Highlights From the 2014 Annual Scientific Meeting of the American Pain Society: Part 1

Recent conference featured diverse slate of talks on pain science and treatment

by Neil Andrews on 30 Jul 2014

Pain researchers and clinicians headed to Tampa, Florida, US, for the 33rd Annual Scientific Meeting of the American Pain Society (APS), held April 30-May 3, 2014. A wide range of plenary talks, symposia, award lectures, and poster sessions, delivered by leading experts in the pain field, generated great excitement about the latest directions in pain science and treatment. This two-part report summarizes selected presentations from the meeting. Part 1 is below; see Part 2.

Chronic low back pain: an integrated view

Is chronic low back pain (LBP) a disease of the spine, the connective tissue, or the brain? The consensus of a session on this common and often debilitating condition was that alterations in all three play important pathophysiological roles.

Laura Stone, McGill University, Montreal, Canada, focused on the spine, and the contribution of intervertebral disc degeneration to chronic LBP—disc or joint degeneration is present in 10 to 25 percent of patients with the condition. Animal models in which disc degeneration is induced by injury (e.g., with a needle into the disc) have been developed, but those models do not faithfully mimic the slow, progressive, and age-dependent disc degeneration observed in humans. To better model intervertebral disc degeneration in people, Stone uses mice missing the extracellular matrix protein SPARC (secreted protein, acidic and rich in cysteine). Decreased SPARC levels have been observed in people with disc degeneration (Gruber et al., 2004), and the SPARC-null mice show accelerated, age-dependent disc degeneration as well as behavioral signs of chronic back pain (Millecamps et al., 2011).

Previously, Stone’s group found that mice lacking SPARC exhibited signs of both low back and spine (axial) pain, as well as pain down one or both legs (radiating pain) (Millecamps et al., 2012). More recently, Stone and colleagues showed that SPARC-null mice have age-dependent increases in sensory nerve fiber innervation in and around the discs, compared to control animals (Miyagi et al., 2014). That finding suggests that pathological sensory innervation is one mechanism by which disc degeneration could lead to pain.

At the meeting, Stone presented unpublished data indicating that axial pain and radiating pain could have different underlying mechanisms in the SPARC-null mice. She showed that the degree of histologically assessed disc disruption correlated with axial pain, while reduced disc height was associated with radiating pain. Furthermore, the axial pain could be relieved with morphine, pregabalin, or ibuprofen, suggestive of a “mixed” pain phenotypic profile, whereas radiating pain responded only to pregabalin, indicative of a neuropathic pain profile. That is an important concept, since treatment approaches to chronic LBP, Stone said, should be mechanism based. Stone also reported that an anti-nerve growth factor (NGF) antibody reversed radiating pain, but not axial pain, in SPARC-null animals.

Finally, Stone and colleagues discovered that exercise (voluntary running on a plastic wheel) reversed radiating, but not axial, pain in the SPARC-null mice. The researchers also observed that exercise gave partial protection against disc pathology including loss of disc height, and against increased disc innervation. The findings suggest that exercise has beneficial effects on disc health, but Stone stressed that exercise also has beneficial effects on other tissues, including muscle, tendon, and brain, so the results should be interpreted with caution.

Helene Langevin, Harvard Medical School and Brigham and Women’s Hospital, Boston, US, and University of Vermont College of Medicine, Burlington, US, turned her attention to a new area of interest: the role of connective tissue as a potential pathophysiological contributor to chronic LBP.

Langevin’s previous work established that people with chronic LBP exhibit thicker connective tissue in and around the muscles of the low back compared to pain-free controls (Langevin et al., 2009). To understand the role of such connective tissue changes in chronic LBP, Langevin studies the thoracolumbar fascia (TF), a type of connective tissue that covers the muscles of the back of the trunk. TF consists of layers of dense connective tissue separated by layers of “loose” (termed areolar) connective tissue. It is this loose tissue that allows the dense layers to glide past one another. To examine whether alterations in TF layers contribute to chronic LBP, Langevin employs ultrasound imaging while subjects are placed on a motorized table that moves the trunk. Her research has shown that in control subjects, TF tissue layers move in opposite directions in a fluid, gliding manner, but in patients with chronic LBP, the layers do not exhibit as much gliding—rather, they look stuck together. Shear strain measurements indicated that shear strain within the TF was reduced in patients, compared to controls with no LBP, indicative of possible connective tissue pathology (Langevin et al., 2011).

To better understand the contribution of connective tissue alterations to chronic LBP, Langevin began to study the sensory innervation of that tissue in animals. In 2011, she and her colleagues documented for the first time the presence of calcitonin gene-related peptide (CGRP)-positive sensory nerve fiber endings in the connective tissue of the lower back in normal rats (Corey et al., 2011). Based on their small diameter, the neurons appeared to be Aδ and/or C fibers, suggesting that sensory innervation of connective tissue may contribute to pain perception in chronic LBP.

Could therapeutic interventions that target connective tissue improve chronic LBP? To address that question, Langevin’s group uses a model of connective tissue inflammation in the rat, specifically to study the effects of stretching; clinical trials of low back pain have shown that stretching can have therapeutic benefits, although the mechanisms underlying those beneficial effects have remained unclear. In the model, injection of carrageenan into subcutaneous connective tissue of the low back results in gait changes (such as decreased stride length) and increased mechanical sensitivity in the low back as assessed by von Frey testing (Corey et al., 2012). Langevin found that a stretch treatment that encourages the animals to stretch the full length of their bodies mitigated those alterations. The findings suggest that stretching has beneficial effects, but what about the converse? Does a lack of stretching have adverse consequences? Langevin is now addressing that question by using a pig model in which animals wearing a hobble to restrict back movement are subjected to a connective tissue injury. Early results suggest that movement restriction worsens connective tissue structure in the animals. Langevin is also using this model to study whether stretching can reverse the effects of movement restriction, and if so, what the right dose might be.

In the final talk of the session, David Seminowicz, University of Maryland School of Dentistry, Baltimore, US, reviewed several lines of evidence from imaging studies suggesting that chronic LBP is a disease that affects the brain. First, it has long been known that chronic LBP is associated with altered brain structure and function (Apkarian et al., 2004; Baliki et al., 2008; for a recent review of gray matter changes in chronic pain, see Davis and Moayedi, 2013).

Second, treatment can reverse such structural and functional changes. For example, Seminowicz previously showed that effective surgical treatment or facet joint injections in chronic LBP patients resulted in increased cortical thickness in the dorsolateral prefrontal cortex (DLPFC), which correlated with reductions in pain (Seminowicz et al., 2011). Treatment also normalized altered cognitive task-related DLPFC brain activity observed in the patients before treatment.

More recently, Seminowicz and colleagues showed that cognitive behavioral therapy (CBT) increased gray matter volume and density in a number of brain regions, including the DLPFC, in patients with chronic musculoskeletal pain, including six with LBP (Seminowicz et al., 2013; and see PRF related news story). The changes were associated with decreased pain and decreased pain catastrophizing, two of the goals of CBT. Finally, Seminowicz pointed to his unpublished data showing that surgical treatment or facet joint block in chronic LBP patients could normalize altered structural and functional connectivity in the insula, a brain region that is particularly important for processing emotional aspects of pain.

Finally, data from clinical studies of the transition from acute to chronic LBP also support the idea that chronic LBP affects the brain. A one-year study found that functional connectivity between the nucleus accumbens—a key mesolimbic brain structure—and the medial PFC predicted which patients with subacute back pain would go on to experience chronic back pain (Baliki et al, 2012). A follow-up study showed that in patients with acute or subacute LBP, brain activity representing back pain was limited to nociceptive regions that play a role in acute pain, while in those with chronic LBP (pain for over 10 years), that activity was limited to regions involved with emotional aspects of pain (Hashmi et al., 2013; and see PRF related news story).

Because chronic LBP affects sensory, cognitive, and emotional brain circuits, Seminowicz sees a future where pharmacotherapy and non-pharmacological approaches (including CBT, yoga and other exercise, meditation, hypnosis, and non-invasive brain stimulation) are used together to target those circuits. But the condition is not one that solely affects the brain, as the other talks in the session made clear. Chronic LBP, he thus concluded, is best viewed in an integrative fashion that considers the pathophysiology present not only in the brain, but also in the spine and connective tissue.

Headache pain: a role for dural fibroblasts

In a session on emerging concepts in headache research, Greg Dussor, University of Texas at Dallas, US, described his recently published work demonstrating a role for fibroblasts as important contributors to headache pathophysiology. Fibroblasts, which synthesize the extracellular matrix, are the main cell type in the meninges that surround the brain, but unlike other resident meningeal cells, such as mast cells and macrophages, they had not previously been linked to headache pain.

As one of the only pain-sensitive structures within the skull, it is thought that the meninges contribute to headache pain, but the exact mechanisms have remained unclear. In previous work, Dussor and colleagues showed that afferent nerves innervating the dura mater (the outermost layer of the meninges) express acid-sensing ion channels (ASICs) and are sensitive to pH (Yan et al., 2011). Upon stimulation of the dura mater with low pH, awake rats exhibited cutaneous (facial and hindpaw) allodynia, suggesting a role for low meningeal pH in migraine-related behaviors. Follow-up work implicated ASIC3 as the specific ASIC mediating the effect of low pH on dural afferent signaling (Yan et al., 2013).

Interestingly, immunostaining and PCR experiments revealed the expression of ASIC3 not only in nerve endings within the dura mater, but also in non-neuronal dural fibroblasts. In their most recent study (Wei et al., 2014), Dussor and colleagues discovered that conditioned media from lipopolysaccharide (LPS)-treated dura mater fibroblasts induced hyperexcitability of trigeminal neurons in vitro, as assessed by patch-clamp recordings. Next, using a model of migraine in rats, the investigators found that application of fibroblast conditioned media to the dura mater produced cutaneous allodynia in the animals, as indicated by a decrease in facial and paw withdrawal thresholds in response to tactile stimuli. Further experiments revealed that dural fibroblasts released interleukin-6 (IL-6) in response to LPS stimulation, suggesting a possible mediator of the fibroblast contribution to headache pain—previously, it had been shown that application of IL-6 to the dura mater in rats causes cutaneous allodynia (Yan et al., 2012), and that IL-6 is elevated during migraine attacks in people. Dussor also found that low pH and ATP promoted IL-6 release from dural fibroblasts, and that conditioned media from low pH- and ATP-treated cells produced allodynia.

Dural fibroblasts may respond to low pH and ATP by releasing pro-nociceptive mediators, but what is the source of those conditions within the meninges? Here, Dussor became interested in a possible role for stress and sympathetic efferent signaling—norepinephrine promotes IL-6 release from fibroblasts, and norepinephrine-conditioned media produces allodynia, which made Dussor curious about how such signaling may be involved. Sympathetic activity is known to release norepinephrine, ATP, and protons in the meninges, and when that happens those substances will activate receptors on fibroblasts. Dussor is now undertaking early studies to tie fibroblast activity directly to stress in vivo.

What other agents do fibroblasts release that could cause pain? To what other stimuli can fibroblasts respond? How do ASICs, as well as P2X and norepinephrine receptors (which fibroblasts also express), function to contribute to pain? And can fibroblast-mediated mechanisms be targeted for human headache therapeutics? These are some of the important questions, Dussor said, for future research to address.

For more, see Part 2.

Image credit: American Pain Society