Iodo-Resiniferatoxin, a New Potent Vanilloid Receptor Antagonist

The vanilloid receptor VR1 is a nonselective cation channel that is most abundant in peripheral sensory fibers but also is found in several brain nuclei. VR1 is gated by protons, heat, and the pungent ingredient of ''hot'' chili peppers, capsaicin. To date, no endogenous compound with potency at this receptor comparable to that of capsaicin has been identified. Here we examined the hypothesis, based on previous structure-activity relationship studies and the availability of biosynthetic precursors, that N-arachidonoyl-dopamine (NADA) is an endogenous ''capsaicin-like'' substance in mammalian nervous tissues. We found that NADA occurs in nervous tissues, with the highest concentrations being found in the striatum, hippocampus, and cerebellum and the lowest concentrations in the dorsal root ganglion. We also gained evidence for the existence of two possible routes for NADA biosynthesis and mechanisms for its inactivation in rat brain. NADA activates both human and rat VR1 overexpressed in human embryonic kidney (HEK)293 cells, with potency (EC50 Ϸ 50 nM) and efficacy similar to those of capsaicin. Furthermore, NADA potently activates native vanilloid receptors in neurons from rat dorsal root ganglion and hippocampus, thereby inducing the release of substance P and calcitonin gene-related peptide (CGRP) from dorsal spinal cord slices and enhancing hippocampal paired-pulse depression, respectively. Intradermal NADA also induces VR1-mediated thermal hyperalgesia (EC50 ‫؍‬ 1.5 ؎ 0.3 g). Our data demonstrate the existence of a brain substance similar to capsaicin not only with respect to its chemical structure but also to its potency at VR1 receptors. V anilloid receptors of type 1 (VR1) are nonselective cation channels, expressed in peripheral sensory C and A␦ fibers and gated by nociceptive stimuli such as low pH, heat, and some plant toxins, of which capsaicin, the pungent principle of chili peppers, is the best known example (1-4). Evidence obtained by several laboratories and using different techniques (5-10) showed that VR1 is present also in the central nervous system, where it is unlikely to be the target of noxious heat and low pH, thus suggesting the existence of brain endogenous agonists for this receptor (11). Indeed, lipid mediators previously known to serve other functions in the brain, i.e., the endocannabinoid anandamide and some lipoxygenase derivatives, activate VR1, albeit with a potency considerably lower than that of capsaicin (12)(13)(14). The antinociceptive effects of VR1 blockers in two models of inflammatory hyperalgesia (15, 16) suggest that ''endovanilloids'' might be produced also by peripheral tissues and act in concert with locally enhanced temperature and acidity during inflammation.If an endovanilloid did exist, what would be the structural prerequisites that would allow for an optimal interaction with vanilloid receptors? Structure-activity relationship studies for vanilloid receptors have indicated that both the vanillyl-amine moiety and a long, unsaturated acyl chain are necessary to...

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“…3a), this effect being attenuated by the two VR1 antagonists, capsazepine and iodo-resiniferatoxin (ref. 31; Fig. 3b).…”

Section: Resultsmentioning

confidence: 99%

An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors

Huang

Bisogno²,

Trevisani³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

892

729

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“…1 A-C). Moreover, this acute writhing was inhibited by the specific TRPV1 antagonist iodoresiniferatoxin (Wahl et al, 2001) (Fig. 1 D).…”

Section: Trpv1 Is Essential For Acute Mgmentioning

confidence: 97%

Extracellular Cations Sensitize and Gate Capsaicin Receptor TRPV1 Modulating Pain Signaling

Ahern¹,

Brooks²,

Miyares³

et al. 2005

J. Neurosci.

164

145

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Transient receptor potential (TRP) channels detect diverse sensory stimuli, including alterations in osmolarity. However, a molecular detector of noxious hypertonic stimuli has not yet been identified. We show here that acute pain-related behavior evoked by elevated ionic strength is abolished in TRP vanilloid subtype 1 (TRPV1)-null mice and inhibited by iodoresiniferatoxin, a potent TRPV1 antagonist. Electrophysiological recordings demonstrate a novel form of ion channel modulation by which extracellular Na ϩ , Mg 2ϩ , and Ca 2ϩ ions sensitize and activate the capsaicin receptor, TRPV1. At room temperature, increasing extracellular Mg 2ϩ (from 1 to 5 mM) or Na ϩ (ϩ50 mM) increased ligand-activated currents up to fourfold, and 10 mM Mg 2ϩ reduced the EC 50 for activation by capsaicin from 890 to 450 nM. Moreover, concentrations of divalent cations Ͼ10 mM directly gate the receptor. These effects occur via electrostatic interactions with two glutamates (E600 and E648) formerly identified as proton-binding residues. Furthermore, phospholipase C-mediated signaling enhances the effects of cations, and physiological concentrations of cations contribute to the bradykinin-evoked activation of TRPV1 and the sensitization of the receptor to heat. Thus, the modulation of TRPV1 by cationic strength may contribute to inflammatory pain signaling.

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“…As RTX is an ultrapotent agonist for TRPV1, the introduction of an iodine atom ortho to the phenolic hydroxyl of the homovanillyl moiety reverts and generates the potent antagonist 5'-IRTX (Wahl et al, 2001). …”

Section: -Iodoresisiniferatoxin (5'-irtx) Belongs To the Class Of Iomentioning

confidence: 99%

Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey

Madasu

Okine

Olango

et al. 2016

Pharmacological Research

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Iodo-Resiniferatoxin, a New Potent Vanilloid Receptor Antagonist

Cited by 251 publications

References 21 publications

An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors

An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors

Extracellular Cations Sensitize and Gate Capsaicin Receptor TRPV1 Modulating Pain Signaling

Genotype-dependent responsivity to inflammatory pain: A role for TRPV1 in the periaqueductal grey

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