"Microglia Disrupt Mesolimbic Reward Circuitry in Chronic Pain"

[Kyla]

http://www.jneurosci.org/content/35/22/8442

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

 

[aimossy]

Medical News Today article on this paper (research done in mice)
http://www.medicalnewstoday.com/articles/295135.php

For the first time, scientists have discovered that brain inflammation caused by chronic nerve pain can affect signaling in the regions of the brain associated with mood and motivation. This discovery suggests there is a mechanism that connects chronic pain with symptoms of depression and anxiety that many patients experience.

The findings of the study, published in the Journal of Neuroscience, could lead to new methods of treatment for chronic pain, the most common form of enduring illness for people aged below 60 in the US.
Researchers from the University of California-Irvine(UCI) and the University of California-Los Angeles (UCLA) made their discovery after examining the growth of immune cells in the brains of mice and rats with chronic pain.

"For over 20 years, scientists have been trying to unlock the mechanisms at work that connect opioid use, pain relief, depression and addiction," states Cahill. "Our findings represent a paradigm shift which has broad implications that are not restricted to the problem of pain and may translate to other disorders."
The researchers are now hoping to establish whether biophysical alterations in the brain are behind the development of mood disorders associated with disruption of reward circuitry and chronic pain.
"We have a drug compound that has the potential to normalize reward-like behavior," explains Cahill, "and subsequent clinical research could then employ imaging studies to identify how the same disruption in reward circuitry found in rodents occurs in chronic pain patients."

 

[Kyla]

This seems like it would line up with the effect of LDN for fibro?

 

[Marco]

This seems like it would line up with the effect of LDN for fibro?

That's Jared Younger's working hypothesis I believe.

 

[voner]

this is an open access paper.

here is a quote from the discussion section of the paper

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.

i'm waiting to see what the comments are from other researchers in the field. I could not find any, yet.

 

[Marco]

On a related note, someone (many thanks) forwarded this paper to be which describes a mouse model of FMS/CFS in which chronic stress induces neuropathic pain via activated microglia in the spinal dorsal horn (paragraph breaks added).

A chronic fatigue syndrome model demonstrates mechanical allodynia and muscular hyperalgesia via spinal microglial activation.

Abstract

Patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS) display multiple symptoms, such as chronic widespread pain, fatigue, sleep disturbance, and cognitive dysfunction. Abnormal pain sensation may be the most serious of these symptoms; however, its pathophysiology remains unknown.

To provide insights into the molecular basis underlying abnormal pain in CFS and FMS, we used a multiple continuous stress (CS) model in rats, which were housed in a cage with a low level of water (1.5 cm in depth). The von Frey and Randall-Seritto tests were used to evaluate pain levels.

Results showed that mechanical allodynia at plantar skin and mechanical hyperalgesia at the anterior tibialis (i.e., muscle pain) were induced by CS loading. Moreover, no signs of inflammation and injury incidents were observed in both the plantar skin and leg muscles. However, microglial accumulation and activation were observed in L4-L6 dorsal horn of CS rats.

Quantification analysis revealed a higher accumulation of microglia in the medial part of Layers I-IV of the dorsal horn.

To evaluate an implication of microglia in pain, minocycline was intrathecally administrated (via an osmotic pump). Minocycline significantly attenuated CS-induced mechanical hyperalgesia and allodynia.

These results indicated that activated microglia were involved in the development of abnormal pain in CS animals, suggesting that the pain observed in CFS and FMS patients may be partly caused by a mechanism in which microglial activation is involved.

http://www.ncbi.nlm.nih.gov/pubmed/24852223

Whether or not chronic neuropathic pain is an adequate model model for 'CFS' or that chronic stress is a relevant 'stressor' is debateable. It's also interesting that microglial activation in specific spinal regions may have been in response to behavioural changes (increased rearing on the hind legs leading to increased muscle tone/strain.

Dopamine attenuation is also implicated :

Establishing animal models with the full list of symptoms of CFS and FMS is actually impossible. However, the
model used in the present study demonstrated some symptoms, such as sleep and endocrine system disorders (Ogawa et al., 2009, 2012), as well as abnormal pain (in this study).

Interestingly, all these disorders have been shown to originate from CNS dysfunctions, such as hypothalamic dopaminergic attenuation (Konishi et al., 2010; Ogawa et al., 2012), and activation of spinal microglia (results from this study).