New Clues to the Negative Emotional Aspects of Pain

Chronic pain, as both clinicians and patients know, is often accompanied by depression. About 60% of people with depression report pain symptoms when diagnosed, and the reverse is also true. One-third to more than half of those who come to chronic pain clinics have major depressive disorder (MDD). As depression sets in, so does lack of motivation and anhedonia, that loss of pleasure in everyday life.¹⁻³

Researchers funded by NIH’s National Institute on Drug Abuse (NIDA) have found what they see as early stage but important clues about the negative emotional aspects of pain. Currently, the pathways that link mood and pain are not well understood.⁴

The team, from the Washington University School of Medicine in St. Louis, has identified the brain circuitry that appears to link pain to these negative emotional states – the lack of motivation and lack of pleasure in everyday life.

So far, the research is only in animals and the researchers are very cautious about jumping too far ahead, says Meaghan Creed, PhD, assistant professor of psychiatry, neuroscience and biomedical engineering at the university and the study’s co-senior investigator.

Dopamine Neurons

However, her team has been able, in rodent studies, to:⁴

• identify specific dopamine neurons in a brain region known as the ventral tegmental area (VTA) that decrease their activity when pain is present; changes in dopamine activity in this area of the brain are also associated with motivation

• find that pain increased rostro medial tegmental nucleus inhibitory tone onto VTA dopamine neurons and made them less excitable

• report that the decreased activity of the dopamine neurons was linked with a reduced motivation for natural reward, consistent with anhedonia-like behavior; the lower the levels of dopamine activity, the less the animals exhibited reward-seeking behavior (in this case, pressing a level to obtain a sugar tablet)

• find that selectively reactivating the dopamine neurons in the VTA area was enough to restore baseline motivation and the hedonic responses to natural rewards; once the dopamine activity was normalized, the rodents began exhibiting reward-seeking behavior again

The findings overall suggest pain-induced changes and adaptations with the dopamine neurons in the VTA underlie the anhedonia-like behaviors, the team says. “We have identified some key changes in the brain, in this model of inflammatory pain” that affect changes in the reward system related to motivation and apathy, Dr. Creed told PPM.

“This paper represents a lovely intersection of techniques to detail a circuit that we all, in some way, know must exist,” said Benedict Kolber, PhD, associate professor at the University of Texas at Dallas. (Dr. Kolber was not involved in the study.)

Pain and Psychiatric Comorbidities

“In the context of pain, most of us feel sad or down and in the contest of chronic pain, we can develop depression and anxiety, so-called comorbidities.” It’s also well known that people in pain suffer from lack of motivation, he adds, and can have difficulty in challenging tasks, such as ones that are cognitively demanding.

He noted that, “People have searched for years for the detailed molecular mechanisms of these circuits that change emotion and motivational behavior during pain. This paper gets at those details.”

Pain and Behavior

Dr. Kolber sees the biggest impact of the new research as “connecting individual dots into a plausible circuit that changes behavior.” The new report helps to put the puzzle pieces together.

Among the findings worth noting, he said, is that “pain increases inhibition to the VTA” and that ultimately decreases motivation to receive a reward.

Also interesting, he noted, is “a result that showed the motivational problems explored here match the motivational problems seen with people in pain. That is, if the reward is great enough (very high motivation), pain patients don’t seem to have big problems completing tasks.”

Dr. Kolber does caution in jumping too far ahead, even though the research suggests the potential to for future drug development.

The paper does have limitations, he explained, including the fact that the main model the researchers used was a transient acute pain model. The study should be repeated in a chronic pain model since serious comorbidities such as depression and anxiety are not truly a major problem with acute pain.

In the paper, Dr. Markovic’s team noted the advances made but did state:

“Our results provide insight into the regulation of the mesolimbic DA pathway by pain and its consequences on anhedonia-like behaviors. It is important to note that the observed decrease in motivation arises at the initial stages of inflammatory pain and is one of the first symptoms of pain-induced negative affect. As such, further adaptations in the VTA DA circuits could additionally contribute to the development of pain-induced depressive-like behaviors…. We propose that changes in the VTA DA pathways serve as a potential driver for alterations in circuits mediating those behaviors.”

Dr. Creed is also cautious but pointed out that, “It is fulfilling to be able to show pain patients that their mental health and behavioral changes are as real as the physical sensations, and we may be able to treat these changes someday.”

See also our special report on the biopsychosocial model in pain management and current program model terminology.