Chronic Pain Disrupts Reward Circuitry

Microglia Disrupt Mesolimbic Reward Circuitry in Chronic Pain | J Neurosci. 2015 Jun | Free Full Text PMC article

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.


In the present study, we show that chronic pain results in decreased accumbal morphine- and cocaine-stimulated extracellular DA levels that contribute to impaired reward-related behaviors.

We have identified activated microglia and BDNF as key mediators in this dysfunction of the mesolimbic DA system by disrupting the Cl− gradient in GABAergic interneurons of the VTA.

Our prior studies have determined that chronic pain leads to a major reduction in total tissue levels of striatal DA

Changes in the DA system likely contribute to the affective disorders associated with chronic pain and may also affect the effectiveness of many analgesics, such as morphine, the therapeutic potential of which is strongly linked to its rewarding capacity

Here again is the horrible misunderstanding that fuels people’s fears about the addictiveness of opioids.

Moreover, this work affirms the importance of microglial activation in modulating reward behavior and suggests microglial inhibitors as an effective therapeutic for disrupted DA transmission

In conclusion, it is well established that neuroplastic changes in reward circuitry, including molecular and cellular changes within the mesolimbic DA system, lead to the genesis of negative affect

Our present data show that chronic pain causes activation of microglia in the VTA that modifies reward by disrupting Cl− homeostasis in GABAergic neurons

These findings represent a paradigm shift in the field of chronic pain by identifying a signaling and biophysical mechanism by which microglia alter the reward pathway.  

Here’s an article from 2011 when they had learned about the relationship between microglia and pain:

Neuronal and microglial mechanisms of neuropathic pain | Mol Brain. 2011

Neuropathic pain is generally defined as a chronic pain state resulting from peripheral and/or central nerve injury

Neuronal mechanisms of neuropathic pain, especially synaptic plasticity, are the major focus of many investigators. N-methyl-D-aspartate (NMDA) receptor dependent synaptic plasticity at the spinal and cortical levels is believed to contribute to enhanced sensory responses after injury.

Glial cells, including astrocytes and microglia, have recently been implicated in neuropathic pain. These glial cells form close interactions with neurons and thus may modulate nociceptive transmission under pathological conditions

In this review, we present recent progress in the study of neuronal and microglial mechanisms underlying neuropathic pain. We propose that activity-dependent neuronal plasticity is a key target for treatment in neuropathic pain.

Glial mechanisms for neuropathic pain

Our understanding of pathological pain has evolved from solely neuronal mechanisms to neuron-glial interactions. In particular, astrocytes and microglia act as possible modulators of neuropathic pain by releasing a number of cytokines and chemokines.

Astrocytes and microglia play different roles in relation to neuronal activity; however, they do have some overlapping functions in mediating CNS innate immune response [5]. Both astrocytes and microglia are activated in neuropathic pain, and their activation leads to pro-inflammatory responses with pathological effects, such as neuronal hyperexcitability, neurotoxcity and chronic inflammation. The roles of astrocytes in neuropathic pain have been summarized in a number of recent reviews [5,49]. Here we will focus on the role of microglia in neuropathic pain

Targeting microglia for neuropathic pain

The therapeutic benefits of targeting microglial molecules may reside in the fewer side effects on acute pain sensation, as most of these molecules are upregulated predominantly in activated microglia.

A few immunosuppressive compounds are being developed to attenuate microglial activation and inflammation and have proven to be effective in animal models of neuropathic pain

For example, minocycline, a second-generation tetracycline antibiotic, selectively targets microglia to globally inhibit metabolism. At a cellular level, this drug suppresses the expression of inducible nitric oxide synthase, the production of pro-inflammatory cytokines, and p38 phosphorylation in microglia; at the behavioral level, it is therapeutically effective in animal models of neuropathic pain

Minocycline can cross the blood-brain barrier and is under clinical investigation as a treatment for multiple sclerosis and amyotrophic lateral sclerosis

However, it should be noted that minocycline also has a variety of side effects, including fever, stomach pain, effects on vision, drowsiness, and even psychiatric problems

Microglia and inflammatory pain

Recent studies have shown that activation of microglial cells in the spinal cord may contribute to inflammatory pain.

the involvement of microglia in inflammatory pain is dependent on the inflammatory stimulus administered.

Conclusions and future directions

After two decades of searching, there is still a lack of effective treatments for neuropathic pain

Understanding neuronal and glial mechanisms in neuropathic pain offers hope of developing painkillers targeting NMDA receptors or microglia-related molecules

One obvious challenge for most treatments is their side effects on cognition.

NMDA receptors play important roles in various cognitive functions, while microglia survey the microenvironment in the brain. Therefore, the use of such drugs for neuropathic pain is likely to require balancing a gain and loss of brain function.

“It may be inevitable that some cognitive functions must be sacrificed in order to control severe pain in some patient populations.”

We are expected to sacrifice our brain, the center of our thinking, the seat of our personality, to have our pain controlled, even when opioids are available to treat our pain without such loss of brain function.

Most of us would be much better off using opioids, rather than taking these “stupid pills” and being sent into early dementia.

Those that suggest we use should use medications like these clearly don’t care much about our quality of life. Will pain patients be denied opioids until they  are desperate enough to make this sacrifice?

It’s frightening how easily and quickly they’re willing to sacrifice our brain function as an “inevitable” side effect of pain medication, and it shows how little they think of us. They would never do this with a heart medication, or any other used by a more powerful group than pain patients.

It’s frightening to hear how casually they dismiss the value of our brain function, how inevitable they believe such incredibly damaging side effects are.

Efforts to find a non-opioid pain medication are the only reason such medications are even being seriously considered.

Recent studies from both human and animal consistently demonstrate that forebrain areas are important for processing pain perception and the unpleasantness of somatosensory stimuli.

Therefore, selectively targeting NMDA receptors in the forebrain would provide new insights into treatment of neuropathic pain

Also see Microglial Regulation of Neuropathic Pain | Dec 2012



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