A unique inbred rat strain with sustained cephalic hypersensitivity as a model of chronic migraine-like pain

Abstract

Animal models of migraine-like pain enabling ongoing study of behaviour typically involve the systemic administration of chemical vasodilators or dural administration of inflammatory algogens. However, neither method mediates prolonged effects on behavior indicative of enduring pathophysiological changes occurring within dural or trigeminal pain circuits. We generated successive generations of a unique inbred rat strain, spontaneous trigeminal allodynia (STA) rats, previously reported to exhibit an episodic migraine-like behavioural phenotype. We show that both male and female STA rats display robust and sustained reductions in periorbital thresholds to cutaneous mechanical stimulation. Otherwise, the general behavior (e.g. locomotor, grooming) of these rats appeared normal. In female STA rats, the mechanical hypersensitivity was confined to the cephalic region, manifested after puberty through adolescence, and was sustained into adulthood recapitulating the clinical manifestation of migraine. We exploited this hitherto unidentified chronic phenotype to show that the migraine-specific drugs sumatriptan (5-HT 1B/1D receptor agonist) and olcegepant (CGRP receptor antagonist) could completely reverse cephalic hypersensitivity using a within subject cross-over paradigm. Our findings indicate that STA rats actually possess a phenotype indicative of migraine chronicity which is exquisitely sensitive to migraine therapeutics. This unique strain could prove to be an invaluable resource in preclinical migraine drug discovery.Animal models of migraine-like pain enabling evaluation of disease-relevant behaviours, typically in mice or rats, are frequently induced by chemical provocation using systemic administration of vasodilating agents such as nitric oxide (NO) donors or dural application of inflammatory mediators 1-6 . These models have variously proven to be of some value in the preclinical setting but have their limitations 7 . Crucially, even with repeated dosing, the systemic administration of NO donors (e.g. glyceryl trinitrate; GTN or isosorbide dinitrate) in rodents has never been reported to produce sustainable cephalic or extracephalic hypersensitivity lasting longer than 1-2 weeks 2,8-10 , thereby limiting their utility in long term behavioural studies.The use of genetic models of migraine-like pain in animals might be expected to partially mitigate such issues. Familial Hemiplegic Migraine is a rare monogenic migraine subtype associated with aura, characterized by weakness on one side of the body during the aura phase 11 . To date, the involvement of three genes has been confirmed in this migraine subtype of which the humanized knock in CACNA1A-related R192Q mouse is probably the best studied 12 . These mice display increased unilateral head grooming and are photosensitive in accordance with a migraine-like phenotype. An advantage of using such models is that the animals possess a pre-defined phenotype, circumventing the need for complicated dosing protocols using NO donors or surgical procedures (e.g. dural ...

Enhanced post-traumatic headache-like behaviors and diminished contribution of peripheral CGRP in female rats following a mild closed head injury

“…The inconsistency between the effectiveness of anti-CGRP mAb treatment in this model and the changes in serum CGRP levels suggests that the latter may be a poor indicator of peripheral CGRP involvement in mediating a headache-like behavior. Our current finding that acute sumatriptan treatment was effective in reducing the cephalic hyperalgesic behavior in mCHI females, as previously reported in males (4), suggests that its therapeutic mode of action in this model may not involve alteration of the peripheral CGRP signaling cascade, and is likely to bypass the processes that are influenced by sex differences, as observed in other rodent models of persistent migraine-like cephalic pain hypersensitivity (36,40,41).…”

Anti‐migraine Calcitonin Gene–Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice

“…Control groups received the same volume of identical vehicle via the same route. The selected olcegepant doses were within the previously reported dose range (1μg/kg–30mg/kg) in experimental models in rodents 29,30,32–37 . In rats, 1mg/kg olcegepant, which we used herein, has yielded a peak plasma concentration of 0.8μM compared with peak plasma concentrations of approximately 0.15μM after a 10mg dose in clinical studies 34,38–41 .…”

“…Guided by previously published studies, 29–31 we obtained the drugs from commercial vendors (Tocris Bioscience, MedChemExpress), rather than the pharmaceutical companies that developed the clinical preparations, and relied upon the product data sheets and purity reports provided by these vendors, all of which are publicly available. Although we have picked the dose ranges from the existing literature, 29–38,42–45 as a caveat we have not measured the plasma or brain drug levels to inform us about the relevance of the dose–route combination used in our study to clinical dose–route combinations. However, as both antagonists we tested showed much higher potency in human compared with mouse vessels, lower plasma levels may be sufficient to observe the same effect on stroke outcomes in humans.…”

Animal models of migraine and experimental techniques used to examine trigeminal sensory processing

“…In addition to specific gene editing approaches, an inbred rat model of spontaneous trigeminal allodynia has been described that is responsive to acute and preventive migraine therapies [190]. This model has recently been further inbred to generate a sustained trigeminal hypersensitivity that is responsive to acute migraine therapies with potential implications for modelling chronic migraine [191].…”