Handbook of experimental pharmacology
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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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For more than a half century, tobacco manufacturers have conducted sophisticated internal research to evaluate nicotine delivery, and modified their products to ensure availability of nicotine to smokers and to optimize its effects. Tobacco has proven to be a particularly effective vehicle for nicotine, enabling manipulation of smoke chemistry and of mechanisms of delivery, and providing sensory cues that critically inform patterns of smoking behavior as well as reinforce the impact of nicotine. ⋯ A review of internal documents indicates important historical differences, as well as significant differences between commercial brands, underscoring the effectiveness of methods adopted by manufacturers to control nicotine dosing and target the needs of specific populations of smokers through commercial product development. Although the focus of the current review is on the manipulation of nicotine dosing characteristics, the evidence indicates that product design facilitates tobacco addiction through diverse addiction-potentiating mechanisms.
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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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The prevalence of people suffering from chronic pain is extremely high and pain affects millions of people worldwide. As such, persistent pain represents a major health problem and an unmet clinical need. The reason for the high incidence of chronic pain patients is in a large part due to a paucity of effective pain control. ⋯ However, there is considerable hope for the development of new classes of analgesic drugs by targeting novel processes contributing to clinically relevant pain. In this chapter we highlight a number of molecular species which are potential therapeutic targets for future neuropathic pain treatments. In particular, the roles of voltage-gated ion channels, neuroinflammation, protein kinases and neurotrophins are discussed in relation to the generation of neuropathic pain and how by targeting these molecules it may be possible to provide better pain control than is currently available.
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Handb Exp Pharmacol · Jan 2009
ReviewThe pharmacology of voltage-gated sodium channels in sensory neurones.
Voltage-gated sodium channels (VGSCs) are vital for the normal functioning of most excitable cells. At least nine distinct functional subtypes of VGSCs are recognized, corresponding to nine genes for their pore-forming alpha-subunits. These have different developmental expression patterns, different tissue distributions in the adult and are differentially regulated at the cellular level by receptor-coupled cell signalling systems. ⋯ We discuss in detail how drugs and toxins interact with archetypal VGSCs and where possible consider how they act on VGSCs in peripheral sensory neurones. Increasingly, drugs that block VGSCs are being used as systemic analgesic agents in chronic pain syndromes, but the full potential for VGSC blockers in this indication is yet to be realized and other applications in sensory dysfunction are also possible. Drugs targeting VGSC subtypes in sensory neurones are likely to provide novel systemic analgesics that are tissue-specific and perhaps even disease-specific, providing much-needed novel therapeutic approaches for the relief of chronic pain.