TY - JOUR

T1 - A unique inbred rat strain with sustained cephalic hypersensitivity as a model of chronic migraine-like pain

AU - Munro, Gordon

AU - Petersen, Steffen

AU - Jansen-Olesen, Inger

AU - Olesen, Jes

PY - 2018

Y1 - 2018

N2 - 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-HT1B/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.

AB - 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-HT1B/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.

KW - Animals

KW - Disease Models, Animal

KW - Drug Hypersensitivity/etiology

KW - Female

KW - Hyperalgesia/drug therapy

KW - Male

KW - Migraine Disorders/drug therapy

KW - Pain/drug therapy

KW - Rats

KW - Rats, Inbred Strains

KW - Rats, Sprague-Dawley

KW - Receptor, Serotonin, 5-HT1B/metabolism

KW - Serotonin 5-HT1 Receptor Agonists/pharmacology

KW - Trigeminal Nerve/drug effects

U2 - 10.1038/s41598-018-19901-1

DO - 10.1038/s41598-018-19901-1

M3 - Journal article

C2 - 29382888

VL - 8

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 1836

ER -