Glial Cells—A New Target for Chronic Pain Treatment

OJAI, CA—Glial cells are promising targets for the treatment of chronic neuropathic pain, according to Linda R. Watkins, PhD. Suppressing glial cell activation, she believes, may pave the way for the development of new drugs, increase the efficacy of opioids, and reduce drug dependence and tolerance.

Research during the past two decades has shown that glial cells are important players in the creation and maintenance of pathologic pain states, and now perhaps in headache and trigeminal neuropathy as well. More recent work has demonstrated that glial cells dysregulate the actions of opioids such as morphine, a finding that has dramatic implications for the treatment of pain.

“The data clearly predict that targeting glial cells and their proinflammatory products will provide superior pain control,” said Dr. Watkins, at the Headache Cooperative of the Pacific’s 2009 Winter Colloquium. Glial cell activation has been demonstrated in every clinically relevant animal model study to date, including that of peripheral nerve injury, bone cancer, multiple sclerosis (MS), spinal cord injury, herniated disks, low back pain, and migraine, noted Dr. Watkins, Professor of Psychology and Neuroscience at the University of Colorado at Boulder. “Targeting the glial cells and their proinflammatory products doesn’t make a patient analgesic, and it doesn’t suppress all pain sensitivity. It simply returns the pain to normal. It removes the abnormal pain, which is a good thing. We don’t want the patients walking around oblivious to all pain…. If you block these proinflammatory cytokines, you return the pain patient to being normal.”

An animal model study, conducted in collaboration with Kirk Johnson, PhD, Vice President of Research and Development at Avigen, has shown that AV411 (ibudilast), a blood-brain permeable glial activation inhibitor, prevented and reversed chemotherapy-induced neuropathic pain. “What’s intriguing, based on data such as these, is that ibudilast has just been approved by the FDA to enter clinical trials in the US for neuropathic pain and for improving the clinical efficacy of opioids,” said Dr. Watkins. Other studies in her laboratory have found that ibudilast has reversed pain from spinal cord injury. “If you now target very specifically one avenue for glial modulation, you can see really remarkable findings,” she said.

Research currently under review for publication from the Watkins lab has found that intrathecal interleukin-10 gene therapy reversed chronic constriction injury–induced neuropathic pain for longer than three months. In addition, in a rat model of relapsing-remitting MS, interleukin-10 gene therapy reversed inflammation-induced paralysis. “If you suppress the glial activation, you go from half of the body paralyzed to a completely normal rat,” said Dr. Watkins. “So how is it that this gene therapy is working? As interleukin-10 spreads across the spinal cord, then all of the glial cells calm down and pain goes away. It is a very different approach than has been taken before for treating neuropathic pain.”

After glial cells become activated, they start to release a host of pain modulatory substances, explained Dr. Watkins. Glial cells also amplify pain signaling to the spinal cord and pain transmission to the brain. “So, once these cells are activated, the question becomes: What are the key things that are causing the problems?... We always thought it was because we were suppressing the activation of neurons. We may be controlling pain, in part, at least, by suppressing the activation of glial cells.”

Glia activation compromises the efficacy of opioids, as it opposes morphine and methadone analgesia. For example, rats given morphine experience analgesia and pain suppression, but over time as the morphine degrades, the analgesia goes away, said Dr. Watkins. “That’s logical,” she commented. “The twist is that morphine also activates glial cells to release interleukin-1, which opposes the pain suppression…. Getting glial cells out of the way makes morphine work ever so much better.” Chronic opioid use leads to even more agitation among glial cells, she added.

The effects of opioids on neurons and glial cells are radically different, as neuronal opioid receptors are stereoselective for opioid agonists and antagonists, while glial receptors are not stereoselective. “So we can now give morphine, and it will produce analgesia by acting on neurons,” said Dr. Watkins. “But if you get glial cells out of the way by giving them something like [+]naloxone, you should potentiate the analgesic effects of morphine…. This is important, because it predicts that we should be able to separate the actions of opioids on neurons from the actions of opioids on glial cells. So we can make opioids work better in the clinic by either structurally modifying opioids to prevent them from finding that glial receptor or create a long-lasting version of [+]naloxone that would block opioid action on glial cells and allow opioids to do their job on neurons to suppress pain.”

Opioids activate glial cells through a nonstereoselective receptor called toll-like receptor-4 (TLR4), said Dr. Watkins. TLR4 receptors are “not me, not right, not OK receptors,” she commented. TLR4 receptors identify bacteria, endotoxins, and viruses, along with endogenous danger signals. “Every clinically relevant class of opioids activates this receptor,” noted Dr. Watkins.

Hutchinson et al, in collaboration with Dr. Johnson, have shown that ibudilast blocks naloxone-precipitated chronic morphine withdrawal, suggesting that glial cells are involved in dependence and withdrawal. “[Glial cells] are also involved in drug reward, which can lead to drug craving, drug addiction, and drug abuse,” said Dr. Watkins. There is also evidence that minocycline suppresses morphine-induced respiratory depression.

In a model of facial chronic constriction injury, researchers showed that “if you block interleukin-1 by injecting it into the CSF near the trigeminal ganglion, all that pain goes away,” related Dr. Watkins. Also, the Watkins lab has found that a supradural inflammatory soup induced facial allodynia, as well as proinflammatory cytokines, in awake, behaving rats, which was then reversed by ibudilast. “The animals given the supradural inflammatory soup had a dramatic fall in their pain threshold,” said Dr. Watkins. “This is correlated with upregulation of cytokines, both within the ganglia and within the trigeminal nucleus itself…. Blocking glial cell activation completely reverses the facial allodynia, which is quite unique from sumatriptan, which did nothing to reverse the pain. Other data have shown that prior morphine administration amplified the efficacy of supradural inflammatory soup for producing facial allodynia.”

Blocking glial activation will make opioids work better, Dr. Watkins asserted. “You will have better analgesia,” she said. “You will have less tolerance. You will have less dependence. You will have less reward linked to drug seeking and drug addiction and less respiratory depression.

“These glial cells are becoming activated, not just by bacteria and viruses, but also by incoming sensory nerves and by pain transmission neurons, by every class of clinically relevant opioids. In response, they are producing a family of proinflammatory cytokines that then lead to a cascade of neuroexcitatory release, in turn, causing enhanced pain by a variety of mechanisms.”

Immunology plays a key role in the overall management of pain, emphasized Dr. Watkins. “It’s been way too many years that pain people have fervently ignored immunology, and immunologists have fervently ignored pain,” she said. In addition, glial cells “can create and maintain pain physiologically as a natural part of the sickness response. Pathologically, they can become activated in response to things like neuropathies, neurotrophic viruses, and pharmacologically by clinically relevant opioids. They are also now implicated in tolerance, dependence, withdrawal, drug reward, and respiratory depression. In every case, the proinflammatory cytokines are key. We believe that targeting glial cells and their proinflammatory products may be a novel approach to pain control and increase the clinical efficacy of drugs like opioids.”

NR