Summary: A rodent study identifies a brain circuit that appears to drive pain-induced anhedonia. Manipulating this pathway restored motivation in preclinical pain models.
Source: NIDA / NIH
A new study published in Nature Neuroscience reveals specific neuronal circuitry in rodents that contributes to pain-induced anhedonia — a reduction in motivation to pursue rewarding activities.
Funded by the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health (NIH), the study mapped how pain alters brain activity in regions that control motivation and reward. By changing activity within that circuit, researchers were able to restore normal motivational behavior in rodents experiencing pain.
Pain has two broad components: a sensory element (the physical sensation) and an affective element (the negative emotional response). Affective pain often produces anhedonia, a hallmark of mood disorders like depression, and may increase vulnerability to opioid use disorder. Understanding the brain circuitry behind affective pain is therefore central to NIDA’s research priorities.
“Chronic pain is experienced on many levels beyond just the physical, and this research demonstrates the biological basis of affective pain,” said NIDA Director Nora D. Volkow, M.D. “These findings underscore that emotional changes tied to pain reflect measurable brain processes, and they point toward potential avenues for treating the motivational and emotional consequences of pain.”
Building on earlier observations that pain can increase opioid consumption and reduce interest in natural rewards, the Washington University in St. Louis team investigated which circuits mediate those behavioral shifts. Earlier studies had shown that rats in pain were more likely to self-administer higher doses of heroin and less likely to pursue natural rewards like sweet treats. The current work aimed to identify the specific brain pathway that links pain to decreased reward-seeking and motivation.
The researchers focused on dopamine-producing neurons in the ventral tegmental area (VTA), a key node of the brain’s reward system that governs motivation and goal-directed behavior. They recorded activity from these VTA dopamine neurons while rats performed a simple task: pressing a lever with a forepaw to receive a sugar tablet as a natural reward.
To create a pain condition, the investigators injected either saline (control) or a solution that induces local inflammation into the animals’ hind paw. Forty-eight hours later, rats in the pain condition showed reduced lever pressing for the sugar pellet, reflecting a drop in motivation consistent with anhedonia. Electrophysiological recordings revealed that VTA dopamine neurons were less active in animals experiencing pain.
Further experiments traced the suppression of dopamine activity to increased signaling from the rostromedial tegmental nucleus (RMTg), a brain region that releases the inhibitory neurotransmitter GABA. Pain heightened activity in RMTg GABAergic neurons, which in turn inhibited VTA dopamine cells and reduced the animals’ motivation for rewards.
Importantly, the team demonstrated that restoring VTA dopamine neuron activity reversed the behavioral effects of pain. Using chemogenetic tools to selectively activate dopamine neurons, researchers reinstated normal lever-pressing for sugar even while the inflammatory pain remained. In complementary experiments, reducing the pain-driven overactivity of RMTg GABA neurons likewise restored dopamine activity and the animals’ preference for a sweet sucrose solution over plain water, indicating a recovery of hedonic capacity despite ongoing pain.
To the authors’ knowledge, this study is the first to show that inflammatory pain increases RMTg GABAergic inhibition of VTA dopamine neurons, establishing an inhibitory pathway that drives anhedonia-like behavior in rodents.
“Pain research has often focused on peripheral mechanisms aimed at reducing the sensory component, while the emotional aspects and comorbidities such as depression and loss of pleasure have been less explored,” said Jose Morón-Concepción, Ph.D., of Washington University in St. Louis. “Demonstrating that these behavioral changes have a measurable neural basis can validate patients’ experiences and open new therapeutic directions.”
“We hope these findings will help develop treatments that specifically target the motivational and emotional consequences of pain,” added Meaghan Creed, Ph.D., also of Washington University.
About this pain research news
Author: NIDA Press Office
Source: NIH
Contact: NIDA Press Office – NIH
Image: The image is in the public domain
Original Research: Closed access. “Pain induces adaptations in ventral tegmental area dopamine neurons to drive anhedonia-like behavior” by Tamara Markovic et al., Nature Neuroscience.
Abstract
Pain induces adaptations in ventral tegmental area dopamine neurons to drive anhedonia-like behavior
Persistent negative affect produced by pain often leads to comorbid conditions such as anhedonia and depression. The cellular and circuit-level mechanisms that drive these behavioral changes have been unclear. Here, inflammatory pain in rodents reduced activity of VTA dopamine neurons—key mediators of motivation—by increasing inhibitory tone from the RMTg via GABAergic signaling. This decrease in dopamine activity correlated with diminished motivation for natural rewards, consistent with anhedonia-like behavior. Selective activation of VTA dopamine neurons restored normal motivational and hedonic responses. These findings identify pain-induced adaptations within the VTA and an RMTg→VTA inhibitory pathway that underlie anhedonia-like behavior and suggest potential targets for interventions that address the emotional and motivational dimensions of chronic pain.