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Published on: September 7, 2019
Microglia disrupt mesolimbic reward circuitry in chronic pain
Anna M W Taylor1, Annie Castonguay2, Alison J Taylor3
1Department of Anesthesiology and Perioperative Care, University of California Irvine, Irvine, California 92697, Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California 90095.
Abstract:
Chronic pain attenuates midbrain dopamine (DA) transmission, as evidenced by a decrease in opioid-evoked DA release in the ventral striatum, suggesting that the occurrence of chronic pain impairs reward-related behaviors. However, mechanisms by which pain modifies DA transmission remain elusive. Using in vivo microdialysis and microinjection of drugs into the mesolimbic DA system, we demonstrate in mice and rats that microglial activation in the VTA compromises not only opioid-evoked release of DA, but also other DA-stimulating drugs, such as cocaine. Our data show that loss of stimulated extracellular DA is due to impaired chloride homeostasis in midbrain GABAergic interneurons. Treatment with minocycline or interfering with BDNF signaling restored chloride transport within these neurons and recovered DA-dependent reward behavior. Our findings demonstrate that a peripheral nerve injury causes activated microglia within reward circuitry that result in disruption of dopaminergic signaling and reward behavior. These results have broad implications that are not restricted to the problem of pain, but are also relevant to affective disorders associated with disruption of reward circuitry. Because chronic pain causes glial activation in areas of the CNS important for mood and affect, our findings may translate to other disorders, including anxiety and depression, that demonstrate high comorbidity with chronic pain.
Insights
Chronic pain disrupts dopamine (DA) signaling and reward behaviors by activating microglia in the brain. This study reveals impaired chloride homeostasis in GABAergic interneurons as the cause, which can be restored with treatment.
Area of Science:
- Neuroscience
- Neuropharmacology
- Pain Research
Background:
- Chronic pain is known to impair reward-related behaviors by attenuating midbrain dopamine (DA) transmission.
- The precise mechanisms by which pain influences DA transmission remain unclear.
- Microglial activation in the ventral tegmental area (VTA) is implicated in altered DA signaling.
Purpose of the Study:
- To investigate the mechanisms by which chronic pain affects mesolimbic DA transmission.
- To determine the role of microglial activation in the VTA in disrupting DA release and reward behavior.
- To explore potential therapeutic interventions for pain-induced disruption of reward circuitry.
Main Methods:
- In vivo microdialysis and microinjection techniques were employed in mice and rats.
- The study focused on the mesolimbic DA system, specifically targeting the VTA.
- Drug effects on extracellular DA levels and reward behavior were assessed.
Main Results:
- Microglial activation in the VTA significantly compromised opioid-evoked DA release and the effects of other DA-stimulating drugs like cocaine.
- The loss of stimulated extracellular DA was attributed to impaired chloride homeostasis in midbrain GABAergic interneurons.
- Treatment with minocycline or interference with BDNF signaling restored chloride transport and recovered DA-dependent reward behavior.
Conclusions:
- Peripheral nerve injury leads to microglial activation in reward circuitry, disrupting dopaminergic signaling and reward behavior.
- Impaired chloride homeostasis in GABAergic interneurons is a key mechanism linking pain to DA dysfunction.
- Findings suggest potential therapeutic strategies for chronic pain and associated affective disorders like anxiety and depression.
