Ana Recober

Role of Calcitonin Gene-Related Peptide in Light-Aversive Behavior: Implications for Migraine

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.

Childhood Maltreatment and Migraine (Part I). Prevalence and Adult Revictimization: A Multicenter Headache Clinic Survey

(Headache 2010;50:20‐31)

Allodynia in Migraine: Association With Comorbid Pain Conditions

Background.— Cutaneous allodynia (CA) in migraine is a clinical manifestation of central nervous system sensitization. Several chronic pain syndromes and mood disorders are comorbid with migraine. In this study we examine the relationship of migraine‐associated CA with these comorbid conditions. We also evaluate the association of CA with factors such as demographic profiles, migraine characteristics, and smoking status that may have an influence on the relationships of CA to pain and mood.

Childhood maltreatment and migraine (part III). Association with comorbid pain conditions.

(Headache 2010;50:42‐51)

Childhood maltreatment and migraine (part II). Emotional abuse as a risk factor for headache chronification

(Headache 2010;50:32‐41)

Calcitonin gene-related peptide: an update on the biology

Purpose of reviewThis review includes the most relevant and recent studies on the biology of calcitonin gene-related peptide (CGRP) as it pertains to primary headaches and particularly to migraine. Especial attention was given to those published within the last year. Recent findingsThe development of CGRP receptor antagonists is discussed in detail, as well as recent advances in our understanding of CGRP actions in migraine. Finally, other important functions of CGRP outside of the nervous system are briefly discussed. SummaryThe advent of CGRP receptor antagonists as a novel therapy for migraine attacks may represent a new era in the acute management of migraine. More than a simple addition to the currently available treatments, this group of drugs may become an outstanding option for patients with cardiovascular disease, given the lack of associated vasoconstriction. Furthermore, nonpeptide CGRP receptor antagonists, CGRP antibodies and CGRP-binding RNA-Spiegelmer are valuable research tools that will further advance our understanding of migraine pathophysiology.

History of childhood maltreatment is associated with comorbid depression in women with migraine

Background: A bidirectional relationship between migraine and depression suggests a neurobiological link. Adverse experiences, particularly childhood maltreatment, may alter neurobiological systems, and predispose to a multiplicity of adult chronic disorders. Our objective is to determine, within a headache clinic population of women, if depression moderates the abuse-migraine relationship. Methods: At six headache specialty clinics, women with migraine were diagnosed using ICHD-II criteria, and frequency was recorded. A questionnaire regarding maltreatment history, headache characteristics, current depression, and somatic symptoms was completed. Results: A total of 949 women with migraine completed the survey: 40% had chronic headache (≥15 headache days/month) and 72% had “very severe” headache-related disability. Major depression was recorded in 18%. Physical or sexual abuse was reported in 38%, and 12% reported both physical and sexual abuse in the past. Migraineurs with current major depression reported physical (p < 0.001) and sexual (p < 0.001) abuse in higher frequencies compared to those without depression. Women with major depression were more likely to report sexual abuse occurring before age 12 years (OR = 2.30, 95% CI: 1.14 to 4.77), and the relationship was stronger when abuse occurred both before and after age 12 years (OR = 5.08, 95% CI: 2.15 to 11.99). Women with major depression were also twice as likely to report multiple types of maltreatment (OR = 2.07, 95% CI: 1.27 to 3.35) compared to those without depression. Conclusions: Childhood maltreatment was more common in women with migraine and concomitant major depression than in those with migraine alone. The association of childhood sexual abuse with migraine and depression is amplified if abuse also occurs at a later age.

Induction of multiple photophobic behaviors in a transgenic mouse sensitized to CGRP

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.

Modulation of CGRP-induced light aversion in wild-type mice by a 5-HT(1B/D) agonist.

The neuropeptide calcitonin gene-related peptide (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 overexpression of the CGRP receptor at endogenous or novel expression sites. We reasoned that if endogenous receptor sites were sufficient for light-aversive behavior, then wild-type 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. Coadministration of rizatriptan, a 5-HT1B/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.

One-Day Behavioral Treatment for Patients with Comorbid Depression and Migraine: A Pilot Study

BACKGROUND Migraine is a common and disabling disorder that is highly comorbid with depression. The comorbidity of depression and migraine is a major health concern as it results in poorer prognosis and quality of life. Yet, effective treatments have rarely been investigated. METHOD 45 patients with comorbid migraine and depression were assigned to a 1-day Acceptance and Commitment Training plus Migraine Education workshop (ACT-ED; N = 31) or to Wait List/Treatment as Usual (WL/TAU; N = 14). Assessment of depressive symptoms, general functioning, and migraine related disability were completed at baseline and 2-, 6-, and 12 weeks after the workshop. RESULTS At the 3-month follow up, participants in the ACT-ED condition exhibited significantly greater improvements in depressive symptoms, general functioning, and migraine-related disability than patients in the WL/TAU group. CONCLUSION A 1-day ACT-ED workshop is a promising approach to the treatment for depression and disability in migraineurs that merits further investigation.