Raising Money for
2011 MRF Research Grantee
FINAL REPORT: Calcium Activated Chloride Channels as a Novel Target for the Treatment of Migraine
The long term goal of this proposal was to determine the molecular identity of the ion channels that underlie pain receptor sensitization and to block them as a first step in the development of a novel target for migraine treatment. While we were able to identify a number of genes differentially expressed in dural and temporalis muscle afferents, none of them appeared to encode a Chloride channel. However, we were able to identify the CaMKII isoform that appeared to be enriched in dural afferents. Interestingly, blocking CaMKII in dural afferents blocked the inflammatory mediator-induced depolarization as well as increased its excitability. These results suggest that it may not be the Chloride channel that is differentially expressed in dural afferents, but that the channel is differentially modulated, enabling this channel to drive long term changes in dural afferent excitability. Thus, while blocking the Chloride channel may still be an effective therapy for the treatment of migraine, the second messenger cascades underlying inflammatory mediators in general, and CaMKII in particular, may provide a novel target for the selective treatment of pain.
Hypothesis vs. Findings
Our results suggest our initial hypothesis was incorrect in that the Chloride channel we originally hypothesized as being unique to dural afferents, may be present in other subpopulations of nociceptive afferents where it also contributes to inflammatory pain. However, this channel appears to be uniquely regulated in dural afferents and we believe we have found at least one of the mechanisms, CaMKII, that contribute to the unique regulation of the channel.
It remains to be determined whether the Chloride channel responsible for the sensitization of dural afferents is ANO1/TMEM16A, the Ca2+ modulated Chloride channel described in other nociceptive afferents. Confirming this would justify moving forward with the identification of selective blockers for this channels as a novel pain therapeutic, while evidence against this would suggest that a novel Chloride channel is responsible for the pain of a migraine attack. This outcome would justify additional effort to identify the channel. It also remains to be determined whether CaMKII is directly responsible for the prolonged activation of the Chloride current in dural afferents. That is, if another molecule(s) is responsible for the Ca2+-independent activation of the channel, these may prove to be even more specific targets for the treatment of migraine.
What This Research Means to You
We have identified a novel mechanism that may account for the prolonged pain of a migraine attack and therefore may prove to be a therapeutic target for aborting a migraine.