Microglia disrupt mesolimbic reward circuitry in chronic pain

J Neurosci. 2015 Jun 3;35(22):8442-50. doi: 10.1523/JNEUROSCI.4036-14.2015.

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.

Keywords: addiction; affective disorder; chronic pain; dopamine; emotion; opioids.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Area Under Curve
  • Chronic Pain / drug therapy
  • Chronic Pain / etiology
  • Chronic Pain / pathology*
  • Cocaine / therapeutic use
  • Conditioning, Classical / drug effects
  • Disease Models, Animal
  • Glutamate Decarboxylase / genetics
  • Glutamate Decarboxylase / metabolism
  • Hyperalgesia / drug therapy
  • Hyperalgesia / etiology
  • Limbic System / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / pathology*
  • Minocycline / therapeutic use
  • Morphine / therapeutic use
  • Nerve Net / pathology*
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Pain Threshold / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Reward*
  • Sciatic Neuropathy / complications
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / physiology

Substances

  • Morphine
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2
  • Minocycline
  • Cocaine