Figure 4. Mechanisms of topical capsaicin-mediated analgesia.

Repeat application of capsaicin or other vanilloid – like compounds can produce a number of local effects on TRPV1 – expressing nociceptor terminals: (A) Desensitization is a calcium-dependent phenomenon where application of capsaicin leads to a decrease in inward current response during continued capsaicin application. When capsaicin is applied at repeated intervals, each subsequent response becomes smaller and is often referred to as tachyphylaxis. It is proposed that under these conditions, TRPV1 may also be refractory to the effect of inflammatory mediators and intracellular secondary messengers. (B) Repeated or prolonged application of capsaicin can produce nociceptor dysfunction. Under this condition, which may be secondary to an influx and/or excess of store-released calcium, other pain transducing receptor – channels may be inactivated. This could explain analgesic effects that are beyond the scope of TRPV1 function. (C) Depletion of neuropeptides (Substance –P, CGRP) from nociceptive terminal is evoked by capsaicin and high dose or repeat applications have been shown to deplete both central and peripheral terminals. Although the activity of Substance –P has been show to play a key role in facilitating nociceptive neurotransmission in the dorsal horn of the spinal cord, blockade of the Substance –P receptor (NK1R) has failed to show analgesia in humans. (D) Destruction of TRPV1-expressing nociceptive terminals has been the most reliable marker correlating the application of vanilloid –like compounds and analgesia. Although a number of mechanisms have been proposed, vanilloid – induced apoptosis appears to be the likely mechanism.