Two research teams, one American and one French, reportedlast week finding a gene sequence that encodes the brainreceptor that binds the active ingredient of marijuana. A thirdgroup announced that it has isolated a peptide produced by thebrain itself, which also binds to that cannabinoid-thirstyreceptor.

Though none of the researchers hails from industry, all threestressed the potential of their findings for drug discovery.

Besides its mood-changing euphoric high, marijuana'spsychoactive effects read like the label on a snake-oil patentmedicine: Its active ingredient, 9-tetrahydrocannabinol (THC),can alleviate pain perception, lessen the ocular pressure ofglaucoma, lower blood-pressure, control nausea, and affectmemory and bodily movement.

In the mid-1970s, a chemical substance secreted by brain cellswas discovered simultaneously by American and Scottishneuropsychopharmacologists. Hailed as "the brain's ownmorphine," this endogenous ligand bound to the same cerebralreceptors turned on by the plant alkaloid, opium and itsderivative, morphine.

What "brain's own marijuana" turns on the cannabinoidreceptor that also flips for THC?

That long-sought natural brain molecule turns out to be afatty-acid amide called "anandamide," after the Sanskrit word"ananda," meaning "internal bliss."

The neuroscientists at Hebrew University in Jerusalem, whodiscovered and named anandamide, reported their find in lastweek's issue of Science. They applied to patent the compoundlast month, said William A. Devane, the paper's first author.

From 4.5 kilograms of pig brain Devane and his associatesextracted 0.6 milligrams of anandamide, which passed theassay for cannabis-mimicking pharmacological activity. Thistest takes the form of applying the drug to a preparation ofmouse vas deferens (testicular duct) and measuring its abilityto inhibit the tissue's twitching. Anandamide decreased twitchheights by 50 percent. Mass spectroscopy indicated its chemicalformula is C22H37NO2

Last week issues of Science and Proceedings of the NationalAcademy of Sciences (PNAS) both reported expression cloningof the cannabinoid receptor gene -- Science by Christopher J.Evans at the University of California, Los Angeles and PNAS byBrigitte L. Kieffer at the Ecole Superieure de Biotechnologie inStrasbourg, France.

Devane has just moved from Jerusalem to the NIH's NationalInstitute of Mental Health (NIMH) to pursue his anadamideresearch. "I've now synthesized enough of the stuff," he toldBioWorld, "so colleagues elsewhere in NIMH can assess itsbehavioral effects, such as anxiety, feeding habits andhyopthermia, in lab animals." He adds that back in Israel"they've hired a behavioral pharmacologist who has alreadyobtained positive results." Devane himself plans to repeat hisporcine extraction in human brains right after the holidays.

"It provides a new molecule to start developing other analogsof anandamide," Devane said, "and a new neuromodulatorypathway with therapeutic potential in pain, glaucoma, seizures,to name a few." Its receptor is one of the most abundant in theentire brain, highly localized at sites implicated inschizophrenia, Parkinson's disease and Huntington's disease.

Kieffer said her team's receptor-cloning feat should ultimatelylead to the design of more specific drugs. So does Evans, whotold BioWorld: "Once we know the different ways each receptorworks, we can map them properly. Is one receptor type onlyassociated with pain? Which with respiration? We'll know theirdistribution, their association with different behavioral ormorphological effects. Then we can start to design specificdrugs."

What's more, Evans added, these discoveries will advance thestudy of addiction, tolerance and dependence. "What happensto the receptor when you constantly bombard it with opiatedrugs? Now that we have the RNA and protein probes andantibodies, we can start dissecting these processes," Evans said.

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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