Resiniferatoxin and its analogs provide novel insights into the pharmacology of the vanilloid (capsaicin) receptor

doi:10.1016/0024-3205(90)90518-V

Life Sciences

Volume 47, Issue 16, 1990, Pages 1399-1408

https://doi.org/10.1016/0024-3205(90)90518-V Get rights and content

Abstract

Capsaicin, the pungent constituent of chili peppers, represents the paradigm for the capsaicinoids or vanilloids, a family of compounds shown to stimulate and then desensitize specific subpopulations of sensory receptors, including C-polymodal nociceptors, A-delta mechanoheat nociceptors and warm receptors of the skin, as well as enteroceptors of thin afferent fibers. An exciting recent advance in the field has been the finding that resiniferatoxin (RTX), a naturally occurring diterpene containing a homovanillic acid ester, a key structural motif of capsaicin, functions as an ultrapotent capsaicin analog. For most of the responses characteristic of capsaicin, RTX is 100–10,000 fold more potent. Structure/activity analysis indicates, however, that RTX and related homovanillyl-diterpene esters display distinct spectra of activity. Specific [³H]RTX binding provides the first direct proof for the existence of vanilloid receptors. We expect that the RTX class of vanilloids will promote rapid progress in understanding of vanilloid structure/activity requirements and mechanism.

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The clinical management of severe and chronic pain relies heavily on opioids that cause serious side-effects. There therefore exists an urgent need to develop safer and effective analgesics. Moreover, there has been significant progress in the understanding of pain physiology, especially the role of some ion channels in the pain process. Thus, the immense potential of ion channel therapeutics in pain management is a subject of current interest.
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The capsaicin (vanilloid) receptor, TRPV1, is a heat-activated cation channel modulated by inflammatory mediators and contributes to acute and chronic pain. TRPV1 channel is one of the most researched and targeted mechanisms for the development of novel analgesics. Over the years, natural products have contributed enormously to the development of important therapeutic drugs used currently in modern medicine. A literature review was conducted using Medline, Google Scholar, and PubMed. Searching the literature resulted in listing 136 natural compounds that interacted with TRPV1 channel. These compounds were phytochemicals that belong to different chemical groups including vanilloids, flavonoids, alkaloids, terpenoids, terpenyl phenols, fatty acids, cannabinoids, sulfur_containing compounds, etc. Other natural TRPV1 modulators were of animal, fungal or bacterial origin. Some natural products were small agonists or antagonists of TRPV1. Others were protein venoms. Most in vitro studies utilized electrophysiological or calcium imaging techniques to study calcium flow through the channel using primary cultures of rat dorsal root and trigeminal ganglia. Other studies used hTRPV1 or rTRPV1 expressed in HEK239, CHO cells or Xenopus oocytes. In vivo studies concentrated on different pain models conducted mainly in mice and rats. In conclusion, natural products are highly diverse in their modulatory action on TRPV1. Many gaps in natural product research are present in distinguishing modality-specific from polymodal antagonists. Species' differences in TRPV1 functionality must be taken into account in any future study. Proceeding into clinical trials needs more efforts to discover potent TRPV1 antagonists devoid of hyperthermia, the main side effect.
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As toxicity is limited to the nociceptors that express TRPV1 receptors, other systems mediating light touch and proprioception would be unaltered. Resiniferatoxin (RTX) obtained from the Euphorbia resinifera plant acts on TRPV1 with a potency that is several orders of magnitude greater than that noted with capsaicin (Szallasi & Blumberg 1990; Iadarola & Mannes 2011). Of interest, the ameliorating effects of intracisternal (IC) and lumbar intrathecal RTX on pain has been shown in dogs with osteoarthritis and osteosarcoma (Karai et al. 2004; Brown et al. 2005, 2015; Iadarola & Mannes 2011).
To evaluate target engagement of intracisternally (IC) delivered TRPV1 agonist, resiniferatoxin (RTX), as measured by primary afferent and dorsal horn substance P immunoreactivity (sP-IR), histopathology and thermal escape latencies in dogs.
Prospective experimental trial.
Fourteen adult male Beagle dogs, weighing 10.3–13.2 kg; 11 dogs surviving to scheduled euthanasia.
Anesthetized dogs were randomly assigned to be administered IC RTX (3.6 μg, 0.1 mL kg^–1) in a hyperbaric (hRTX, n = 6), normobaric (nRTX, n = 4) vehicle or a hyperbaric vehicle (hVehicle, n = 4). Over 16 days, animals were examined for thoracic and pelvic limb paw thermal withdrawal latencies and neurologic function. Spinal cords, trigeminal ganglia and dorsal root ganglia (DRGs) were assessed for morphologic changes and sP-IR.
IC RTX in anesthetized dogs resulted in a < 1 hour increase in blood pressure. Acute reactions leading to euthanasia within 8 hours occurred in three dogs (two hRTX, one nRTX). All other animals recovered with normal neurologic, bowel and bladder function. Final groups were: vehicle n = 4, hRTX n = 4 and nRTX n = 3. Animals in nRTX and hRTX showed increases in escape latencies in thoracic paws and, to a lesser extent, in pelvic paws, correlating to a loss of sP-IR in cervical cord with smaller reductions in thoracic and lumbar cord. In animals surviving to euthanasia, thickening of the arachnoid membrane (predominantly in the cervical region) was the most consistent change. This change, present in controls, was interpreted to be vehicle related. There was no evidence of structural changes in brain and spinal cord.
IC RTX produced localized loss of spinal and DRG sP with a corresponding thermal analgesia, absent motor impairment or spinal pathology. Loss of three animals emphasizes the need to refine the use of this promising therapeutic modality in managing companion animal pain.
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Citation Excerpt :
To date, a large plethora of compounds that activate TRPV1 have been identified. Some of these are of natural origin: capsaicin, allicin, and resiniferatoxin (from Capsicum chili peppers, garlic, and from the cactus-like Euphorbia resinifera, respectively) (Caterina et al., 1997; Salazar et al., 2008; Szallasi & Blumberg, 1990). Furthermore, there are some TRPV1 activators which are endogenously produced such as anandamide, N-arachidonoyl-dopamine, metabolic products of lipoxygenase, lysophosphatidic acid, and among others (Morales-Lazaro, Simon, & Rosenbaum, 2013).
The transient receptor potential (TRP) family of ion channels is constituted by several nonselective cation channels that are activated by diverse stimuli and that function as polymodal receptors. TRP ion channels are expressed in neural and nonneural tissues where they play important roles in cell physiology. The activation of these ion channels is achieved through changes in temperature, osmolarity, voltage, pH, pressure, and by some natural or synthetic chemical compounds that directly bind to these proteins to regulate their activity.
Other compounds that regulate TRP ion channel function are some endogenously synthetized lipid compounds. One such example of a compound of lipidic nature, commonly found in cells, is cholesterol. Cholesterol has been shown to exert positive and negative roles on TRP ion channel activity, albeit through different mechanisms which include a direct interaction of this molecule with specific amino acids located in the sequence of these channels or through the recruitment of the channels into specialized membrane microdomains (lipid rafts or caveolae). In this chapter, we will discuss important aspects of cholesterol as a regulator of some members of the TRP family of ion channels, and we will highlight the role of cholesterol on thermo-, chemo-, and osmosensation through regulation of the activity of these proteins.
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The toxicology of riot control agents (RCAs) has been the focus of numerous reviews, publications, and textbooks. RCAs comprise a diverse array of chemical compounds with similar toxicities since their introduction on the battlefield in the early part of the past century. They are all designed with the purpose of disabling a targeted group or individual through sensory irritation of the eyes, respiratory tract, and/or skin. By providing a minimal force alternative for controlling and managing individuals, RCAs are a desired public health and safety tool for military, domestic law enforcement, and personal use. The chemistry and physical properties of the most common RCAs in use today are discussed. The mechanism of action, toxicokinetics, and toxicity of these RCAs in animals and humans follow. Finally, we outline the process or risk assessment and characterize the safety, effectiveness, and risk of these agents in situations in which they may be used.
Modulation of defensive behavior by Transient Receptor Potential Vanilloid Type-1 (TRPV1) Channels
2014, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
This fact, together with its biological effects, led to the proposal of an orphan “capsaicin receptor” in mammalian organisms. This receptor was indeed identified by autoradiographic studies using [3H] resiniferatoxin (RTX), a potent capsaicin analog, in tissues of several species, including humans (Acs et al., 1994; Szallasi, 1994; Szallasi and Blumberg, 1990a,b). Since capsaicin and RTX share a vanillyl group as the key structural recognition site the receptor was initially denominated “vanilloid” (Szallasi and Blumberg, 1990b).
The Transient Receptor Potential Vanilloid Type-1 (TRPV1) was first characterized in primary afferent fibers as a receptor for capsaicin (the pungent ingredient of chili peppers). Later on, this cation-permeable ion channel was also described in the central nervous system, where its main putative endogenous ligand is N-arachidonoyl ethanolamide (an endocannabinoid, also known as anandamide). Recent results employing genetic, pharmacological and histochemical techniques indicate that TRPV1 tonically modulate anxiety, fear and panic responses in brain regions related to defensive responses, such as the dorsal periaqueductal gray, the hippocampus and the medial prefrontal cortex. Genetic deletion or antagonism of this ion channel induces anxiolytic-like effects in several animal models. The main mechanism responsible for TRPV1-mediated effects on anxiety seems to involve facilitation of glutamatergic neurotransmission. In addition, there is evidence for interactions with other neurotransmitter systems, such as nitric oxide and endocannabinoids.

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MinireviewResiniferatoxin and its analogs provide novel insights into the pharmacology of the vanilloid (capsaicin) receptor

Abstract

Gen. Pharmacol.

Neuroscience

Brain Res.

Trends in Pharmacol. Sci.

Arch. Biochem. Biophys.

Biochem. Pharmacol.

Brain Res.

Neurosci. Lett.

Life Sci.

Tetrahedron Lett.

Life Sci.

Neuroscience

Brain Res.

Neurosci. Lett.

Br. J. Pharmacol. Chemother.

Pharmacol. Rev.

Neuroscience

J. Physiol.

Minireview
Resiniferatoxin and its analogs provide novel insights into the pharmacology of the vanilloid (capsaicin) receptor