The Role of Glutamate in Opioid Addiction

This week in class we learned about opioid addiction and the role that glutamate plays in it.  Opioids enjoy widespread use as pain relievers, some well known opioids are codeine and morphine.  They are specifically used in order to treat acute pain, or in order to treat chronic, disabling pain that is associated with terminal diseases.  Recently however, opioids are being used to treat non-malignant chronic pain, that is pain that is not associated with an illness or injury.  This has lead to a growing number of people becoming addicted to opioids.  For this reason it is very important that we understand what causes opioid addiction and how to prevent it.
The article that we have read for this week tells us that the brain pathway that is most responsible for addiction is the mesocorticolimbic dopaminergic pathway.  The pathway is composed of the ventral tegmental area(VTA), the nucleus accumbens(NAc), the amygdala(AMY), and the medial prefrontal cortex(mPFC).  These regions of the brain are responsible for the reward system of the brain, meaning that it reinforces certain actions once they are performed.
Now we can talk about how glutamate and its receptors play a role in opioid addiction.  In the article it was said that the NMDA ionotropic receptor is very important in the development of addiction to opioids, as there are more NMDA receptors in the brains of morphine addicted rats.  It was also shown in this paper that the substance MK801, which blocks the NMDA receptor upon binding with the receptor, can block the pain tolerance and physical dependence which opioid use can lead to, as well as the drug seeking behavior which drug addicted individuals display.  It is also revealed in this paper that there are a number of specific metabotropic receptors which are linked to withdrawal symptoms in opioid addicts.
The article also investigates the signal transduction pathways which are responsible for opioid addiction.  The release of calcium ions upon activation of the NMDA receptor leads to many different effects on the cell which all create withdrawal symptoms if the NMDA receptor is overstimulated.  Another important pathway to consider is that of protein kinase C which upon the increase in the calcium concentration in the cell, the kinase promotes the creation of copies of itself and phosphorylates, that is attaches a phosphate to a G-protein which leads to desensitization when the G-protein in question is on an opioid receptor.  Another important pathway to consider is the CREB pathway which is a common factor in many other cases of physical and psychological dependence.  The application of opioids increases the concentration of CREB and related proteins and causes the copying of new proteins and leads to addiction.  Lastly, the MAP kinase pathway which is important in rewarding response and behavioral sensitization which is brought on by the administration of psychostimulants.
The interaction of glutamate with other neurotransmitters was also explored in this article.  It is said in the article that there is an interaction between opioid receptors and glutamate receptors which is vital to opioid dependence.  It is also shown that there is a connection between glutamate and dopamine as it is shown that glutamate increases the amount of dopamine in NAc and increases the activity of dopaminergic neurons.  It is also shown that activation of opioid receptors in the brain inhibited the activity of GABA neurons and inhibited the chemicals release.  GABA normally inhibits dopamine, so the result of the opioid application is the increase of dopamine in the system.  The article also briefly mentions substance P which the researchers writing this paper say that it has a relationship with glutamate, but that its role in opioid dependence still has to be studied.
In our small groups this week we primarily discussed changes in medical procedure, as in if we could ameliorate the concerns about addiction in the prescription of opioids.  One very interesting thing we talked about was whether it would be better to just sever the nerve bringing pain sensation to the brain rather than worry about medication and the discussion gradually shifted to not over whether the severing of the nerve would be the practical thing to do, but what the implications would be if we gave this procedure to people.  We talked about how pain is a valuable teacher, telling us about whether an object is dangerous or not, or whether we have been hurt or are hurting ourselves.