Vanilloid Receptor TRPV1 Antagonists as the Next Generation of Painkillers. Are We Putting the Cart before the Horse?

摘要

A unique responsiveness to capsaicin (1), the irritant principle of hot peppers, is a functional signature of nociceptive neurons. The resulting transient excitation of sensitive pathways is followed by a long-lasting refractory state, traditionally referred to as desensitization, during which the neurons become unresponsive not only to subsequent capsaicin challenges but also to unrelated noxious stimuli such as heat and acids. A membrane recognition site for capsaicin was identified as the vanilloid receptor VR1, recently renamed as TRPV1 (transient receptor potential channel, vanilloid subfamily member 1). Desensitization to capsaicin has a clear therapeutic potential. In fact, capsaicin and its ultrapotent analogue resiniferatoxin (2a) have been tried on an empirical basis in diverse disease states ranging from chronic intractable pain through vasomotor rhinitis to the overactive bladder.1 These clinical trials have been reviewed extensively and will not be dealt with here. Instead, we focus on vanilloid receptor antagonists as an emerging class of novel, analgesic, antiinflammatory agents.