Capsaicin: Selective Toxicity for Thin Primary Sensory Neurons

Holzer, Peter

doi:10.1007/978-3-642-85117-9_12

Cited by 9 publications

(3 citation statements)

References 351 publications

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“…Capsaicin (CPS, 1 ), the pungent principle of hot pepper, excites and then desensitizes a subset of primary sensory neurons involved in nociception, neurogenic inflammation, thermoregulation, and a variety of local regulatory functions. , Upon binding to a specific receptor, CPS opens a ligand-gated channel permeable to both monovalent and divalent cations . This leads to calcium influx and a subsequent release of inflammatory neuropeptides (e.g., tachykinins, calcitonin gene-related peptide) which mediate the afferent and efferent functions of CPS-sensitive neurons. − The remarkable selectivity of CPS for primary sensory neurons makes desensitization to CPS an attractive therapeutical approach to mitigate neurogenic pain and inflammation. − In fact, CPS-containing creams (e.g., Axsain, Zostrix) are already commercially available for these purposes, but irritance severely limits the pharmacological use of CPS. The synthesis of capsaicin-like compounds with an improved desensitization/irritation ratio or with a selective spinal antinociceptive activity has thus been pursued, with very limited success, for decades. − These efforts have been further stimulated by the discovery of a naturally occurring ultrapotent agonist (resiniferatoxin, RTX, 2 ) , and by the synthesis of a competitive antagonist (capsazepine, 3 ) …”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Phorboid 20-Homovanillates: Discovery of a Class of Ligands Binding to the Vanilloid (Capsaicin) Receptor with Different Degrees of Cooperativity

Appendino¹,

Cravotto²,

Palmisano³

et al. 1996

J. Med. Chem.

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A number of phorboid 20-homovanillates were prepared by condensation of phorbol 12,13-diesters and 12-dehydrophorbol 13-esters with Mem-homovanillic acid followed by removal of the protecting group with SnCl4 in THF. These compounds were evaluated for their ability to inhibit [3H]resiniferatoxin (RTX) binding to rat spinal cord membranes. Compounds bearing a lipophilic ester group on ring C were considerably active, but a surprising tolerance of the vanilloid receptor toward the location and the orientation of this ester group was disclosed. Unexpectedly, these ligands could also diminish, to a variable degree, the positive cooperativity which characterizes RTX binding to the vanilloid receptor. Phorbol 12-phenylacetate 13-acetate 20-homovanillate (PPAHV, 6a), a compound which abolished binding cooperativity, was further tested in a variety of in vivo assay used to characterize vanilloid-like activity. PPAHV showed only a marginal pungency and failed to induce a measurable hypothermia response at doses (up to 200 mg/kg) at which it effectively desensitized against neurogenic inflammation. These data suggest that the peculiar binding behavior of these ligands might be associated with a distinct spectrum of biological activity.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Phorboid 20-Homovanillates: Discovery of a Class of Ligands Binding to the Vanilloid (Capsaicin) Receptor with Different Degrees of Cooperativity

Appendino¹,

Cravotto²,

Palmisano³

et al. 1996

J. Med. Chem.

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“…All thermal stimuli were applied to the inner forearm of participants’ non-dominant hand after sensitization of the skin using 0.075% topical capsaicin cream to allow for potent pain relief as reward and pain increase as punishment without the risk of skin damage ( Becker et al, 2015 ; Gandhi et al, 2013 ). By activating temperature-dependent TRPV1 (vanilloid transient receptor potential 1) ion channels capsaicin as the active ingredient of chili pepper induces heat sensitization ( Holzer, 1991 ). To ensure that the entire area of thermal stimulation during the wheel of fortune game was sensitized the cream was applied to an area on the forearm exceeding the area of stimulation by about 1 cm on each side.…”

Section: Methodsmentioning

confidence: 99%

Evidence for dopaminergic involvement in endogenous modulation of pain relief

Desch

Schweinhardt

Seymour

et al. 2023

eLife

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Relief of ongoing pain is a potent motivator of behavior, directing actions to escape from or reduce potentially harmful stimuli. Whereas endogenous modulation of pain events is well characterized, relatively little is known about the modulation of pain relief and its corresponding neurochemical basis. Here we studied pain modulation during a probabilistic relief-seeking task (a 'wheel of fortune' gambling task), in which people actively or passively received reduction of a tonic thermal pain stimulus. We found that relief perception was enhanced by active decisions and unpredictability, and greater in high novelty-seeking trait individuals, consistent with a model in which relief is tuned by its informational content. We then probed the roles of dopaminergic and opioidergic signaling, both of which are implicated in relief processing, by embedding the task in a double-blinded cross-over design with administration of the dopamine precursor levodopa and the opioid receptor antagonist naltrexone. We found that levodopa enhanced each of these information-specific aspects of relief modulation but no significant effects of the opioidergic manipulation. These results show that dopaminergic signaling has a key role in modulating the perception of pain relief to optimize motivation and behavior.

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“…Resultantly, it induces longterm functional changes and structural alterations in the sensory fibers (Porseva, 2013;Szallasi & Blumberg, 1999;Xu et al, 2010). Moreover, capsaicin causes long-term functional changes and structural damage that are not limited to the peripheral end (Duitama et al, 2020;Frias & Merighi, 2016;Holzer, 1991;Jin et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Neuronal nitric oxide synthase and calbindin expression in sympathetic preganglionic neurons following capsaicin treatment

Porseva

Preobrazhensky

2022

The Anatomical Record

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Along with well‐known data on the neurochemical mechanisms of nociceptor activation, there are still no clear data regarding changes in the cellular composition and morphological characteristics of spinal preganglionic neurons (SPN) after capsaicin treatment. The mechanism of capsaicin toxicity differs in developing and mature nerve cells. This study aimed to determine the number of SPN in the autonomic nuclei on spinal cord (SC) sections and their cross‐sectional area, the localization, percentage, and profile area of SPN containing neuronal nitric oxide synthase (nNOS) and calbindin (CB) in the thoracic SC of rats of different ages (from birth to 1‐year‐old) after capsaicin treatment. Neonatal capsaicin treatment generally decreased the cross‐sectional area of the SPN pericarya. However, the cross‐sectional area of the CB‐immunoreactive (IR) SPN increased in the central autonomic area in rats aged 10–30 days old after capsaicin treatment. The number of SPN decreased only in the central autonomic area of rats aged <20 days. The proportion of nNOS‐IR neurons remained steady and did not change during development. The cross‐sectional area of nNOS‐IR SPN in capsaicin‐treated rats was less than that in control rats. The results obtained will promote further studies on the mechanisms of sensory processing in the SC and the development of the sympathetic nervous system.

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Capsaicin: Selective Toxicity for Thin Primary Sensory Neurons

Cited by 9 publications

References 351 publications

Synthesis and Evaluation of Phorboid 20-Homovanillates: Discovery of a Class of Ligands Binding to the Vanilloid (Capsaicin) Receptor with Different Degrees of Cooperativity

Synthesis and Evaluation of Phorboid 20-Homovanillates: Discovery of a Class of Ligands Binding to the Vanilloid (Capsaicin) Receptor with Different Degrees of Cooperativity

Evidence for dopaminergic involvement in endogenous modulation of pain relief

Neuronal nitric oxide synthase and calbindin expression in sympathetic preganglionic neurons following capsaicin treatment

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