PET Scans Provide First Evidence for Glial Activation in Brain in Chronic Pain Patients

by Stephani Sutherland on 1/20/2015

In recent years, glial cells have emerged as critical players in establishing and maintaining chronic pain states following nerve injury and other conditions—in rodents. An extensive body of work in animals suggests that glial cells might represent viable targets for dampening chronic pain, but evidence of glial involvement in pain in humans has been scant. That has changed with a study from Marco Loggia and colleagues at Massachusetts General Hospital and Harvard Medical School in Boston, US, that shows evidence of glial cell activation in the brains of people with chronic low-back pain (LBP). The work, published January 12 in Brain, lends support to glia-directed approaches, both as imaging markers and as therapeutic targets in people.

Some researchers may breathe a sigh of relief at the new report, which indicates that glial involvement in pain pathology is not limited to animals. The failure of a clinical trial of propentofylline, an agent directed at reducing microglial activity, had cast doubt on some researchers’ conviction that glial cells are intimately involved in chronic pain pathology in humans (see PRF related news story). Two studies have shown evidence of glial activation in postmortem tissue from patients with chronic pain due to human immunodeficiency virus (HIV; Shih et al., 2012) and complex regional pain syndrome (CRPS; Del Valle et al., 2009). And Richard Banati and colleagues (Banati et al., 2001) used an earlier PET radioligand to show evidence of glial cell activation in the thalamus in people with limb denervation years after injury—mostly amputation accompanied by phantom limb pain.

In the new study, the research team used integrated positron emission tomography/magnetic resonance (PET/MR) imaging to visualize a radioligand, [¹¹C]PBR28, directed at translocator protein 18 kDa (TSPO), a marker of glial cell activation. The researchers compared [¹¹C]PBR28 binding in the brains of nine patients who had had LBP for at least two years to age- and sex-matched healthy control subjects. Importantly, the pairs were also matched for a polymorphism in the TSPO gene that affects [¹¹C]PBR28 binding affinity.

In side-by-side PET scans from pain patients and healthy subjects, it was clear to the eye who were patients and who were controls, Loggia told PRF. In every pair, the people with pain displayed dramatically more [¹¹C]PBR28 in the thalamus, the region of interest where Loggia initially focused. A comparison of labeling across other brain regions also revealed TSPO in the primary somatosensory and motor cortices of the pain patients. Those data hinted that chronic pain might activate glia in the cortex according to somatotopic organization, because the areas with high TSPO binding corresponded to regions that have been described in previous imaging studies as the sensorimotor representation of the low back and legs, where patients reported pain.

Whole-brain voxel-wise analysis of [11C]PBR28 binding shows median Standardized Uptake Values (SUVRs) map from healthy controls (n = 9) and patients with chronic LBP (n = 10). Matched-pairs tests revealed significantly higher TSPO levels in patients, in thalamus, pre- and postcentral gyri, and paracentral lobule. Image adapted from Loggia et al., 2014. Not for reuse without permission from Oxford University Press.

Banati, now at the University of Sydney, Australia, spoke with PRF. Importantly, he said, the new report confirms his early study’s central hypothesis: that long-lasting plasticity—in the form of glial activation—can manifest far from the initial lesion site, and specifically in the thalamus. That spread along neural circuits gives pain its “distributedness,” Banati told PRF, contributing to its phenomenal complexity.

Enigmatic protein

Curiously, pain patients who reported the highest pain levels had the lowest TSPO signal. Because TSPO expression is thought to indicate glial cell activation, the finding might seem counterintuitive, Loggia noted, but the observation is, in fact, supported by the literature. “Animal studies suggest that the role of TSPO in activated glia is actually to limit the glial response,” Loggia said. One recent study (Bae et al., 2014) found in mice that TSPO overexpression decreased proinflammatory mediators during neuroinflammation, whereas knockdown of the protein boosted proinflammatory activity. In a complementary study (Wei et al., 2013), intrathecal injection of a TSPO agonist alleviated neuropathic pain behaviors in rodents. According to these studies, Loggia said, “When there is a lot of TSPO, the proinflammatory glial response is kept under control, but low levels of TSPO lead to an exaggerated proinflammatory response.”

Marco Loggia

In line with that idea, Loggia found that pain patients with low TSPO had the highest levels of circulating pro-inflammatory cytokine interleukins 1β and 6 (IL1β, IL6).

The exact nature or function of TSPO remains highly questionable, however. “It is one of the oldest proteins we know of,” said Banati, who has been studying TSPO for over a decade. The mitochondrial membrane protein has variably been described as a peripheral benzodiazepine receptor (PBR), a translocator protein, and key to steroid production, but Banati said theories about TSPO are undergoing a “massive shift … the whole notion of what TSPO does is pretty much up in the air.” TSPO had been long assumed vital for life, but even that notion was thrown into question by a report from Banati last November that mice deficient for TSPO had no readily detectable phenotype (Banati et al., 2014).

The questions surrounding TSPO only emphasize the complex nature of glial activation. Researchers agree that the term falls short of describing the multifaceted changes that glial cells can undergo, and that the cells’ unactivated states are by no means passive. Further, TSPO labeling does not differentiate between microglia and astrocytes; both might participate in different phases of neuropathic pain pathology.

The new work highlights the need to understand the specifics of glial “activation” in human chronic pain conditions and how those processes might be targeted. How the work might one day translate to benefit people with chronic pain remains unclear, but one thing has emerged: although glial activities might not yet be understood, they do appear to happen in people with pain.

Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.

Image: Mean [¹¹C]PBR28 signal measured in patients with chronic low-back pain and overlaid onto a structural MRI of an actor simulating a pain expression. Credit: Marco Loggia.