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  Opioid receptors, addiction and beyond

Posted: June 14, 2006 13:30

Inter-Institutional Narcotic and Ethanol Group Lecture
1:00pm Tuesday, May 2, 2006 - Caspary Hall 1B, Rockefeller University, York Avenue, NYC.



Professor Brigitte Kieffer, Ph.D.,
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Université de Strasbourg, France



Dear Colleagues,

In little over an hour, this informative presentation brought us up to date on the state of the art regarding cloned opioid receptors, rat experiments, fluorescent antibodies and cellular changes associated with opioids. Clinically in opioid addiction, these involve: initiation, maintenance, dependency, habituation, withdrawal, abstinence and relapse to drug use.

Dr Kieffer started with the simplest description of drug use and the inevitable brain changes which occur with tolerance at the receptor level. As she pointed out, all of the consequences of drug use are mediated by such receptors and can be understood in terms of old pharmacology research with corroboration from more recent work on the defined receptors themselves. Dr Kieffer's group in Strasbourg was the first to clone the opioid receptor, which was also done independently at the same time by Evans' group in California.

We were told about behavioural experiments in mice cloned to have one, two or three gene 'knock-outs' being mu, kappa or delta opioid receptors. The first and most important finding was that such animals (even triple 'knock-outs') are still viable, proving that (some) mammals do not require the opioid system for survival and procreation.

Such receptors were predicted long before they were specifically isolated and such rats were bred in the late 1980s. The experiments with mu receptors were all completely predictable based on previous pharmacology but this was not the case with delta or kappa receptors. To examine analgesic and euphoric effects, they used tests of self administration ('press the lever'), tail immersion, dark room, bright lights, place preference, preferred routes, maternal smell recognition and a number of other interesting tests on the cloned and 'wild type' rodents. Consistent with some of the pharmacology, similar results were found in relation to alcohol and cannabis, demonstrating that some of their properties are mediated by the mu system as well. Dr Kieffer's particular interest seemed to be the delta receptors which she feels are related to learning, stress and even mood alterations such as anxiety and depression.

Much of the second part of the talk went over my head, dealing with sub-cellular and membrane changes, much amazingly documented visually.

A fascinating power point clip showed a 20 minute neuron clip speeded up to just 8 seconds showing fluorescence for delta-receptors. In this time, smooth layers of visible glowing membrane-bound receptor rapidly became clumps of granulated intracellular material, altering the cell dramatically. I was told that this was not depolarisation, but a much slower response to other stimuli, some of which may have regulated sensitivities. Most impressive of all, perhaps, were several 3-D representations of the actual receptor molecule with neat little indentations where opioid molecules could trigger pre-determined responses for depolarisation or blocking of the neurone involved or in some cases, movement of dopamine and other neuro-transmitters. So the old 'key in lock' analogy is also valid on a physical molecular level!

Finally there were some questions about the fine points of her field of cloning, obtaining antibodies, etc. It is always a delight to return to Rockefeller University in York Avenue on the East River. Its gardens are quite spectacular and the modern paintings hanging in the dining area are a pleasure and an education. All are on loan from the Rockefeller family collections (see sample below). Dr Kreek's office has a fine view of Brooklyn and Queens across the elegant Queensborough Bridge. Just three blocks away on York Avenue, Sotherby's Auctions were previewing some important French impressionist to be sold in London later in the year (see below). Several had reserves over a million dollars. The only sadness this year is that Dr Vincent P. Dole, aged 94, is quite unwell and no longer able to contribute actively to the field although he did sign the award certificates and send a greeting to the AATOD conference in Atlanta in April.

Comments by Andrew Byrne ..

 

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