Introduction: The selective excitatory action of capsaicin followed by long-term chemoanalgesia due to an action on the 'capsaicin receptor' of C-polymodal nociceptors, cloned 15 years ago, opened up fascinating perspectives for a class of nociceptor blocking analgesics.
Areas covered: The TRPV1/capsaicin receptor is an integrative, chemoceptive, noxious heat-gated cation channel also gated by several endogenous ligands and sensitized by phosphorylation through intracellular cascades triggered from receptors of bradykinin, prostanoids, NGF and interactions with TRPA1. In this review, types of sensory receptors and unique mechanisms for blocking nociceptor action, e.g., 'pore dilation' intracellular acidosis and the long-term function-related mitochondrial swelling at the nerve terminals and sensory neurons are summarized. In humans the 8% capsaicin dermal patch is already in usage for nondiabetic neuropathic pain and two topical preparations of civamide have also been approved recently for cluster headache and osteoarthritis. Evidence for epidermal nerve terminal loss in humans after topical applications and misleading results on sensory neuron death evoked by TRPV1 agonism in animals are discussed.
Expert opinion: The unique 'multisteric' gating of TRPV1 channel which is opened and modulated in various conformational changes to natural stimuli differs from the operation of canonical ligand-gated channels and makes it suitable to initiate development of second generation of TRPV1 antagonists without on-target side effects of hyperthermia and risk of burn injury.