The blues shed light on grey matters

Striking discovery -- emotional and physical pain are reprocessed through the same neurochemical opioid system

BY ELSIE WAGNER

The inner workings of the mu-opioid neurotransmitter system -- long studied for its role in pain regulation -- have been revealed. A breakthrough study led by Dr Jon-Kar Zubieta at the University of Michigan, using positron emission tomography (PET) and radiotracing deciphered its molecular mechanics to prove that these receptors are also involved in the physiologic modulation of affective states, was discussed in an article in the November issue of Archives of General Psychiatry. The researchers confirm that their work is a first: it demonstrated dynamic changes in the function of a neurotransmitter network during an emotional state.

The team enlisted 14 healthy women, hooked them up to intravenous catheters filled with a radiotracer in a PET scanner gantry, and asked them to self-induce a neutral emotional state or recall a sad experience for at least 30 minutes. The sustained despondent condition significantly deactivated mu-opioid neurotransmission, confirming the system's role in modulating emotional states.

Brain imaging is essential to a new wave of technologic experimentation where results are witnessed live and in real time. Functional magnetic resonance imaging highlights grey matter activity, but PET reveals how its molecules behave -- and are potentially manipulated for therapeutic effect.

• Selected participants had to be remarkably healthy, with no personal or family history of medical or psychiatric illness or substance abuse, weren't taking any medication or hormonal birth control and had regular menstrual cycles.

• The opt for an all-female cohort controlled for gender differences in neurobiologic responses to pain, a finding from a similar PET study, also headed by Dr Zubieta and published in the December 2002 issue of The Journal of Neuroscience, which showed that men and women are indeed distinct.

• Neutral vs. sadness states were counter-balanced and randomized, with subjects blinded to the order of the emotional condition until they were fully prepped for scanning.

In the neutral phase, the women relaxed and remained passive to transient sensory input. During the negative affect test, subjects were asked to recall a personal event that elicited profound feelings of sadness. Participants rated the emotional experience every 10 minutes (sad, blue, downhearted, lonely, alone), a subset from the Positive and Negative Affectivity Scale.

This experiment took up where pain studies left off. The mu-opioid receptor system is usually associated with kicking to cope with physiologic pain. As Dr Zubieta puts it, "in intense prolonged situations, like traumatic accidents or combat where pain could otherwise be paralysing, a galvanized anti-pain system has to be in full force for survival." But this same network can be deactivated in certain regions of the brain by simply revisiting a sad event. According to Dr Zubieta, "this tells us that the opioid system mostly involved in pain also modulates how we feel emotions."

The finding sets the stage for extrapolation. For instance, "the mu-opioid neurotransmission system," observes Dr Zubieta, "probably contributes to the fact that chronic pain and depression are comorbid." He asserts that, "by tracking molecular actions, we stand to find differences in subtypes of psychiatric conditions and how alterations differ from patient to patient. Understanding the biology leads us to new pathways to tailoring treatment."

Coming soon: Dr Zubieta's team is preparing to publish PET studies in patients with major depression and borderline personality disorders. "This was a cornerstone paper for us, but now we can go beyond healthy controls and into the clinical arena -- the disease states themselves." We'll keep you posted.