Researchers separate analgesic effects from addictive aspects of pain-killing drugs

[~lostgurl~]

Researchers separate analgesic effects from addictive aspects of pain-killing drugs

Aug. 20, 2007
eurekalert

For the first time, pain researchers at Washington University School of Medicine in St. Louis have shown that it's possible to separate the good effects of opiate drugs such as morphine (pain relief) from the unwanted side effects of those drugs (tolerance, abuse and addiction).

The investigators, led by Zhou-Feng Chen, Ph.D., associate professor of anesthesiology, psychiatry and molecular biology and pharmacology, report their results online in the Proceedings of the National Academy of Sciences.
They found that opiates like morphine don't relieve pain as well in mice genetically engineered to lack neurons that produce a neurotransmitter called serotonin in the central nervous system. In fact, some opiates completely lost their analgesic, or pain-relieving, effects in the mutant mice. But to the surprise of the investigators, those mice still developed tolerance to the drugs and actively sought them out.

Serotonin is involved in a wide range of behavioral and psychological processes including cognition, circadian rhythm and mood. Serotonin also is an important regulator for pain sensation, and abnormal levels of serotonin can contribute to painful events such as migraine headaches. "

The number of serotonin-producing neurons, which also are know as 5-HT neurons, is relatively small, and they are found in a very restricted area of the hindbrain," Chen explains. "Importantly, however, these neurons make extensive connections to other parts of the brain and are able to release serotonin almost everywhere in the central nervous system. These neurons have been implicated in almost every aspect of physiological function and in psychiatric disorders including anxiety and depression."

For several decades, scientists have been interested in the role these 5-HT neurons play in the analgesic effects of opiate drugs such as morphine. Studies done in the 1970s and the 1980s determined that the serotonin system was involved in the pain-killing effects of these drugs. But other studies have contradicted that "classical" view. As a result, the involvement of 5-HT neurons in the analgesic effects of opiates has remained uncertain.

In 2003, Chen's research team found that mice missing a gene called Lmx1b were completely unable to produce serotonin in the brain. But those mice could not be used for behavioral studies because they died soon after birth. To overcome that problem, Chen and his collaborators developed a line of mice lacking Lmx1b only in 5-HT neurons. Remarkably, despite the loss of all 5-HT neurons in the central nervous system, the mutant mice live to adulthood with apparently normal motor function.

Earlier this year, Chen's team reported in the Journal of Neuroscience that the mutant mice had increased pain when they encountered a painful stimulus. In this new study, Chen's team compared the pain-relieving effects of opiate drugs in normal mice to the effects in the mice without 5-HT neurons. "We performed a number of tests to measure the response of the mice to different opiate drugs," he says. "In contrast to previous studies that used drugs to destroy or disable 5-HT neurons, our study provides the first genetic evidence to support the 'classical' view that 5-HT neurons are a very important component of the neural circuits required for the analgesic effects of these drugs."

They also compared unwanted side effects such as tolerance and morphine-induced drug-seeking behaviors in mice with and without serotonergic neurons, and they found no differences. "These findings demonstrate that opiates exert their analgesic effects through a serotonin mechanism but that serotonin is not responsible for the negative, addictive side effects associated with those pain-killing drugs," Chen says. "That was unexpected because serotonin has been known to interact with other neurotransmitters like dopamine or to modulate the levels of these neurotransmitters in the forebrain, which is important for reward-seeking behaviors."

Chen says the finding raises the possibility that serotonergic neurons or opiate receptors on those neurons could be potential targets for opiate drugs that might suppress pain without risk of tolerance and drug addiction.

###

Zhao ZQ, Gao YJ, Sun YG, Zhao CS, Gereau RW, Chen ZF. Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward. Proceedings of the National Academy of Sciences; Early Edition, www.pnas.org/cgi/doi/10.1073/pnas.0705740104, Aug. 20, 2007.

This research was funded by the National Institutes of Health and the National Natural Science Foundation of China. (related articles)

Zhao ZQ, Chiechio S, Sun YG, Zhang KH, Zhao CS, Scott M, Johnson RL, Deneris ES, Renner KJ, Gereau RW, Chen ZF. Mice lacking central serotonergic neurons show enhanced inflammatory pain and impaired analgesic response to antidepressant drugs. Journal of Neuroscience, vol. 27, pp. 6045-6053; doi: 10.1523/JNEUROSCI.1623-07.2007. May 2007

Zhao ZQ, Scott M, Chiechio S, Wang JS, Renner K, Gereau RW, Johnson R, Deneris E, and Chen ZF. Lmx1b is required for maintenance of central serotonergic neurons and mice lacking central serotonergic system exhibit normal locomotor activity. Journal of Neuroscience, vol. 26, pp. 12781-12788; doi:10.1523/JNEUROSCI.4143-06.2006. Dec. 2006

Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

http://www.eurekalert.org/pub_releas...rsa082007.php#

Reputation Comments on this post:

	fascinating, thanks for bringing this here
	breaking news
	Much interesting find!

[Heretic.Ape.]

Wow, interesting. Are these studies now part of our own archive or shall I see if I can find them?

[~lostgurl~]

Thanks h.a. that would be great.

[Jacco]

Poor mice without serotonergic neurons.

Seems like they might turn to using MDMA or one of its analogues as an effective painkiller, since those are great 5HT releasing agents, no? Perhaps the down-scheduling of MDMA would lead to renewal of interest in its off-label and classical use as a psychotherapy tool.

[Jatelka]

There's an article here...

http://www.drugs-forum.com/forum/loc...=3115&catid=36

on the antinociceptive effects of MDMA

[Nature Boy]

Definitely an important breakthrough. Maybe 22nd century heroin will be the moderate drug user's weapon of choice.

[Heretic.Ape.]

PNAS (hehe, they said penis) just sent me the study referred to. It is now available in the archive: http://www.drugs-forum.com/forum/loc...=3221&catid=69

I didn't bother uploading the other two studies as it seems they are mainly just earlier works supporting this more recent one but I would be happy to if anyone is interested.
I've been daydreaming about the future possibilities of this all day... could be very nice
h.a.

[Nagognog2]

Nice article, Jatelka. But I think it supports my allegation that Ritalin (methylphenidate) doesn't actually make children diagnosed (often by laymen) as having ADHD more attentive in classrooms - just makes the kid too stoned to bother to move or talk.

I didn't know they were still using the WMHPJT (White Mouse Hot-Plate Jump Test) and/or equivalent to test the efficasy of analgesics.

[~lostgurl~]

Pain relief without the numbness

Oct. 3, 2007
Courtesy Harvard Medical School and World Science staff

Anyone who has received a stiff dose of painkiller knows that full pain relief is almost unimaginable without an accompanying numbness, if not unconsciousness.

But that’s only because we don’t know a better way, researchers say. In fact, the nerve cells that sense painful stimuli are distinct from those that pick up other sensations. So it should be possible to knock out the first type and not the others, and thus wipe out the pain alone. Current drugs instead zap nerve cells indiscriminately, explaining their drastic side effects.

In a new study with rats, scientists claim to have finally figured out how to knock out the pain-sensing cells only, potentially revolutionizing pain treatment.

The catch: as it stands, the new technique involves an initial injection of hot pepper spice—a brief burst of pain as the price of reprieve from later suffering. The researchers hope to later find a way to avoid this unpleasantness.

“Eventually this method could completely transform surgical and post-surgical analgesia, allowing patients to remain fully alert without experiencing pain or paralysis,” said Clifford Woolf of Massachusetts General Hospital in Boston. He is the senior author of a paper on the findings to appear in the Oct. 4 issue of the research journal Nature. Woolf said the findings raise the odd possibility that you could, for example, feel a pinprick as a normal sensation, but without discomfort.

Despite intense research, surgical pain management has changed little since the first demonstration of general anesthesia at Massachusetts General in 1846, using ether, Woolf and colleagues said. The new study, conducted with scientists at Harvard Medical School in Boston, builds on research done since the 1970s. This has examined how electrical signaling among nerve cells depends on protein molecules called ion channels. The channels form openings in the membranes, or skin-like protective covering, of neurons, or nerve cells.

One such channel, called TRPV1, exists only in pain-sensing neurons, Woolf and colleagues said. Molecules can enter and exit the cell through the channel. But a molecular “gate” typically blocks the opening. The gate opens in response to heat or to the spicy ingredient of chili-peppers, capsaicin.

The investigators injected rats with capsaicin and a compound called QX-314, a normally inactive derivative of a local anesthetic, lidocaine.
Because the channels were open, the chemical was able to enter the cells and shut them down, the researchers found. But other types of nerve cells were unaffected because they don’t have TRPV1 channels.

“We’re optimistic that this method will eventually be applied to humans and change our experience during procedures ranging from knee surgery to tooth extractions,” said Woolf. The treated rats seemed immune to pain, such as uncomfortable heat and pricks; yet they continued to move normally and respond to other stimuli, the investigators found.

But there are several hurdles to overcome before the method can be applied to humans, they said: it’s unclear how to open the channel without producing a temporary burning pain, and the treatment’s effects aren’t long enough yet for clinical use. But it should be possible to solve these problems, Woolf claimed. “The possibilities seem endless,” he added. “I could even imagine using this method to treat itch, as itch-sensitive neurons fall into the same group as pain-sensing ones.”