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Developing “Migraneous” Rat Models to Evaluate the Efficacy of OMT on Various Migraine Biomarkers
Byrd, K. E. [1]
Gregory, C. [2]
Krishna, S. [1]
Xie, J. Y. [5]
Fleming, R. K. [13]

Journal: Journal of Osteopathic Medicine Date: 2019/12, 119(12):Pages: e63-e65. doi: Subito , type of study: animal experiment

Full text    (https://www.degruyter.com/document/doi/10.7556/jaoa.2019.128/html)

Keywords:

animal experiment [36]
biomechanics [55]
migraine [57]
OMT [2951]
osteopathic manipulative treatment [2973]

Abstract:

Statement of Significance: Migraine is a disabling disorder characterized by recurrent unilateral throbbing cephalic pain often associated with hypersensitivity to a variety of external stimuli including light and sound. Initiating events remain unknown, although the ultimate activation of the trigeminovascular system is considered to be essential for pain. Current pharmacologic treatments, both abortive and prophylactic, for migraine headache have been shown to be inadequate for many patients due to lack of efficacy or intolerable side effects. This brings the focus to providing noninvasive therapies such as osteopathic manipulative treatment (OMT) to reduce migraine frequency and intensity. Methods: Our first model examines the efficacy of OMT through the lens of the cephalic pain often experienced during migraines. We used adult female Sprague-Dawley rats to limit sex differences and reflect the gender susceptibilities in humans (female:male migraineurs ratio 2:1). Migraines were induced using a “double-hit” strategy starting with bilateral injections of Complete Freund Adjuvant (CFA, 10 ul/injection, 5 injections/side) to the trapezius muscle on D1. CFA produced mild inflammation. However, the periorbital tactile threshold remained normal. On D8, umbellulone (50 mM/50 ul), a migraine trigger from the “headache tree”, was introduced to awake rats via inhalation for 30 min at 2 L/min O2. Soft tissue technique (STT), an OMT commonly used to manage migraines, was adapted to this rat model and compared with sham treatments. STT was applied at the dorsal aspect of the neck for 2 min under isoflurane anesthesia at D2 and 4 postCFA. A final treatment was applied at D8 after umbellulone exposure. Periorbital tactile threshold was assessed prior to CFA administration and for 5 h following umbellulone using calibrated von Frey filaments (cut off 8 g). We are now working on a new behavioral testing method examining voluntary wheel-running activities for 5h following umbellulone inhalation using customized running-wheel cages in order to examine OMTs efficacy in migraneurs return to normal physical activities. Described procedures were in line with accepted IACUC protocol. Data Analysis: Prism was used for data analysis. Mean or median and SEM are reported. P<.05 was considered statistically significant. For the periorbital threshold, 2-way ANOVA post hoc Dunnett multiple comparison test was performed to compare OMT vs SHAM treatment on CFA-primed “migrainous” rats and CFA-primed rats that received the vehicle. Initial analysis revealed significant interaction among all groups [F(5,82)=2.953, P=.017]. Posthoc analysis revealed a significant difference in periorbital allodynia in 2-5h testing in groups who received OMT vs Groups who received the SHAM treatment with those receiving a sham treatment with the greatest mean difference occurring in hour 5 with a mean difference of 3.259 [CI95 (1.43, 5,09), P=<.0001) with an adjusted P value of .05 for all 5 hours. The percent change in voluntary running wheel data for both umbellulone and vehicle groups was analyzed using the Mann-Whitney Test. A Mann Whitney test indicated that the vehicle group (n=4) had greater levels of activity (Mdn=24.37) than the umbellulone group (n=4, Mdn =-61.43), U= 0, P=.014. Umbellulone group (n=4) had a mean drop in activity of -57.37±16.7%, while the vehicle group displayed a mean increase in the activity of 117.86±101.5%. Results: The results showed that umbellulone successfully induced cephalic allodynia at 2-5 h postdose selectively in CFA-primed rats, which was effectively mitigated by STT (P<.05 compared with the sham treatment). At this point in time, we have also been able to demonstrate a significant decrease (∼ 57%) in voluntary wheel-running activity in rats exposed to umbellulone with previous trapezial injections of CFA Conclusion: The data from the cephalic allodynia model imply that OMT may function as an effective treatment for the headache and neck pains experienced during migraines. The initial running wheel model demonstrates a drop in physical activities after undergoing our “double-hit“ strategy with Complete Freund Adjuvant and umbellulone. Our next step is to determine whether OMT could restore the physical activities in “migraineous” rats. We will attempt to do OMT in awake animals to eliminate the potential interference of the isoflourane. Further studies could further determine the optimal amount of OMT necessary to provide sufficient pain relief as well as OMT's effects on other biomarkers of migraine such as plasma CRGP levels.

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