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.”
—Colby Stong