Authors Jan L. Brozek, MD, PhD – Department of Clinical Epidemiology & Biostatistics and Medicine, McMaster University, Hamilton, Canada Jean Bousquet, MD, PhD – Service des Maladies Respiratoires, Hopital Arnaud de Villeneuve, Montpellier, France, INSERM, CESP U1018, Respiratory and Environmental Epidemiology Team, France, and WHO Collaborating Center for Rhinitis and Asthma Carlos E. Baena-Cagnani, MD – Faculty of Medicine, Catholic University of Cordoba, Cordoba, Argentina Sergio Bonini, MD – Institute of Neurobiology and Molecular Medicine – CNR, Rome, Italy and Department of Medicine, Second University of Naples, Naples, Italy G. Walter Canonica, MD – Allergy & Respiratory Diseases, DIMI, Department of Internal Medicine, University of Genoa, Genoa, Italy Thomas B. Casale, MD – Division of Allergy and Immunology, Department of Medicine, Creighton University, Omaha, Nebraska, USA Roy Gerth van Wijk, MD, PhD – Section of Allergology, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands Ken Ohta, MD, PhD – Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan Torsten Zuberbier, MD – Department of Dermatology and Allergy, Charite Universitatsmedizin Berlin, Berlin, Germany Holger J. Schunemann, MD, PhD, MSc – Department of Clinical Epidemiology & Biostatistics and Medicine, McMaster University, Hamilton, Canada

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Allergic Rhinitis and Its Impact on Asthma

Natural products afford a window of opportunity to study important biology. If the natural product is used or abused by human beings, finding its biological target(s) is all the more significant. Hot pepper is eaten on a daily basis by an estimated one-quarter of the world’s population and

Vanilloid (Capsaicin) Receptors and Mechanisms

A set of related medical disorders that lack a proper classification system and diagnostic criteria is like a society without laws. The result is incoherence at best, chaos at worst. For this reason, the International Classification of Headache Disorders (ICHD) is arguably the single most important breakthrough in headache medicine over the last 50 years. The ICHD identifies and categorizes more than a hundred different kinds of headache in a logical, hierarchal system. Even more important, it has provided explicit diagnostic criteria for all of the headache disorders listed. The ICHD quickly became universally accepted, and criticism of the classification has been minor relative to that directed at other disease classification systems. Over the 20 years following publication of the first edition of the ICHD, headache research has rapidly accelerated despite sparse allocation of resources to that effort. In summary, the ICHD has attained widespread acceptance at the international level and has substantially facilitated both clinical research and clinical care in the field of headache medicine.

International Classification of Headache Disorders

Capsaicin, a pungent ingredient of hot peppers, causes excitation of small sensory neurons, and thereby produces severe pain. A nonselective cation channel activated by capsaicin has been identified in sensory neurons and a cDNA encoding the channel has been cloned recently. However, an endogenous activator of the receptor has not yet been found. In this study, we show that several products of lipoxygenases directly activate the capsaicin-activated channel in isolated membrane patches of sensory neurons. Among them, 12- and 15-(S)-hydroperoxyeicosatetraenoic acids, 5- and 15-(S)-hydroxyeicosatetraenoic acids, and leukotriene B4 possessed the highest potency. The eicosanoids also activated the cloned capsaicin receptor (VR1) expressed in HEK cells. Prostaglandins and unsaturated fatty acids failed to activate the channel. These results suggest a novel signaling mechanism underlying the pain sensory transduction.

https://www.pnas.org/content/pnas/97/11/6155.full.pdf

Direct activation of capsaicin receptors by products of lipoxygenases: Endogenous capsaicin-like substances

Capsaicin-sensitive sensory neurons convey to the central nervous system signals (chemical and physical) arising from viscera and the skin which activate a variety of visceromotor and neuroendocrine reflexes integrated at various levels (intramurally in peripheral organs, at level of prevertebral ganglia, spinal and supraspinal level). Much evidence is now available that peripheral terminals of certain sensory neurons, widely distributed in skin and viscera have the ability to release, upon adequate stimulation, their transmitter content. In addition to the well-known "axon reflex" arrangement, the capsaicin-sensitive sensory neurons have the ability to release the stored transmitter also from the same terminal which is excited by the environmental stimulus. The efferent function of these sensory neurons is realized through the direct and indirect (i.e. mediated by activation of other cells) effects of released mediators. The action of released transmitters on postjunctional elements covers a wide range of effects which may have a physiological or pathological relevance. Development of drugs capable of controlling the sensory-efferent functions of the capsaicin-sensitive sensory neurons represent a new and very promising area of research for pharmacological treatment of various human diseases.

The sensory-efferent function of capsaicin-sensitive sensory neurons

Prophylactic and therapeutic properties of 1-methyl-lysergic acid butanolamide in migraine.

1. Topical application of capsaicin to the human nasal mucosa induced a burning sensation and sneezing. A dose-dependent seromucous nasal secretion was also observed. Capsaicin (75 micrograms) was more potent than methacholine (50 mg) in producing nasal secretion, while topical histamine (200 micrograms), substance P (135 micrograms) and calcitonin gene-related peptide (36 micrograms) did not induce rhinorrhea. 2. Pretreatment with either topical ipratropium bromide, systemic dexchlorpheniramine or indomethacin did not influence the effects induced by capsaicin. Topical pretreatment with lidocaine inhibited the painful sensation but failed to block the rhinorrhea. Desensitization to the effects of capsaicin occurred following 4-5 subsequent applications, and full recovery was observed within 30-40 days. 3. It is proposed that the effects of capsaicin in human nasal mucosa are due to excitation of primary afferent neurones that (a) convey burning and painful sensation, (b) evoke a sneezing reflex and (c) induce nasal secretion by releasing transmitter(s) from their peripheral terminals.

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Secretion, pain and sneezing induced by the application of capsaicin to the nasal mucosa in man.

A multicenter study was carried out in 10 Italian Headache Centers to investigate the prevalence of psychosocial stress and psychiatric disorders listed by the IHS classification as the "most likely causative factors" of tension-type headache (TTH). Two hundred and seventeen TTH adult outpatients consecutively recruited underwent a structured psychiatric interview (CIDI-c). The assessment of psychosocial stress events was carried out using an ad hoc questionnaire. The psychiatric disorders that we included in the three psychiatric items of the fourth digit of the IHS classification were depressive disorders for the item depression, anxiety disorders for the item anxiety, and somatoform disorders for the item headache as a delusion or an idea. Diagnoses were made according to DSM-III-R criteria. At least one psychosocial stress event or a psychiatric disorder was detected in 84.8% of the patients. Prevalence of psychiatric comorbidity was 52.5% for anxiety, 36.4% for depression, and 21.7% for headache as a delusion or an idea. Psychosocial stress was found in 29.5% of the patients and did not differ between patients with and without psychiatric comorbidity. Generalized anxiety disorder (83.3%) and dysthymia (45.6%) were the most frequent disorders within their respective psychiatric group. The high prevalence of psychiatric disorders observed in this wide sample of patients emphasizes the need for a systematic investigation of psychiatric comorbidity aimed at a more comprehensive and appropriate clinical management of TTH patients.

Psychiatric Comorbidity and Psychosocial Stress in Patients with Tension-Type Headache From Headache Centers in Italy

SYNOPSIS

Headache is the most common side effect of nitroglycerin, administered for angina pectoris. Two phases can be distinguished in nitroglycerin-induced headache: the first phase (immediate headache), a mild sensation of temporal pulsating pain, can be due, at least in part, to the vasodilation provoked by nitroglycerin; the second phase (delayed headache), an increasing pain, possibly with nausea and vomiting, lasting even for a number of hours, is independent from the vasomotility, since it arises and persists when all vasomotor and metabolic nitroglycerin-induced changes are over. The present investigation demonstrates that healthy subjects, neither suffering from idiopathic headache nor with a family headache history, never complain of delayed headache after nitroglycerin; healthy subjects not suffering from headache but who have one or both parents suffering from migraine, exhibit the delayed long-lasting headache in 28.6% of cases; finally, 66.7% of their migrainous parents complain of the delayed long-lasting headache after nitroglycerin. The following conclusions can be drawn: nitroglycerin-induced delayed headache 1) is not a true side effect of nitroglycerin, since it is never present in healthy subjects; 2) is peculiar to migraine sufferers: or 3) is an index of migraine predisposition, as it may be present in healthy subjects, but only if they have one or two migrainous parents. The features of nitroglycerin-induced delayed headache suggest an analogy with the phenomenon of overreaction, a painful and exaggerated response (in latency, intensity and duration) to a stimulus, that is the most typical aspect of central pain. In nitroglycerin-induced delayed headache, which shows close similarities to the spontaneous attack of migraine, the trigger stimulus could be the moderate immediate headache which is probably correlated with the vasodilation provoked by nitroglycerin.

Unmasking latent dysnociception in healthy subjects.

The pain relieving effect of somatostatin treatment during 72 attacks of cluster headache in 8 male patients was compared to treatment with ergotamine or placebo in a double-blind study. Infusion of somatostatin (25 μg/min for 20 min i.v.) reduced the maximal pain intensity and the duration of pain significantly compared to placebo treatment, and to a degree comparable to ergotamine tartrate treatment (250 μg i.m.). The results obtained provide new information concerning the possible mechanism of cluster headache attacks and suggest a new therapeutic approach.

Federigo Sicuteri

Papers

Prophylactic and therapeutic properties of 1-methyl-lysergic acid butanolamide in migraine.

Secretion, pain and sneezing induced by the application of capsaicin to the nasal mucosa in man.

Psychiatric Comorbidity and Psychosocial Stress in Patients with Tension-Type Headache From Headache Centers in Italy

Unmasking latent dysnociception in healthy subjects.

Pain relief by somatostatin in attacks of cluster headache.