Migraine is a chronic neurological disorder characterized by recurrent episodes of severe unilateral throbbing head pain and associated symptoms, such as photophobia. Our current understanding of the mechanisms underlying migraine has been hampered by limitations in ascertaining migraine symptoms in animal models. Clinical studies have established the neuropeptide calcitonin gene-related peptide (CGRP) as a key player in migraine. Here, we establish a genetic model of photophobia by engineering increased sensitivity to CGRP in mice. These transgenic mice (nestin/hRAMP1) display light-aversive behavior that is greatly enhanced by intracerebroventricular injection of CGRP and blocked by coadministration of the CGRP receptor antagonist olcegepant. This behavior appears to be an indicator of photophobia and cannot be fully explained by gross abnormality of ocular anatomy or differences in general anxiety or motor activity. Our findings demonstrate that a single gene, receptor activity-modifying protein 1 (RAMP1), can be a modifier of photophobia and, by extension, suggest that genetic or epigenetic modulation of RAMP1 levels may contribute to migraine susceptibility. Moreover, they validate CGRP hypersensitive mice as a tool for exploring the neurobiology and novel therapies for migraine and other disorders involving photophobia.

The neuropeptide CGRP plays a critical role in the pathophysiology of migraine. We have focused on the role of CGRP in photophobia, which is a common migraine symptom. We previously used an operant-based assay to show that CGRP-sensitized transgenic (nestin/hRAMP1), but not control, mice exhibited light aversion in response to an intracerebroventricular CGRP injection. A key question was whether the transgenic phenotype was due to over-expression of the CGRP receptor at endogenous or novel expression sites. We reasoned that if endogenous receptor sites were sufficient for light aversive behavior, then wildtype mice should also show the phenotype when given a sufficiently strong stimulus. In this study, we report that mice with normal levels of endogenous CGRP receptors demonstrate light avoidance following CGRP administration. This phenotype required the combination of two factors: higher light intensity and habituation to the testing chamber. Control tests confirmed that light aversion was dependent on coincident exposure to CGRP and light and cannot be fully explained by increased anxiety. Furthermore, CGRP reduced locomotion only in the dark, not in the light. Co-administration of rizatriptan, a 5HT1B/D agonist anti-migraine drug, attenuated the effects of exogenous CGRP on light aversion and motility. This suggests that triptans can act by mechanisms that are distinct from inhibition of CGRP release. Thus, we demonstrate that activation of endogenous CGRP receptors is sufficient to elicit light aversion in mice, which can be modulated by a drug commonly used to treat migraine.

Objectives.-To examine the prevalence of childhood maltreatment and adult revictimization in migraineurs and the association with sociodemographic factors, depression and anxiety.Background.-Population and practice-based studies have demonstrated an association of childhood abuse and headache in adults, although further details on headache diagnoses, characteristics, and comorbid conditions are lacking. There are mounting data suggesting substantial impact of early maltreatment on adult physical and mental health.Methods.-Electronic surveys were completed by patients seeking treatment in 11 headache centers across the United States and Canada. Physicians determined the primary headache diagnoses based on the International Classification of Headache Disorders-2 criteria and average monthly headache frequency. Self-reported information on demographics (including body mass index), social history, and physician-diagnosed depression and anxiety was collected. The survey also included validated screening measures for current depression (Patient Health Questionnaire-9) and anxiety (The Beck Anxiety Inventory). History and severity of childhood (<18 years) abuse (sexual, emotional, and physical) and neglect (emotional and physical) was gathered using the Childhood Trauma Questionnaire. There were also queries regarding adult physical and sexual abuse, including age of occurrence. Analysis includes all persons with migraine with aura, and migraine without aura.Results.-A total of 1348 migraineurs (88% women) were included (mean age 41 years). Diagnosis of migraine with aura was recorded in 40% and chronic headache (Ն15 days/month) was reported by 34%. The prevalence of childhood maltreatment types was as follows: physical abuse 21%, sexual abuse 25%, emotional abuse 38%, physical neglect 22%, and emotional neglect 38%. Nine percent reported all 3 categories of childhood abuse (physical, sexual, and emotional) and 17% reported both physical and emotional neglect. Overlap between maltreatment types ranged between 40% and 81%. Of those reporting childhood abuse, 43% reported abuse in adulthood, but infrequently (17%) over the age of 30 years. In logistic regression models adjusted for sociodemographic variables, current depression was associated with physical (P = .003), sexual (P = .007), and emotional abuse (P < .001), and physical and emotional neglect (P = .001 for both). Current anxiety was also associated with all childhood abuse and neglect categories (P < .001 for all). A graded relationship was observed between the number of childhood maltreatment types and remote or current depression and anxiety. In adjusted logistic regression analysis, migraineurs reporting 3 or more categories of childhood trauma were more likely to have received diagnoses of both depression From the University of Toledo, Toledo, OH, USA

SUMMARY Migraine is a complex neurological disorder with a significant impact on patients and society. Clinical and preclinical studies have established the neuropeptide calcitonin gene-related peptide (CGRP) as a key player in migraine and other neurovascular headaches. To study the role of CGRP in these disorders, we have characterized the photophobic phenotype of nestin/hRAMP1 mice, a transgenic model with genetically engineered increased sensitivity to CGRP. These mice have increased nervous system expression of a regulatory subunit of the CGRP receptor, human receptor activity-modifying receptor (hRAMP1). We have previously demonstrated that nestin/hRAMP1 mice display a light aversive behavior that is greatly enhanced by CGRP and blocked by a CGRP receptor antagonist used to treat migraine. Here we have compared their behavior in two different experimental setups with testing chambers of different sizes and light intensities as well as in complete darkness. We demonstrated similar degrees of light aversion in nestin/hRAMP1 mice with 1000 and 50 lux. To control for other possible factors driving nestin/hRAMP1 mice to the dark zone, we tested them in the absence of any light and they showed identical behavior as littermates. Furthermore, both nestin/hRAMP1 and control mice have decreased motility in response to CGRP in the dark, but not the light side of the chamber. Our findings confirm the robust CGRP-induced light aversive phenotype of nestin/hRAMP1 mice, which can be a surrogate of photophobia, and validates its usefulness as a model of migraine and other disorders associated with photophobia.

Symptoms of CA in migraine were associated with current anxiety, depression, and several chronic pain conditions. A graded relationship was observed between number of allodynic symptoms and the number of pain conditions, even after adjusting for confounding factors. This study also presents the novel association of CA symptoms with younger age of migraine onset, and with cigarette smoking, in addition to confirming several previously reported findings.