded: "I think that these compounds that we have now are not yet potent enough to move into people, but our collaborators are certainly working on getting more potent agents. They must first ensure they're not toxic, followed by testing for clinical efficacy. I'd say we'll be ready to move fairly quickly - in a few years.

"One application of direct implication for our work," she suggested, "would combine it with the opiate treatment. So we get combined opiate galnon therapy that would allow the morphine to be more effective for pain control, and less likely to result in addiction and then withdrawal. Also, galnon has been shown to decrease seizure activity, so that's another potential clinical application.

"Galanin and its chemical mimic, galnon, appear to modulate opiate withdrawal by affecting the firing rate of neutrons in the locus ceruleus, a region of the brain involved in the sleep-wake cycle, arousal, anxiety and fear. Further research is needed to determine," she concluded, "whether galnon would have similar effects on humans addicted to opiates."