Handbook of experimental pharmacology
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Neuropathic pain syndromes, i.e., pain after a lesion or disease of the peripheral or central nervous system, are clinically characterized by spontaneous pain (ongoing, paroxysms) and evoked types of pain (hyperalgesia, allodynia). A variety of distinct pathophysiological mechanisms in the peripheral and central nervous system operate in concert: In some patients the nerve lesion triggers molecular changes in nociceptive neurons that become abnormally sensitive and develop pathological spontaneous activity (upregulation of sodium channels and receptors, e.g., vanilloid TRPV1 receptors, menthol-sensitive TRPM8 receptors, or alpha-receptors). These phenomena may lead to spontaneous pain, shooting pain sensations, as well as heat hyperalgesia, cold hyperalgesia, and sympathetically maintained pain. ⋯ Therefore, a new hypothetical concept was proposed in which pain is analyzed on the basis of underlying mechanisms. The increased knowledge of pain-generating mechanisms and their translation into symptoms and signs may in the future allow a dissection of the mechanisms that operate in each patient. If a systematic clinical examination of the neuropathic pain patient and a precise phenotypic characterization is combined with a selection of drugs acting against those particular mechanisms, it should ultimately be possible to design optimal treatments for the individual patient.
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Adenosine (Ado) regulates diverse cellular functions in the lung through its local production, release, metabolism, and subsequent stimulation of G-protein-coupled P1 purinergic receptors. The A(2B) adenosine receptor (A(2B)AR) is the predominant P1 purinergic receptor isoform expressed in surface airway epithelia, and Ado is an important regulator of airway surface liquid (ASL) volume through its activation of the cystic fibrosis transmembrane conductance regulator (CFTR). Through a delicate balance between sodium (Na(+)) absorption and chloride (Cl(-)) secretion, the ASL volume is optimized to promote ciliary activity and mucociliary clearance, effectively removing inhaled particulates. ⋯ Adenosine triphosphate (ATP) also regulates transepithelial Cl(-) conductance, but through a separate system that relies on stimulation of P2Y(2) purinergic receptors, mobilization of intracellular calcium, and activation of calcium-activated chloride channels (CaCCs). These pathways remain functional in CF, and may serve a protective role in the disease. In this chapter, we will review our current understanding of how Ado and related nucleotides regulate CFTR and Cl(-) conductance in the human airway, including the regulation of additional intracellular and extracellular signaling pathways that provide important links between ion transport and inflammation relevant to the disease.
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Pharmacotherapy can provide effective treatment of tobacco dependence and withdrawal, and thereby facilitate efforts to achieve and sustain tobacco abstinence. Currently approved medications for smoking cessation are nicotine replacement medications (NRT), including nicotine patch, gum, lozenge, sublingual tablet, inhaler and nasal spray, the antidepressant bupropion, and the nicotinic partial agonist varenicline. This review discusses the pharmacological basis for the use of these medications, and the properties that might contribute to their efficacy, safety, and abuse liability. The review also discusses how pharmacological principles can be used to improve existing medications, as well as assist in the development of new medications.
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Migraine is a neurovascular disorder which affects one fifth of the general population. Disability due to migraine is severe and involves patients from infancy through senescence and it is aggravated by the fact there is no complete cure. ⋯ These novel antagonists block the receptor for the sensory neuropeptide calcitonin gene-related peptide (CGRP), which upon release from peripheral terminals of trigeminal perivascular neurons dilates cranial arterial vessels. Whether neurogenic vasodilatation is the major contributing factor to generate the pain and the associated symptoms of the migraine attack or whether other sites of action of CGRP receptor antagonists are responsible for the antimigraine effect of these compounds is the subject of current and intense research.
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Handb Exp Pharmacol · Jan 2009
ReviewCough sensors. V. Pharmacological modulation of cough sensors.
Several airway afferent nerve subtypes have been implicated in coughing. These include bronchopulmonary C-fibers, rapidly adapting airway mechanoreceptors and touch-sensitive tracheal Adelta-fibers (also called cough receptors). ⋯ In this review we catalogue the chemical agents that stimulate and/or modulate the activity of the airway afferent nerves involved in cough, and describe the specific mechanisms involved in these effects. In addition, we describe the mechanisms of action of a number of chemical inhibitors of these afferent nerve subtypes, and attempt to relate this information to the regulation of coughing in health and disease.