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"Addiction” refers, in the broadest terms, to an unhealthy relationship with a substance – a drug or alcohol.  While all addictions have some biochemical and neurobehavioral features in common, this article will focus on the phenomenon of opioid addiction. 
 
First it is important to note that not everyone exposed to opioid drugs becomes addicted.  The syndrome of addiction appears to occur in biologically vulnerable individuals in a particular context that favors its development.  There are multiple and diverse pathways that lead to addiction, and as of now there is no universal theory that accounts for their totality.  Nonetheless, the neurobiology of the disorder has been studied in detail, and some features of it are presented here. 
 
There are circuits in the brain that are affected by opioids.  The key means by which opioids affect how the central nervous system functions are receptors – specialized cell-surface molecules that bind the opioid and translate its presence into a cascade of events within the neuron, the basic functional unit of the brain.  Neurons are grouped into nuclei, a neuroanatomical locus of neurons with a common function.  Receptors and neurons particular to opioid addiction are the focus of this article. 
 
When an opioid enters the brain, it starts binding to receptors.  An especially important type of receptor is the mu opioid receptor, named for the Greek letter mu (µ).  When opioids bind to mu receptors they activate the pleasure/reward circuitry in the brain that produces drug liking, in addition to its therapeutic action, pain relief.  The basic brain circuit involved in the euphoric/drug liking effect of the opioid molecule has its foundation in nuclei in the ventral tegmental area of the midbrain, abbreviated VTA.  Opioids binding to neurons in the VTA trigger them to release dopamine in various parts of the brain.  Dopamine is one of a number of neurotransmitters, chemical signaling molecules that are one of the ways that neurons in the brain communicate with each other and affect each other’s functioning.   The VTA neurons release dopamine into another nucleus, the nucleus accumbens, or NAc.  This causes feelings of pleasure.  VTA neurons project to other areas of the brain as well, releasing dopamine there, creating a lasting memory of the circumstances in which the euphoric effects of the drug were experienced.  These “conditioned associations” involve the “persons, places, and things” associated with the use of the drug and euphoria it produces.  This causes craving for the drug when those persons, places, and things are encountered. 
 
Ordinarily, the activity of the NAc is moderated by the neurotransmitter gamma-amino butyric acid, or GABA, produced by the prefrontal cortex, or PFC, a part of the brain associated with the exercise of judgement, prudence, and restraint.  This activity selects for healthy behavior with respect to pleasurable activities such as eating, sex, and the mood elevation accompanying opioid receptor stimulation.  This “feedback” from the PFC to the NAc appears compromised in persons who become addicted to opioids, thus the deterioration in judgement related to obtaining, using, and recovering from the effects of opioids. 
 
Another nucleus besides the VTA that has mu opioid receptors is the locus ceruleus, or LC, located in the brainstem.  The LC sends another neurotransmitter, norepinephrine, throughout the brain.  Among its many actions, norepinephrine released from the LC stimulates wakefulness, respiration, blood pressure, and alertness in general.  Unlike its effects in the VTA, when opioids bind to mu receptors in the LC, rather than stimulating the release of its neurotransmitter, opioids inhibit the activity of the LC.  This results in drowsiness (“nodding off”), respiratory depression, and low blood pressure.  This respiratory depression can be fatal. 
 
Even in normal, healthy circumstances, the repeated use of opioids leads, over time, to desensitization of the mu opioid receptor.  This has different consequences for the functioning of the VTA- and LC- based brain circuitry.  Larger and larger doses of the opioid are required to bring about the VTA-mediated pleasurable experience of the drug.  Likewise, larger and larger doses of the drug are needed to keep the LC from pouring out norepinephrine, causing jitters, anxiety, muscle cramps, and diarrhea.  The net effect is that the addicted person needs to use the opioid just to feel and function normally- to combat the bad feeling of an understimulated NAc, called dysphoria, and an overstimulated LC.  This leads to compulsive drug-using and drug-seeking behavior. 
 
We have discussed the neurobiology of the major features of opioid addiction:  Dependence, or the susceptibility to withdrawal symptoms, and tolerance, the need to take more and more of an opioid drug to get the same effect – and ultimately, just to feel and function normally.  Dependence symptoms are largely mediated by the LC, and tolerance by the VTA-NAc circuitry.  Finally, conditioned associations place the vulnerable individual at risk for using drugs in situations and circumstances where drug use has occurred in the past. 
 
A natural question at this point is what is to be done to help the addicted individual? Traditionally, medications like methadone have been used to help the addicted person stay away from the harmful effects of opioids of abuse by moderating withdrawal, and blunting the desire to use and the pleasure of use.  Medications like naltrexone can discourage drug use by blocking any potential “high”; naltrexone is also associated with some reduction in the craving and urge to use drugs.  It is often given as a long-acting injection to a patient who has been fully detoxified from opiates.  More recently, the medication buprenorphine has proven most effective.  It does not simply “replace one drug with another,” as it is not associated with the pathological aspects accompanying opioid addiction.  Rather, it has a normalizing effect on the opioid system.  It blunts withdrawal, cravings, urge to use, and the “high” that accompanies illicit opioid use.  Online resource for the opioid-addicted person include  www.samhsa.gov for information on addiction, and www.naabt.org for assistance in locating physicians treating with buprenorphine. Call us for details, (440) 234-5700 or to discuss options with our staff.          

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