Resiniferatoxin Mediated Ablation of TRPV1+ Neurons Removes TRPA1 as Well

Abstract

234Mammalian temperature sensors of the transient receptor potential (TRP) family are tetrameric 6-transmembrane cation channels gated by heat, cold, as well as either endogenous or exogenous agonists 1,2 . The vanilloid receptor (VR1/TRPV1) is a non-selective ligand-gated Na + /Ca 2+ -channel [3][4][5][6] . TRPV1 is selectively activated by heat above 42ºC, pH < 6.3 7 , endogenous lipid mediators such as anandamide and oleoylethanolamide 4,8,9 , intracellular signaling molecules 10,11 and plant toxins, including capsaicin (CAPS) and resiniferatoxin (RTX).TRPA1 has recently been suggested to serve as receptor of noxious cold temperature 12 , and it transduces pain induced by ABSTRACT: Objectives: Resiniferatoxin, the most potent agonist of inflammatory pain/vanilloid receptor/cation channel (TRPV1) can be used for neuron subtype specific ablation of pain generating cells at the level of the peripheral nervous system by Ca 2+ -excytotoxicity. Molecular neurosurgery is an emerging technology either to alleviate severe pain in cancer or treat/prevent different local neuropathies. Our aim was determining sensory modalities that may be lost after resiniferatoxin treatment. Methods: Newborn or adult mice were treated with resiniferatoxin, then changes in chemical and heat sensitivity were correlated with alterations of the cell composition of sensory ganglions. Results: Only mice treated at adult age became less sensitive to heat stimuli, while both treatment groups lost sensitivity to specific vanilloid agonists of TRPV1 and, interestingly, to allyl-isothiocyanate, a selective agonist of TRPA1. Our in vivo and post mortem analytical results confirmed that TRPV1 and TRPA1 function together and resiniferatoxin-mediated neurosurgery removes both sensor molecules. Discussion: In adult mice resiniferatoxin causes: i) desensitization to heat and ii) sensitization to cold. Cold hyperalgesia, an imbalance in thermosensation, might be conferred by a prominent cold receptor that is expressed in surviving resiniferatoxin-resistant sensory neurons and compensates for pain signals lost with TRPA1 and TRPV1 double positive cells in the peripheral nervous system. RÉSUMÉ: L'ablation de neurones TRPV1+ par la résinifératoxine élimine aussi les neurones TRPA1.Objectifs : La résinifératoxine, l'agoniste le plus puissant de la douleur inflammatoire/du récepteur vanilloïde/du canal cationique (TRPV1), peut être utilisée pour l'ablation spécifique par excytotoxicité Ca2+, d'un sous-type de neurones faisant partie des cellules génératrices de douleur au niveau du système nerveux périphérique. La neurochirurgie moléculaire est une technologie émergente, pour soulager la douleur cancéreuse sévère ou pour traiter ou prévenir différentes neuropathies locales. Notre but était de déterminer les pertes sensitives suite au traitement par la résinifératoxine. Méthodes : Des souris ont été traitées par la résinifératoxine à la période néonatale ou adulte et les changements de la sensibilité chimique et calorique ont été corrélés aux altérations de l...

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…17, 20, and 21;Story et al, 2003;Kobayashi et al, 2005). Ablation of TRPV1 + neurons by RTX in mice results in an almost complete loss of sensitivity to allylisothiocyanate, a TRPA1 agonist (Pecze et al, 2009). These data support a high degree of colocalization between TRPV1 and TRPA1 in sensory neurons.…”

Ion channel TRPV1-dependent activation of PTP1B suppresses EGFR-associated intestinal tumorigenesis

“…Given the potential role of TRPV1-expressing sensory neurons in the regulation of intestinal tumorigenesis, we also evaluated the phenotype of Apc Min/+ mice that underwent systemic ablation of TRPV1 + neurons. Apc Min/+ mice were treated with the ultrapotent TRPV1 agonist resiniferatoxin (RTX) during the neonatal period (47). Ocular challenge with capsaicin (eye wipe test) confirmed systemic TRPV1 + sensory neuron ablation.…”

Identification of the Plant Steroid α-Spinasterol as a Novel Transient Receptor Potential Vanilloid 1 Antagonist with Antinociceptive Properties

“…To further explore the role of TRPV1-positive fibers in the antinociceptive effect of ␣-spinasterol in the paw reaction test to a heat stimulus, animals were submitted to a systemic desensitization protocol with RTX as described previously (Pecze et al, 2009). Pecze et al (2009) previously demonstrated that 50 g/kg s.c. of RTX largely reduced the expression of TRPV1 as well as increased noxious heat latencies and abolished capsaicin-induced eye irritation 7 days after treatment in adult mice. Moreover, they also observed that greater doses of RTX caused mice mortality.…”