The Mysteries of Capsaicin-Sensitive Afferents

Abstract

A fundamental subdivision of nociceptive sensory neurons is named after their unique sensitivity to capsaicin, the pungent ingredient in hot chili peppers: these are the capsaicin-sensitive afferents. The initial excitation by capsaicin of these neurons manifested as burning pain sensation is followed by a lasting refractory state, traditionally referred to as “capsaicin desensitization,” during which the previously excited neurons are unresponsive not only to capsaicin but a variety of unrelated stimuli including noxious heat. The long sought-after capsaicin receptor, now known as TRPV1 (transient receptor potential cation channel, subfamily V member 1), was cloned more than two decades ago. The substantial reduction of the inflammatory phenotype of Trpv1 knockout mice has spurred extensive efforts in the pharmaceutical industry to develop small molecule TRPV1 antagonists. However, adverse effects, most importantly hyperthermia and burn injuries, have so far prevented any compounds from progressing beyond Phase 2. There is increasing evidence that these limitations can be at least partially overcome by approaches outside of the mainstream pharmaceutical development, providing novel therapeutic options through TRPV1. Although ablation of the whole TRPV1-expressing nerve population by high dose capsaicin, or more selectively by intersectional genetics, has allowed researchers to investigate the functions of capsaicin-sensitive afferents in health and disease, several “mysteries” remain unsolved to date, including the molecular underpinnings of “capsaicin desensitization,” and the exact role these nerves play in thermoregulation and heat sensation. This review tries to shed some light on these capsaicin mechanisms.

CRISPR Deletion of a SVA Retrotransposon Demonstrates Function as a cis-Regulatory Element at the TRPV1/TRPV3 Intergenic Region

“…However, there have been difficulties translating advances identified in preclinical studies utilizing mouse models [ 36 ]. To our knowledge, to date, no regulatory domain contributing to the human specific expression of TRPV3 has yet been identified [ 37 , 38 ]. There are reports of TRPV1 and TRPV3 forming heteromeric channels in humans which are hypothesized to contribute to the fine tuning of sensory inputs, therefore the influence of the SVA and its role in TRPV1/TRPV3 regulation may have contributed to this molecular phenotype in human tissues and contributed to difficulties in developing drugs that are translatable based on mouse models [ 39 , 40 ].…”

TRPV1: Role in Skin and Skin Diseases and Potential Target for Improving Wound Healing

“…Additionally, sensitization or desensitization of the TRPV1 channel can be achieved through the modulator protein calmodulin (CaM) depending on where it is bound to TRPV1 [ 23 , 24 ] or phosphorylation ( Figure 2 b) [ 24 ] of the channel by protein kinase C (PKC) [ 25 ], protein kinase A (PKA) [ 26 ], or calcium calmodulin-dependent kinase II (CaMKII) [ 27 ]. Activators of TRPV1 include not only capsaicin, the compound isolated from chili peppers that is responsible for their burning sensation, and other vanilloids and endovanilloids, but also noxious heat (>43 °C) [ 16 ], acidic conditions [ 28 ], divalent cations [ 29 ], and several animal toxins [ 30 , 31 , 32 , 33 ], though this list is still under investigation (reviewed by Fischer et al [ 34 ]). These activators can act individually through distinct pathways as well as functionally coupled, making the channel activation polymodal and complex (reviewed in detail by Zheng [ 23 ]).…”

“…Indeed, TRPV1 activation by capsaicin forms the basis for a number of therapeutic and diagnostic approaches. However, the reversibility and extent of desensitization reached using capsaicin or its ultrapotent analog, resiniferatoxin (RTX), remained elusive [ 34 ], as shown by RTX being sensory nerve specific and not affecting TRPV1 expression in skin [ 39 ]. In 2000, the Julius lab created and characterized a TRPV1 knockout mouse (Trpv1 −/− ) that lacks exon 13, encoding the pore loop and transmembrane domain 6 of the channel, and does not respond to capsaicin [ 40 ].…”

Beyond Hot and Spicy: TRPV Channels and their Pharmacological Modulation

“…Interestingly, TRPV1 agonists as well as antagonists are efficient as analgesics especially in neuropathic pain. While blocking of TRPV1 channels directly prevents Ca 2+ influx and subsequent signal transduction from sensory neurons, overactivation by agonists lead to internalization and subsequent desensitization of afferent nerve endings or degeneration of neurons by Ca 2+ -induced neurotoxicity [57]. Today, this therapeutic concept is used in form of transdermal application of high dose capsaicin for the treatment of neuropathic pain in the periphery [58].…”

“…Today, this therapeutic concept is used in form of transdermal application of high dose capsaicin for the treatment of neuropathic pain in the periphery [58]. Also, the local application of the highly potent agonist resiniferatoxin (RTX) as a "molecular scalpel" in the treatment of extensive pain (cancer) is under clinical trial [57]. It should be noted, that some TRPV1 antagonists failed in clinical trials due to the induction of hyperthermia as well as the increment of sensation threshold for noxious heat in human increasing the risk for severe injuries [59].…”