The triple function of the capsaicin-sensitive sensory neurons: In memoriam János Szolcsányi

Abstract

This paper is dedicated to the memory of János Szolcsányi (1938-2018), an outstanding Hungarian scientist. Among analgesics that act on pain receptors, he identified capsaicin as a selective lead molecule. He studied the application of capsaicin and revealed several physiological (pain, thermoregulation) and pathophysiological (inflammation, gastric ulcer) mechanisms. He discovered a new neuroregulatory system without sensory efferent reflex and investigated its pharmacology. The authors of this review are his former Ph.D. students who carried out their doctoral work in Szolcsányi's laboratory between 1985 and 2010 and report on the scientific results obtained under his guidance. His research group provided evidence for the triple function of the peptidergic capsaicin-sensitive sensory neurons including classical afferent function, local efferent responses, and remote, hormone-like anti-inflammatory, and antinociceptive actions. They also proposed somatostatin receptor type 4 as a promising drug target for the treatment of pain and inflammation. They revealed that neonatal capsaicin treatment caused no acute neuronal death but instead long-lasting selective ultrastructural and functional changes in B-type sensory neurons, similar to adult treatment. They described that lipid raft disruption diminished the agonist-induced channel opening of the TRPV1, TRPA1, and TRPM8 receptors in native sensory neurons. Szolcsányi's group has developed new devices for noxious heat threshold measurement: an increasing temperature hot plate and water bath. This novel approach proved suitable for assessing the thermal antinociceptive effects of analgesics as well as for analyzing peripheral mechanisms of thermonociception.

Keywords: Capsaicin-sensitive neuron; TRPV1; lipid raft; neurogenic inflammation; noxious heat threshold; pain; somatostatin; thermonociception.

Figure 1.

Prof. János Szolcsányi participating in the annual meeting of the European Neuropeptide Club in April 2007, Santorini, Greece (photo by Erika Pintér).

Figure 2.

After intravenous administration of the Evans blue dye, peripheral stumps of the cut L4–L5 spinal dorsal roots were electrically stimulated on one side and the other side (left panel). Plasma protein extravasation was detected in the skin of both hind limbs and quantified by spectrophotometric determination of Evans blue accumulation. As shown in the right panel, a 5 min delay (dt = 5 min) between stimulations resulted in about 50% reduced effect from the second stimulation. However, either a 60 min delay (dt = 60 min) between stimulations or simultaneous stimulation (dt = 0 min) results in no difference between the plasma extravasation responses between the two sides (source: Ph.D. Thesis by Erika Pintér, 1996).

Figure 3.

A: Filipin staining of CHO cells on control and MCD-treated plates. MCD reduced the cholesterol-binding filipin labeling of the plasma membrane in CHO cells. Micrographs have been generated using an Olympus Fluoview-1000 system on an Olympus IX81 microscope stage equipped with an Olympus DP70 digital camera and through an Olympus UPlan FL N, Phase2 objective (40x/0.75). B: Effect of MCD on capsaicin-evoked Ca²⁺ accumulation in TRPV1-expressing CHO cell line in radioactive ⁴⁵Ca²⁺ uptake experiments. Ca²⁺ influx is presented in % of control (without MCD treatment). *P < 0.05, **P < 0.01 (MCD-treated vs. control; One-way ANOVA).

Figure 4.

Measurement of the noxious heat threshold of the rat hindpaw by the increasing-temperature water bath (photos by Kata Bölcskei).

Figure 5.

Representative confocal images of mouse Trpa1 and Trpv1 mRNA on dorsal root ganglion (DRG). Trpa1 (green) and Trpv1 (red) mRNA co-localized with calcitonin gene-related peptide (CGRP, purple) and somatostatin (SOM, blue) mRNA on peptidergic and non-peptidergic sensory neurons of C57Bl/6 J mouse lumbar 4 (L4) DRG, counterstained with DAPI (cyan) (a). Trpa1 (green) co-localized Trpv1 (red) mRNA (b), calcitonin gene-related peptide (CGRP, purple) co-localized with somatostatin (SOM, blue) mRNA (c). Samples were imaged by using LSM 710 confocal laser scanning microscope (Carl Zeiss, Jena, Germany). Brightness/contrast adjustment was processed using Fiji, 1.53c, NIH, USA. Scale bar: 20 µm (image prepared by Angéla Kecskés).