The following is Part 2 of a three-part series of selected presentations from the 2015 annual meeting of the Society for Neuroscience, held October 17-21, 2015, in Chicago, Illinois, US. Also see Part 1 and Part 3.
Nerve growth factor (NGF) is required for the development and health of sensory neurons, but it also plays a more nefarious role in establishing and maintaining chronic pain. In recent years, NGF has shown remarkable clinical promise as a target for analgesics, most notably for osteoarthritis. Research in animals presented at the 2015 annual meeting of the Society for Neuroscience showed that NGF might also be targeted to alleviate neuropathic pain, and that NGF is a pain-causing component of intervertebral discs and thus may contribute to low back pain.
In a collaboration between David Seminowicz, University of Maryland, Baltimore, US, and Marucia Chacur, University of Sao Paulo, Brazil, Joyce Teixeira, working at both institutions, investigated the role of NGF in the chronic constriction injury (CCI) model of neuropathic pain. Male rats received CCI surgery at the sciatic nerve and over two weeks developed the mechanical and thermal hypersensitivity typical of CCI. The researchers injected the animals in the affected hindpaw with an antibody directed against NGF. Mechanical hypersensitivity, measured by a pressure plate assay, was relieved over several hours after anti-NGF treatment. Cold allodynia, measured by behaviors such as licking and shaking the paw after acetic acid application, was also reduced by the treatment, but hypersensitivity to heat was not significantly changed. “Anti-NGF was able to reverse the often difficult-to-treat symptoms of this type of chronic pain pathology,” Teixeira said [during her presentation]. Immunostaining of dorsal root ganglia (DRG) showed that NGF levels were doubled in CCI animals compared to naïve or sham-operated rats two weeks after surgery, indicating that NGF contributes to maintain chronic neuropathic pain, Teixeira said.
In a separate experiment, the researchers investigated changes in the rodent brain in another neuropathic pain model. They performed functional magnetic resonance imaging (fMRI) on female rats over five months following spared nerve injury (SNI), which revealed an increase in resting functional connectivity between the periaqueductal gray (PAG) and the thalamus, the first two major brain processing centers in the pain pathway leading from the spinal cord and important contributors to descending pain modulation. The researchers plan to repeat that experiment in CCI rats with and without anti-NGF treatment to determine whether this approach could prevent or reverse such changes. The interesting question, Teixeira wrote to PRF in an email, is “can we change the brain with a peripheral treatment?” They hypothesize that NGF might indirectly influence brain regions related to pain by increasing production of other pain-related chemicals including substance P, calcitonin gene-related peptide (CGRP), and glutamate, which sensitize pain neurons.
Magali Millecamps and Laura Stone, McGill University, Montreal, Canada, used their SPARC-null mouse model of low back pain to investigate the role of NGF in intervertebral discs (see PRF related news). Mice that do not produce SPARC (secreted protein, acidic and rich in cysteine), an important component of the extracellular matrix, develop disc degeneration including dehydrated, compressed, bulging, and herniated discs, similar to degeneration associated with human low back pain. SPARC-null mice develop signs of axial pain—affecting the spine and trunk—which the researchers propose may stem from pathological ingrowth of nerves into the discs. SPARC-null mice also display radiating limb pain, which the researchers previously found was highly correlated with disc height—an indication that nerves might be subject to physical impingement. That finding suggests that physical impingement contributes to the pain, but they hypothesized that chemical irritants such as NGF might also contribute to it.
To test that theory, Millecamps first measured the level of NGF present in intervertebral discs. Normal mice had negligible levels of NGF in the discs, but SPARC-null mice discs contained about 300 picograms per milligram of disc by the age of 18 months. Elevated levels of NGF have also been found in diseased discs from human patients. Anti-NGF treatment in the mice at one year of age reduced signs of radiating and axial pain.
Next, the researchers turned to findings they had previously presented that axial and radiating pain were alleviated in SPARC-null mice given access to voluntary exercise. Wheel running also protected disc height and prevented disc dehydration in the mice. Could this exercise treatment exert its benefit by changing NGF levels? Millecamps measured NGF in the discs of exercising SPARC-null mice and found it was significantly lowered compared to sedentary SPARC-null mice. Because anti-NGF improved symptoms of axial and radiating pain, the authors concluded that NGF upregulation in discs might contribute to both types of pain.
Early clinical trials of antibodies directed at NGF for osteoarthritis pain showed the strategy was very effective, but concerns about joint destruction in patients spurred the U.S. Food and Drug Administration (FDA) to halt most trials of anti-NGF treatment in 2010 (see PRF related news). That hold was lifted in 2012 for trials of osteoarthritis and for other, intractable pain conditions for which no other treatments are available (see PRF related news here and here). “That permission opened the door to look at the mechanisms behind anti-NGF therapy for pain as well as brain changes after its use,” Teixeira wrote to PRF in an email. “Our aim is to provide a deeper understanding of the mechanisms involved in anti-NGF use as a new pharmacological treatment for chronic neuropathic pain.”
Concerns remain about the safety and promise of anti-NGF therapy (Bannwarth and Kostine, 2014). Still, Stone wrote to PRF in an email, “… anti-NGF is the most promising potential new treatment to come along in pain in a long, long time.” All drugs carry risks, she added, and “if you talk to individuals with severe pain refractory to current treatment, I think they would tolerate a lot of risk for some relief”—relief that Stone and others hope will come with future anti-NGF treatments.
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California.
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