What's a nice organ like the human brain doing with built-inreceptors that attract a dicey narcotic like morphine?

It turns out that the brain synthesizes its own morphine-like opiatepeptide _ a fact discovered simultaneously on both sides of theAtlantic just over two decades ago:

* John Hughes and Hans Kosterlitz of the addictive drugs researchunit at Aberdeen (Scotland) University reported in Nature dated Dec.18, 1975, their discovery earlier that year of a morphine analoguesecreted in pig brain. They christened their five-amino-acid peptide"enkephalin."

* Meanwhile, neuropharmacologist Solomon Snyder, of JohnsHopkins University, described to the Society of Neurosciencesannual meeting in November 1975 an identical natural opiate he hadidentified. Snyder named his peptide "endorphin," but later withdrewthis designation in favor of the Scottish team's molecule.

By either name, the endogenous, morphine-mimicking moleculesapparently have a hand in micro-managing the brain's pain andpleasure sensations.

Morphine, whether extracted from opium or made in the brain, bindsto the same cerebral receptor. This molecular wide receiver carriesthe Greek-letter designation, mu (m) opioid receptor (MOR) _ forwhich it is an agonist ligand. The delta (d) opioid receptor (DOR) ishome port for enkephalin. And dynorphin, another opiate peptide,docks on the kappa (k) opioid receptor (KOR)

A research paper titled "k opioid receptors in human microglia down-regulate human immunodeficiency virus 1 expression" appears in thecurrent issue of the Proceedings of the National Academy of Sciences(PNAS), dated July 23, 1996. Its senior author is infectious-diseasespecialist Phillip Peterson, a professor of medicine at the Universityof Minnesota Medical School in Minneapolis.

What is a dire pathogen like the AIDS virus doing in human braincells?

"It turns out," Peterson told BioWorld Today, "that the only cell theAIDS virus is known to productively infect in the brain is themicroglial cell. There are as many microglia in the human brain," henoted, "as there are neurons _ billions of each.

"When the virus enters microglia," he added, "there's a massive lossof neurons, and damage far out of proportion to what one sees interms of viral infection."

Virus Enters Microglia; Dementia May Ensue

That damage, Peterson observed, inflicts on its late-stage HIV-infected victim an encephalopathy called AIDS dementia complex(ADC). It's the commonest nervous-system disorder in late-stageHIV infection.

"In the early and mid-1980s," he recalled, "at the start of the AIDSepidemic, studies suggested that up to 70 percent of HIV-infectedpatients with AIDS would develop ADC before they died." Later inthat decade and now in the 1990s, he added, "this complicationbecame much less common, and the most ready explanation thatmade sense was the introduction of anti-retroviral drugs, in particularAZT, which does get across the blood-brain barrier."

Usually, the first sign of ADC is forgetfulness; then apathy andwithdrawal. Later, loss of intellectual function and musclecoordination may occur, and severe dementia, paraplegia evenconvulsions, can mark the syndrome's final stages.

Peterson continued: "We know that microglia behave in the brain likemacrophages in the body's immune system. They're avidlyphagocytic in areas of nerve injury or inflammation, and will engulf avariety of microorganisms. They certainly play an important biologicfunction in the developing fetal brain, where there's evidence thathalf the neurons will die during embryonic development."

Prenatal Waste Disposal; Post-Natal Black Box

"It's thought," Peterson went on, "that prenatal microglia arescavenger cells, which get rid of those dead and dying neurons. Butonce you're born, it's not at all clear what these resident macrophagesare doing in the mature normal brain."

One thing they're not doing is reliably repelling HIV's infectivepenetration. "Microglia appear to be targets for many intracellularmicroorganisms," he observed, "not just HIV."

Why they are targets of infection rather than agents of disinfection isbaffling to Peterson. "My unsupported hypothesis," he surmised, "isthat it's the other way round. Those intracellular pathogens havelearned how to exploit microglia for their own purposes."

Peterson's paper shows that activation of the kappa opioid receptorson the microglial surface, by means of synthetic peptides acting asKOR ligands, can damp down HIV expression. "Ours is the firstdemonstration," he said, "that microglial cells possess this KORreceptor."

To arrive at this finding, he and his co-authors created an in vitromodel of HIV-1 infecting microglia. They discerned viral expressiona week after exposing the cells to the virus, and this replicationpersisted for 21 days.

Their treatment of the microglia cultures with synthetic agonistmolecules that bound the kappa receptors "resulted in a dose-dependent, bell-shaped inhibition of HIV expression," the PNASarticle reported. The investigators used synthetic rather than nativeligands to avoid likely cleavage of the latter by proteases.

They found that the microglia constitutively expressed KOR, anddetermined that its genomic sequence was identical to that of thehuman brain KOR gene.

Therapeutic Uses Possible But Problematic

Peterson observed that "no effective therapy has yet been developedto treat AIDS dementia complex. Our work," he suggested, "certainlydoes pose the possibility that regulating this receptor's activity andfunction could in the future end up having clinical implications indiseases where these microglia are involved. But this is all veryspeculative."

His team is "quite interested in linking up with the medicinalchemists and pharmacologists who may have novel kappa ligands. Ifthese do indeed show more potent activity, those receptors may beinvolved in inhibiting HIV infections."

Peterson also remarked, "If we had a good animal model of AIDSdementia, we'd be doing preclinical studies right now. Simianimmunodeficiency virus encephalopathy clearly is the best one, butwe don't have that model ourselves. Of course," he concluded, "onewould like to undertake a screening system to find the most potentligand, and take those into an animal model." n

-- David N. Leff Science Editor

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

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