Transient Receptor Potential Channels and Itch
Tian-Le Xu, Long-Jun Wu in Nonclassical Ion Channels in the Nervous System, 2021
Trpv1 deletion or TRPV1+ neuronal ablation has differential effects on itch transmission. A global knockout of Trpv1 shows attenuation in histamine-induced itch, whereas non-histaminergic itch evoked by alpha-methyl-serotonin (alpha-Me-5-HT, a ligand of serotonin receptors) or endothelin-1 (ET-1, a ligand of endothelin receptors) is unaffected. However, pretreatment with resiniferatoxin (RTX), a potent TRPV1 agonist that can effectively ablate the TRPV1+ sensory central terminals, or deletion of TRPV1+ neurons by the expression of diphtheria toxin, can result in attenuation of both histaminergic and non-histaminergic itch (28). Interestingly, a gain of function mutation (G564S) in the TRPV1 channel can cause decreased trafficking of TRPV1 channels to the plasma membrane. In the animal model of G564S gain-of-function mutation in the TRPV1 channel, histamine-induced itch is dramatically decreased, whereas non-histaminergic itch remains unaffected (29). Hence, histaminergic itch is mediated by TRPV1 channels, while both histaminergic and non-histaminergic itch are dependent on TRPV1+ sensory neurons.
Interstitial Cystitis
Gary W. Jay in Practical Guide to Chronic Pain Syndromes, 2016
Two neurotoxins, resiniferatoxin and capsaicin, have been employed as potential treatments for IC. Currently, there is no data supporting the use of capsaicin. In a meta-analysis, Mourtzoukou et al. concluded that, although well tolerated, the efficacy of resiniferatoxin still remains questionable (58). Clorpactin and silver nitrate are two other agents that have been used, but both are caustic. Caution is advised when administering these agents, as they can result in ureteral and bladder scarring. Intravesical bacillus Calmette-Guerin (BCG) has also been investigated as a potential treatment. After 34 weeks in a randomized, controlled trial, overall response rates to both BCG and placebo were low; and there was no statistically significant difference in response rate between the BCG and placebo groups (59).
Proinflammatory Peptides in Sensory Nerves of the Airways
Sami I. Said in Proinflammatory and Antiinflammatory Peptides, 2020
A further development that has advanced our understanding of capsaicin-sensitive nerves is the introduction of resiniferatoxin, an ultrapotent analog of capsaicin (222). Although capsaicin and resiniferatoxin are derived from a different genus of plants (Capsicum and Euphorbia, respectively), they share a common homovanillic acid motif, and hence their binding site has been termed the vanilloid receptor (223). Use of radiolabeled resiniferatoxin has permitted the direct visualization of binding sites on sensory nerve fibers in the dorsal horn of the spinal cord (224). Resiniferatoxin has a similar spectrum of actions to capsaicin, for example, it causes the release of peptides from sensory nerves in the airways (162,225), and desensitization and destruction of sensory nerves [20], but it is up to several orders of magnitude more potent. Interestingly, the relative potency of resiniferatoxin compared to capsaicin varies for different actions. Resiniferatoxin is 1000 times more potent at inducing neurogenic inflammation, but does not stimulate pulmonary chemoreceptors or cause apnea, as does capsaicin (20,223). This suggests the possible existence of subtypes of vanilloid receptors. The strong binding of radiolabeled resiniferatoxin to the vanilloid receptor has permitted the direct visualization of binding sites on sensory nerve fibers in the dorsal horn of the spinal cord (224), and offers hope for the isolation and molecular characterization of the receptor (222). It is not yet clear why vanilloid receptors should exist on sensory nerves at all, or whether there is an endogenous ligand that stimulates these receptors.
Emerging injectable therapies for osteoarthritis
Published in Expert Opinion on Emerging Drugs, 2022
In a phase II trial, a single dose of intraarticular CNTX-4975, a synthetic form of capsaicin, resulted in a significant dose-dependent improvement in pain among patients with knee OA after 24 weeks. The most common adverse effect was, unsurprisingly, initial procedural-related pain as might occur with initial exposure to chili [79]. This procedural-related pain was addressed in a phase III trial with cold gel wraps or ice water packs, which was found to be clinically acceptable and well tolerated. This trial is currently underway, and preliminary data has shown high levels of clinical response 8 weeks post a single intraarticular injection of CNTX-4975 [80]. Another phase III trial of repeated doses of CNTX-4975 is also in progress, the effects of which will be measured up to 52 weeks [81]. Resiniferatoxin is an another TRPV1 agonist, and preliminary results of a phase 1b study demonstrate safety and efficacy after intra-articular administration [82].
Emerging drugs for the treatment of bladder storage dysfunction
Published in Expert Opinion on Emerging Drugs, 2022
Other potential drug targets that would be worthwhile to further explore clinically are the different TRP channels. It has been known for decades that TRPV1 receptors are involved in afferent signaling in humans as shown by the agonists, capsaicin, resiniferatoxin. In sufficient dosage these drugs are clinically effective in bladder overactivity and then act by inactivating the receptors by desensitization. However, even if they prove the principle of inactivation of the receptors, they are associated with many disadvantages, making blockade of the receptor a more attractive approach. However, the development of small molecule blockers of different TRP channels has been slow and disappointing and most compounds still need to be tested on urological disorders. Blockers of TRPV1 channels have so far not been successful due to hypothermia and the only agent showing promise is the TRPA1 blocker, GRC-17356.
A patent review of transient receptor potential vanilloid type 1 modulators (2014–present)
Published in Expert Opinion on Therapeutic Patents, 2021
Mengkang Gao, Yusui Wang, Lanqi Liu, Zhenrui Qiao, Lin Yan
In fact, in addition to TRPV1, many other receptors are expressed in nociceptive neurons and play important roles in the development and maintenance of pain. TRPV1 agonists (capsaicin and RTX) not only cause TRPV1-expressing nociceptive neurons desensitization but also make other receptors dormant. This development renewed interest in TRPV1 agonists. Currently, low-concentration capsaicin creams such as Zostrix (0.075%) and Axsain (0.025% capsaicin mixed with lidocaine) are popular over-the-counter (OTC) analgesic agents. Moreover, high-concentration capsaicin dermal patch (NGX-4010), liquid formulations (NGX-1998), and site-specific injections (ALGRX-4975) were also developed. In addition, the safety and clinical efficacy of RTX (with unique pharmacological properties) is also an area of active research. In 2009, a clinical trial was initiated on patients with chronic intractable bone pain caused by cancer metastasis (NCT0252261). In August 2020, resiniferatoxin (NCT04044742) enter Phase 3 clinical trials to evaluate its efficacy and safety in the treatment of pain due to osteoarthritis of the knee. We believe that reasonably developing and improving the drug delivery system of TRPV1 agonists (especially RTX) will be an excellent and safe strategy.
Related Knowledge Centers
- Calcium
- Capsaicin
- Nociception
- Physiology
- Sensory Nerve
- Functional Analog
- Chili Pepper
- Scoville Scale
- Trpv1
- Ion