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.