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Review
. 2017 Jun 2:8:378.
doi: 10.3389/fphys.2017.00378. eCollection 2017.

Molecular Surgery Concept from Bench to Bedside: A Focus on TRPV1+ Pain-Sensing Neurons

László Pecze  1 , Béla Viskolcz  2 , Zoltán Oláh  2   3
Affiliations
Review

Molecular Surgery Concept from Bench to Bedside: A Focus on TRPV1+ Pain-Sensing Neurons

László Pecze et al. Front Physiol. .

Abstract

"Molecular neurosurgery" is emerging as a new medical concept, and is the combination of two partners: (i) a molecular neurosurgery agent, and (ii) the cognate receptor whose activation results in the selective elimination of a specific subset of neurons in which this receptor is endogenously expressed. In general, a molecular surgery agent is a selective and potent ligand, and the target is a specific cell type whose elimination is desired through the molecular surgery procedure. These target cells have the highest innate sensitivity to the molecular surgery agent usually due to the highest receptor density being in their plasma membrane. The interaction between the ligand and its receptor evokes an overactivity of the receptor. If the receptor is a ligand-activated non-selective cation channel, the overactivity of receptor leads to excess Ca2+ and Na+ influx into the cell and finally cell death. One of the best known examples of such an interaction is the effect of ultrapotent vanilloids on TRPV1-expressing pain-sensing neurons. One intrathecal resiniferatoxin (RTX) dose allows for the receptor-mediated removal of TRPV1+ neurons from the peripheral nervous system. The TRPV1 receptor-mediated ion influx induces necrotic processes, but only in pain-sensing neurons, and usually within an hour. Besides that, target-specific apoptotic processes are also induced. Thus, as a nano-surgery scalpel, RTX removes the neurons responsible for generating pain and inflammation from the peripheral nervous system providing an option in clinical management for the treatment of morphine-insensitive pain conditions. In the future, the molecular surgery concept can also be exploited in cancer research for selectively targeting the specific tumor cell.

Keywords: TRPV1; apoptosis; capsaicin; necrosis; resiniferatoxin; sensory neurons; vanilloids.

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Figures

Figure 1
Figure 1
Ca2+ imaging. (A) NIH-3T3 cells ectopically expressing TRPV1 were loaded with the cytosolic Ca2+ indicator Fluo-4-AM. (B) Minute scales imaging of [Ca2+]i reveals two populations in NIH-3T3TRPV1 cell line. A set of cells responds to 1 μM CAP with non-declining increase of [Ca2+]i and dies very soon while the other population survives the initial necrotic-phase in which the [Ca2+]i transitions back to closed to its resting levels. This later option rarely occurs with RTX, as RTX is several thousandfold more potent than CAP in several assays (Szallasi and Blumberg, 1999). The original experiment was published in 2004 (Karai et al., 2004).
Figure 2
Figure 2
Time-lapse analysis of vanilloid evoked structural changes in MCF7 breast cancer cell line. MCF7 cells were transiently transfected with TRPV1-GFP construct. These show green fluorescence. Cells were treated with 50 μM CAP. TRPV1-GFP expressing cells, and only these cells, blow blebs during a 10-min period (red arrowheads). MCF7 cells also endogenously express low levels of TRPV1 channels. This level is not enough to induce bleb formation, but some MCF7 cells produce invadopodium, an ameboid structure promoting cancer cell invasion, in response to CAP treatment (yellow arrowheads). The original experiment was published in 2016 (Pecze et al., 2016b).
Figure 3
Figure 3
Necrotic and apoptotic processes after TRPV1 stimulation. (A) In the unstimulated state, the resting [Ca2+]i is the result of the low rate of influx and efflux across the plasma, ER- and mitochondria membranes. Red and blue arrows indicates the energy-requiring and energy-independent fluxes, respectively. After stimulation, two types of Ca2+ response can be observable leading to necrotic (B) and potentially apoptotic processes (C). (B) During the necrotic processes TRPV1 activation results in a sustained increase in [Ca2+]i. After that, Ca2+ ions are accumulated in the mitochondria (Pecze et al., 2016b) but released from the endoplasmatic reticulum. These processes lead to the fragmentation of these organelles (Olah et al., 2001). Blebs appears at the plasmamembrane due to the cell volume increase. (C) During the apoptotic processes TRPV1 activation does not result in a sustained increase in [Ca2+]i, but rather to a transient Ca2+ signal mainly due to the depletion of the ER Ca2+ stores. In this situation, Ca2+ extruding systems is still able to create an equilibrium between the Ca2+ influx and Ca2+ efflux reverting [Ca2+]i close to its basal levels before stimulation. However, this new equilibrium requires elevated energy consumption. Mitochondria therefore produce more energy, but during their normal operation they also produce reactive oxygene species (ROS; Michael Murphy, 2009). ROS production was significantly increased in cultured DRG neurons after bath application of CAP (1 μM) or RTX (200 nM) compared with the untreated neurons (Ma et al., 2009). This can induce oxidative stress and apoptosis Fleury et al., .
Figure 4
Figure 4
Topical intravesical medication of RTX via transurethral instillation promises several advantages over oral systemic CAP therapy. Intravesically administered RTX penetrates the vesical mucosa and submucosa by diffusion and binds to TRPV1+ nerve endings. The suggested “balloon dilator” method benefits from the increased surface of urothelium due to the thinning of the bladder mucosa.
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