There is no clearly agreed upon mechanism that explains physical dependence to opiates. Possibilities include up and down regulation of receptors, changing levels of natural opiates in the brain, and activity of specialized nuclei within the brain. This discussion will present evidence suggesting that activity of the locus coeruleus (a nucleus of cells located in the brainstem that release a substance similar to adrenaline) is important for opiate dependence, tolerance, and withdrawal.
What happens to opiate addicted patients when
they are given naltrexone? Resnick
administered naloxone 1.2 mg IM (intramuscular) every 30 minutes
to 13 awake opiate addicted patients and obtained detoxification
within 24 hours.
Note that the severity of
withdrawal increased dramatically soon after naloxone
administration (Segment A). Then, symptoms decreased quickly over
the next 2-3 hours (Segment B) with a slower decrease over the
rest of the day (Segment C) Fig1.
Ideally, we would like to correlate the temporal course of
withdrawal signs to activity of specific areas in the brain.
Unfortunately, the only known nucleus with activity that does
correlate with signs of withdrawal, the locus coeruleus, is too
small to image or measure in humans. Subsequently, it is
necessary to look at data obtained from a rat model and evaluate
applicability to humans.
Rasmussen placed a
measuring device in the locus coeruleus of opiate dependent rats.
Subsequently, he administered naltrexone while simultaneously
recording the activity of the L.C. and signs of withdrawal.
Similar to the results obtained by Resnick in human subjects,
withdrawal signs increased dramatically, then decreased in two
phases; quickly over four hours then more slowly over 72 hours.
Activity of the locus coeruleus paralleled signs of withdrawal
revealing all three phases of increasing and decreasing activity.
I urge you to review Rassmussen's paper. It is impressive how
closely the data in the rat model correlates to the human data
obtained by Resnick.
The structure and function of cells in the locus
coeruleus have been well studied. Functionally, these cells show
evidence of opiate tolerance and dependence. Fig.2 is a
representation of such a cell with specific receptors for opiates
and clonidine on the cellular membrane.
Basically, when opiates or clonidine bind to their
respective receptor, the intracellular cAMP system is down
regulated. This, in turn, opens potassium channels while
simultaneously closing sodium channels. In effect, cellular
activity is inhibited Fig 2.
When opiates are administered to the cells of the locus coeruleus chronically, a very different situation occurs. The cells adapt to the presence of opiates by up-regulating the intracellular levels of cAMP and protein kinase. The mechanism for this action is unknown. At this time the cell becomes active again and exhibits tolerance to further opiate administration. In other words, it takes more opiate to produce the same effect observed prior to chronic opiate administration. An opposite effect is observed when opiate is removed from its receptor by the administration of an antagonist, i.e. naloxone or naltrexone. The previously dependent cell becomes hyperactive, functioning at five times its normal activity. Soon thereafter, activity decreases to 2 times normal within four hours, followed by a slower decrease in activity over the next 72 hours.
In summary:
The central neurological mechanism for opiate dependence, tolerance, and withdrawal is not clearly understood. However, in a rat model, activity of the locus coeruleus seems to play a major role. On a cellular level, there is evidence of opiate tolerance and dependence. On a clinical level, activity of the locus coeruleus closely mirrors signs of withdrawal. While one must be cautious in applying data from a rat model to humans, the temporal and quantitative similarities in signs of withdrawal are intriguing at least.
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