Raising Money for
Migraine Research

2009 MRF Research Grantee
FINAL REPORT: Why Opioids Enhance Migraine Pain: The Puzzle Points to Glia
Summary
Opioid pharmacotherapies are often used to treat migraine pain, and while these therapies may be effective in the short term, they become less so with repeated administration. We have previously shown that morphine activates spinal cord glia (non-neuronal cells), and the experiments here were designed to test if morphine- activated-glia in the nucleus caudalis of the trigeminal complex creates a vulnerability.
Using our animal model of migraine, we tested this hypothesis and determined vulnerability by degree of facial allodynia (when a previously non-painful touch is now painful). Facial allodynia was the focus here as it represents a critical point in migraine development. When the migraine is treated prior to facial allodynia, standard migraine medications are often successful; when the treatment is administered after the development of facial allodynia, migraine therapies generally fail. Prior treatment with morphine did indeed increase migraine vulnerability. To test if this morphine-induced vulnerability to rat migraine was dependent on glial activity, morphine was co-administered with a glial inhibitor. This injection paradigm suppressed the morphine-induced vulnerability thereby preventing the later development of facial allodynia. The behavioral data support that morphine activates glia, priming the microenvironment to be more responsive to a future challenge. We are currently performing studies to further characterize these effects.
The behavioral data collected in this experiment led to the development of a clinically relevant headache model for medication overuse headache (MOH), a common phenomenon with little understanding of the underlying mechanisms. MOH is a headache induced in patients by the over-use of medications such as opioids to treat migraine. It is noteworthy that MOH does not develop de novo with treatment of pain conditions other than headache.
Our behavioral data were collected when morphine was administered shortly after surgery. Because MOH does not develop except during headache treatment, we tested if the enhancement we initially observed was due to the administration of morphine just a few days post-surgery. Indeed, when we tested 10 days post-surgery, the morphine did not create the enhanced responsiveness to low dose inflammatory mediators. Next we tested if, at 10 days post-surgery, supradural inflammatory mediators, at a dose known to induce facial allodynia, followed by morphine created the vulnerability previously observed when morphine was given just a few days after surgery. The low dose of supradural inflammatory mediators reliably induced facial allodynia.
Taken together, these data suggest that morphine increases the effectiveness of the biochemical environment that creates enhanced pain states.
Hypothesis v. Findings
Our hypothesis that prior exposure to morphine creates a vulnerability to allodynia induction by subsequent supradural immune challenge was validated, as was the hypothesis that this vulnerability is dependent on glial activity as supported by a blockade of this morphine-induced vulnerability by the co-administration of a glial activation inhibitor.
Unanswered Questions
A key question left unanswered centers around the fact that the mechanisms underlying morphine-induced vulnerability remain unknown. Further, it remains unknown how the glial activation inhibitor was able to prevent morphine-induced vulnerability. Given the wide use of morphine and other opioids in the treatment of migraine, and the general issues surrounding medication overuse headache, undertaking studies to understand these questions would be very important.
What This Research Means To You
We have identified a potential mechanism underlying opioid-induced medication overuse headaches, providing a novel target for the development of pharmacotherapies to be administered with headache treatment.