From capsaicin to TRPV1: The “hot” legacy of János Szolcsányi

Capsaicin represents an area of sensory pharmacology intimately familiar to the estimated quarter of the world’s population who consume hot pepper on a daily basis. Hot pepper is indeed “hot” because capsaicin and noxious heat activate the very same receptor on sensory neurons, now known as Transient Receptor Potential, Vanilloid-1 (TRPV1) [1]. In fact, TRPV1 is the founding member of the family of temperature-sensitive TRP channels, collectively referred to as “thermoTRPs.”

Capsaicin is a “hot” topic in pharmacology, as evidenced by the 16,423 papers in PubMed. But it was not always like this. Indeed, in 1962 when János Szolcsányi joined the research duo of Professor Nicholas (Miklós) Jancsó and his wife and associate, Aurelia (Aranka) Jancsó-Gábor, only two papers were published on capsaicin actions. This is all the more surprising because Professor Jancsó discovered the phenomenon of capsaicin desensitization as early as 1949 [2].

Despite the apparent lack of interest by the scientific community in capsaicin actions, Szolcsányi doggedly pursued his experiments. He had a shoestring budget, therefore he became very creative in his means of research. For example, he used his own tongue for testing the pungency of capsaicin congeners! Based on the structure-activity relations that these compounds displayed in pungency, Szolcsányi predicted in 1970 the existence of a capsaicin receptor. Capsaicin, however, remained a scientific oddity.

Capsaicin as a research tool started to gain popularity in the late 1970ies, when its remarkably selective action on primary sensory neurons was finally recognized. In specific, capsaicin was shown to deplete substance P from these cells. Approximately at the same time, the action of capsaicin on thermoregulation was also discovered.

With the molecular cloning of the capsaicin receptor TRPV1 in 1997 [1], capsaicin research skyrocketed. Pharmaceutical companies started to search their compound libraries for antagonists as clinical candidates to relieve chronic pain and cough. It was also recognized that TRPV1 is expressed, albeit at much lower levels than in primary sensory neurons, both in brain nuclei and non-neuronal tissues.

The 2021 Nobel Prize in Medicine and Physiology was awarded to David Julius (shared with Ardem Patapoutian), in part, for discovering the molecular mechanisms of heat sensation. Admittedly, David Julius was inspired by the observations of Szolcsányi, and these observations guided him in his search for the capsaicin receptor. Sadly, János Szolcsányi died in 2018 – he did not live long enough to see the recognition of this work by the Nobel committee.

Capsaicin was already featured in a Temperature special issue in 2015, with Szolcsányi writing the review on thermoregulatory actions [3]. Eight years later, another special issue (the present one), edited by us (Erika Pintér, András Garami and Árpád Szállási), is dedicated to the memory of János Szolcsányi. We are not only the editors but also contributors. Erika Pintér succeeded János Szolcsányi in 2013 as Chair of the Department of Pharmacology and Pharmacotherapy (University of Pécs), and still carries on his experiments on the role of capsaicin-sensitive neurons in pain and inflammation. Szolcsányi’s later students – in chronological order, Erika Pintér, Gábor Pethő, Zsuzsanna Helyes, Éva Szőke and Kata Bölcskei – have summarized their PhD work supervised by Szolcsányi in a review, and thus pay tribute to his memory in this special issue [4]. András Garami continues the thermoregulatory line of capsaicin research: a research article about discovery of the neural pathway of TRPV1 antagonist-induced hyperthermia and its physiological relevance is published in this special issue [5]. Árpád Szállási’s current interest is focused on capsaicin, TRPV1 and cancer. His subjective review about the latest developments in that field can be also found in this special issue [6].

We are glad that a number of experts answered our call. The author of the introductory editorial summarizing Szolcsányi’s early scientific results [7] is Loránd Barthó, who was János Szolcsányi’s first colleague at the beginning of his years in Pécs (from 1970 to 1985), and who took over the Chairmanship of the Department in 2003. One of the highlights of this special issue is the comprehensive review from Wade Van Horn’s group [8] presenting a “molecular perspective” on the heat-activation of TRPV1.