Lights reflect off of the gleaming road in the rain. The highway embankment funnels traffic into a valley where pools of black water flood the lanes. Your car suddenly hydroplanes and you veer into the other lane. The sound of metal wrinkling like tin foil ricochets in your ear. You wake up in the hospital with a horrendous pain emanating from your broken legs. Morphine is dispensed to ease the pain. Rehabilitation is slow and the pain is incessant. Tolerance develops. Withdrawal symptoms like abdominal cramps and depression begin. You want to stop taking morphine, but the pain in your legs persists and makes it difficult to walk. What do you do?
Morphine has the possibility to help those in pain, but it also has the potential to create a dangerous addiction. Morphine has been in use since Byzantine times because it's a powerful and effective painkiller. Research is now looking into morphine's mode of action in the body, to better mitigate the unfortunate side effects of tolerance and addiction for long-term pain control. In the November 30th issue of the Journal of Neuroscience, a group led by Dr. Ping Zheng in China found that chronic morphine treatment actually switches the effect of dopamine from inhibition to excitation on pyramidal cells of the basolateral amygdala. Pyramidal cells in the BLA are involved in emotion. Excitation of these cells could change the emotional response, which is especially important in withdrawal, when negative feelings can contribute to a relapse.
The researchers used rats to test the effects of chronic morphine treatment. They induced morphine tolerance in rats and then used brain slices to study excitatory postsynaptic currents (EPSC) using the whole-cell patch clamp method. Compared to the control group injected with saline, the morphine treated rats had higher amplitude EPSCs by 50%. After this observation, the team wanted to investigate the reason behind this change. They used a dopamine D1 receptor antagonist in the morphine treated rats, and the EPSC was now the same as the saline control group. Thus they concluded a change in D1 receptors is responsible for the excitatory response.
But what changed about the dopamine D1 receptors at the molecular level? The researchers determined that morphine treated rats had a higher release of glutamate from the presynaptic neuron. Looking at the expression of D1 receptors using Western blotting, they saw there was increased expression of D1 receptor, versus saline. The researchers hypothesized this increased expression might be dependent on protein kinase A (PKA) so they tested this with a PKA inhibitor. They indeed found that the increased release was due to PKA activation.
To supplement these studies, a behavioral test called conditioned place aversion (CPA) were performed on the rats. In this test, rats were placed in one section on days when they received the drug, and in another section on days when they did not receive the drug and were experiencing unpleasant withdrawal symptoms. The rats were then allowed to freely go into either section, plus a third section. Time was clocked for how long the rats spent in each section and the CPA score was determined by the difference between the time spent in the withdrawal-paired compartment divided by the time spent in the drug-paired compartment. The researchers used this to test to determine whether the increase of D1 receptors is responsible for the withdrawal induced conditioned place aversion. The morphine rats strongly avoided the withdrawal compartment, but when a D1 receptor antagonist was injected into their BLA, they no longer avoided that compartment. Therefore, D1 receptors are responsible for part of the withdrawal process.
This study could lead us to understand more about the molecular nature of morphine tolerance and addiction. Using these findings, new ways to combat the negative side effects of morphine use could be implemented.
Li, Z., Luan, W., Chen, Y., Chen, M., Dong, Y., Lai, B., Ma, L., Zheng, P. (2011). Chronic Morphine Treatment Switches the Effect of Dopamine on Excitatory Synaptic Transmission from Inhibition to Excitation in Pyramidal Cells of the Basolateral Amygdala. Journal of Neuroscience, 31(48): 17527-17536.