The role of TRP ion channels in migraine and headache.

Migraine afflicts more than 10% of the general population. Although its mechanism is poorly understood, recent preclinical and clinical evidence has identified calcitonin gene related peptide (CGRP) as a major mediator of migraine pain. CGRP, which is predominantly expressed in a subset of primary sensory neurons, including trigeminal afferents, when released from peripheral terminals of nociceptors, elicits arteriolar vasodilation and mechanical allodynia, a hallmark of migraine attack. Transient receptor potential (TRP) channels include several cationic channels with pleiotropic functions and ubiquitous distribution in various cells and tissues. Some members of the TRP channel family, such as the ankyrin 1 (TRPA1), vanilloid 1 and 4 (TRPV1 and TRPV4, respectively), and TRPM3, are abundantly expressed in primary sensory neurons and are recognized as sensors of chemical-, heat- and mechanical-induced pain, and play a primary role in several models of pain diseases, including inflammatory, neuropathic cancer pain, and migraine pain. In addition, TRP channel stimulation results in CGRP release, which can be activated or sensitized by various endogenous and exogenous stimuli, some of which have been proven to trigger or worsen migraine attacks. Moreover, some antimigraine medications seem to act through TRPA1 antagonism. Here we review the preclinical and clinical evidence that highlights the role of TRP channels, and mainly TRPA1, in migraine pathophysiology and may be proposed as new targets for its treatment.

Migraine-provoking substances evoke periorbital allodynia in mice.

BACKGROUND: Administration of endogenous mediators or exogenous chemicals in migraine patients provoke early headaches and delayed migraine-like attacks. Although migraine provoking substances are normally vasodilators, dilation of arterial vessels does not seem to be the sole contributing factor, and the underlying mechanisms of the delayed migraine pain are mostly unknown. Sustained mechanical allodynia is a common response associated with the local administration of various proalgesic substances in experimental animals and humans. Here, we investigated the ability of a series of endogenous mediators which provoke or do not provoke migraine in patients, to cause or not cause mechanical allodynia upon their injection in the mouse periorbital area. METHODS: Mechanical allodynia was assessed with the von Frey filament assay. Stimuli were given by subcutaneous injection in the periorbital area of C57BL/6J mice; antagonists were administered by local and systemic injections. RESULTS: Calcitonin gene related peptide (CGRP), but not adrenomedullin and amylin, pituitary adenylyl cyclase activating peptide (PACAP), but not vasoactive intestinal polypeptide (VIP), histamine, prostaglandin E2 (PGE2) and prostacyclin (PGI2), but not PGF2α, evoked a dose-dependent periorbital mechanical allodynia. The painful responses were attenuated by systemic or local (periorbital) administration of antagonists for CGRP (CLR/RAMP1), PACAP (PAC-1), histamine H1, PGE2 (EP4), and PGI2 (IP) receptors, respectively. CONCLUSIONS: The correspondence between substances that provoke (CGRP; PACAP, histamine, PGE2, PGI2), or do not provoke (VIP and PGF2α), migraine-like attacks in patients and periorbital allodynia in mice suggests that the study of allodynia in mice may provide information on the proalgesic mechanisms of migraine-provoking agents in humans. Results underline the ability of migraine-provoking substances to initiate mechanical allodynia by acting on peripheral terminals of trigeminal afferents.

Development and validation of the ID-EC - the ITALIAN version of the identify chronic migraine.

BACKGROUND: Case-finding tools, such as the Identify Chronic Migraine (ID-CM) questionnaire, can improve detection of CM and alleviate its significant societal burden. We aimed to develop and validate the Italian version of the ID-CM (ID-EC) in paper and as a smart app version in a headache clinic-based setting. METHODS: The study investigators translated and adapted to the Italian language the original ID-CM questionnaire (ID-EC) and further implemented it as a smart app. The ID-EC was tested in its paper and electronic version in consecutive patients referring to 9 Italian tertiary headache centers for their first in-person visit. The scoring algorithm of the ID-EC paper version was applied by the study investigators (case-finding) and by patients (self-diagnosis), while the smart app provided to patients automatically the diagnosis. Diagnostic accuracy of the ID-EC was assessed by matching the questionnaire results with the interview-based diagnoses performed by the headache specialists during the visit according to the criteria of International Classification of Headache Disorders, III edition, beta version. RESULTS: We enrolled 531 patients in the test of the paper version of ID-EC and 427 in the validation study of the smart app. According to the clinical diagnosis 209 patients had CM in the paper version study and 202 had CM in the smart app study. 79.5% of patients returned valid paper questionnaires, while 100% of patients returned valid and complete smart app questionnaires. The paper questionnaire had a 81.5% sensitivity and a 81.1% specificity for case-finding and a 30.7% sensitivity and 90.7% specificity for self-diagnosis, while the smart app had a 64.9% sensitivity and 90.2% specificity. CONCLUSIONS: Our data suggest that the ID-EC, developed and validated in tertiary headache centers, is a valid case-finding tool for CM, with sensitivity and specificity values above 80% in paper form, while the ID-EC smart app is more useful to exclude CM diagnosis in case of a negative result. Further studies are warranted to assess the diagnostic accuracy of the ID-EC in general practice and population-based settings.

Transient receptor potential channels as novel drug targets in respiratory diseases.

A subpopulation of nociceptive primary sensory neurons expresses six different transient receptor potential (TRP) ion channels of the vanilloid (V1, V2, V3 and V4), melastatin (M8) and ankyrin (A1) subtypes. TRPV1 mediates the tussive action of capsaicin, which is widely used in cough provocation studies. The upregulation of TRPV1 expression and function has been reported in asthma and other inflammatory conditions. TRPA1 is targeted by a series of byproducts of oxidative and nitrative stress, including acrolein, 4-hydroxy-2-nonenal and hydrogen peroxide. Proinflammatory neuropeptides are released from nociceptive nerve terminals after TRPV1/TRPA1 stimulation, thereby causing airway neurogenic inflammation. In addition, the early inflammatory response to cigarette smoke is mediated entirely by neuronal TRPA1. TRPV1 and TRPA1 antagonists may therefore represent potential antitussive and anti-inflammatory therapeutics for respiratory airway diseases.

Continuing follow-up of malignant hypertension.

The history of accelerated (malignant) hypertension is reviewed, and unsolved problems related to the disease are illustrated, including its relationship to malignant nephrosclerosis, as well as terminology, current frequency and treatment. Over the past 25 years, out of a series of 131 patients, 53 were classified as suffering from essential malignant hypertension, the only suitable model on which the effects of pharmacological treatment on the disease can correctly be evaluated. In 2000, there were 24 survivors in our series and the maximum follow-up was 290 months. Multiple daily B.P. self-measurements allowed us to establish that pharmacological treatment was only able to approximate, to a varying degree, the conventional threshold of 140/90. Yet, despite this incomplete control over blood pressure levels, renal function was maintained in those patients whose initial creatininemia levels had not been higher than 2 mg/L. The renal protection effect of treatment was preserved even in patients who relapsed intoaccelerated disease phase one or more times over the study period.