Ž . European Journal of Pharmacology 405 2000 113–129 www.elsevier.nlrlocaterejphar Excitatory non-adrenergic–non-cholinergic neuropeptides: key players in asthma Aletta D. Kraneveld a, ) , Deborah E. James b , Annick de Vries a , Frans P. Nijkamp a a Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht UniÕersity, PO Box 80082, 3508 TB Utrecht, Netherlands b Faculty of Pharmacy and Pharmaceutical Sciences, UniÕersity of Alberta, Edmonton, AB, Canada Accepted 28 June 2000 Abstract Professor David de Wied first introduced the term ‘neuropeptides’ at the end of 1971. Later peptide hormones and their fragments, Ž . endogenous opioid morphine-like peptides and a large number of other biogenic peptides became classified as neuropeptides. All of Ž these peptides are united by a number of common features including their origin nervous system and peptide-secreting cells found in . various organs such as skin, gut, lungs , biosynthesis, secretion, metabolism, and enormous effectiveness. Neuropeptides are biologically active at extremely low concentrations. The past decade, neuropeptide research has revealed that neuropeptides also participate strongly in immune reactions. The neuro-immune concept has opened up a whole new research area. In the last 20 years, significant advances have been made in investigations of the interaction between immune and nervous systems in chronic inflammatory diseases such as asthma. Ž . The goal of this review is to bring together the functional relevance of excitatory non-adrenergic–non-cholinergic NANC nerves and the interaction with the immune system in asthma. q 2000 Elsevier Science B.V. All rights reserved. Ž . Ž . Keywords: Asthma; NANC non-adrenergic–non-cholinergic nerve, excitatory; Neuropeptide; Animal model; Human 1. Introduction Bronchoconstriction, cough, mucus production and air- way hyperreactivity to bronchoconstrictor mediators are the main clinical manifestations of asthma and these fea- tures correlate well with the severity of the disease Ž . O’Byrne, 1988 . The exact mechanisms responsible for these effects are not fully elucidated. Airway inflammation and alterations in neuronal function are believed to play a role. Asthmatic patients are exquisitely sensitive to a num- ber of bronchoconstrictor agents. For example, bradykinin Ž Simonsson et al., 1973; Fuller et al., 1987; Polosa and . Ž Holgate, 1990 , sulfur dioxide Tan et al., 1982; Sheppard . Ž .Ž et al., 1980 , distilled water e.g. fog Anderson et al., . Ž . 1983 , adenosine Cushley et al., 1983, 1984 and cap- ) Corresponding author. Tel.: q 31-30-253-4509; fax: q 31-30-253- 7420. Ž . E-mail address: a.d.kraneveld@pharm.uu.nl A.D. Kraneveld . Ž . saicin Fuller et al., 1985 cause bronchoconstriction in asthmatic subjects, while modest or no effects have been found on respiratory function in healthy individuals. A common feature of these stimuli is that they can cause Ž . changes in lung function as a result of indirect stimula- tion of airway nerves. Human airways are innervated by efferent and afferent autonomic nerves which regulate many aspects of airway Ž . function Barnes, 1986a,b; Richardson, 1982 . Neuronal control of airways may be abnormal in asthmatic patients and neurogenic mechanisms contribute to the pathogenesis of asthma. The parasympathetic nervous system is the dominant neuronal pathway of airway smooth muscle tone. Stimulation of cholinergic nerves causes bronchoconstric- Ž tion, mucus secretion, and bronchial vasodilatation White, 1995; Lammers et al., 1989; Zaagsma et al., 1997; Barnes, . 1992; Minette and Barnes, 1988 . Recently, the evidence for cholinergic dysfunction in asthmatic patients is not Ž . convincing Van der Velden and Hulsmann, 1999 . Sym- pathetic nerves control bronchial blood vessels, but no innervation of human smooth muscle has been demon- 0014-2999r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. Ž . PII: S0014-2999 00 00546-X