Analgesic strategies beyond the inhibition of cyclooxygenases.
Blocking the formation of prostaglandins with cyclooxygenase (COX) inhibitors has been the treatment of choice for inflammatory pain for more than a century. Although these agents provide profound pain relief, their long-term use is hampered by severe side-effects, mainly ulceration of the upper gastrointestinal tract. The development of COX-2-selective inhibitors ("coxibs") has significantly reduced gastrointestinal toxicity, but evidence from controlled clinical trials and experimental studies indicates that the use of coxibs has a significant cardiovascular risk. Recently, signalling elements downstream of COX-2 inhibition have been identified, which offer a great diversity of possible targets. This review focuses on prostaglandin E synthases, prostaglandin receptors and downstream effectors of prostaglandins in the PNS and CNS, including transient receptor potential channels, tetrodotoxin-resistant Na(+) channels and inhibitory glycine receptors. These novel targets should enable inflammatory pain to be treated with improved specificity and, possibly, fewer side-effects.
Zeilhofer
Hanns Ulrich
HU
Institute of Pharmacology and Toxicology, University of Zürich, and Institute of Pharmaceutical Sciences, ETH Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. zeilhofer@pharma.unizh.ch
Brune
Kay
K
D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000502:physiology; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D000071876:Prostaglandin-E Synthases; D018078:Receptors, Prostaglandin E / Q000502:physiology; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype
D016861:Cyclooxygenase Inhibitors; C545635:PTGER1 protein, human; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone