Elsevier

Neuropeptides

Volume 38, Issue 6, December 2004, Pages 377-384
Neuropeptides

Review
Forty years in capsaicin research for sensory pharmacology and physiology

https://doi.org/10.1016/j.npep.2004.07.005Get rights and content

Abstract

Capsaicin, the pungent ingredient of chilli peppers has become a “hot” topic in neuroscience with yearly publications over half thousand papers. It is outlined in this survey how this exciting Hungarian research field emerged from almost complete ignorance. From the initial observation of the phenomenon of “capsaicin desensitization”, a long-lasting chemoanalgesia and impairment in thermoregulation against heat, the chain of new discoveries which led to the formulation of the existence of a “capsaicin receptor” on C-polymodal nociceptors is briefly summarized. Neurogenic inflammation is mediated by these C-afferents which are supplied by the putative capsaicin receptor and were termed as “capsaicin sensitive” chemoceptive afferents. They opened new avenues in local peptidergic regulation in peripheral tissues. It has been suggested that in contrast to the classical axon reflex theory, the capsaicin-sensitive sensory system subserves a “dual sensory-efferent” function whereby initiation of afferent signals and neuropeptide release are coupled at the same nerve endings. Furthermore, in the skin at threshold stimuli which do not evoke sensation elicit already maximum efferent response as enhanced microcirculation. In isolated organ preparations large scale of new type of peptidergic capsaicin-sensitive neurogenic smooth muscle responses were revealed after the first one was described by ourselves on the guinea-pig ileum in 1978. Recently the “capsaicin receptor” has been cloned and it is now named as the “transient receptor potential vanilloid 1” (TRPV1). Hence, capsaicin research led to the discovery of the first temperature-gated ion channel gated by noxious heat, protons, vanilloids and endogenous ligands as anandamide, N-oleoyldopamine and lipoxygenase products. Another recent achievement is the discovery of a novel “unorthodox” neurohumoral regulatory mechanism mediated by somatostatin. Somatostatin released from the TRPV1-expressing nerve endings reaches the circulation and elicits systemic antiinflammatory and analgesic “sensocrine” functions with counter-regulatory influence e.g. in Freund’s adjuvant-induced chronic arthritis. Nociceptors supplied by TRPV1 and sst4 somatostatin receptors has become nowadays promising targets for drug development.

Introduction

The steeply increasing number of publications on capsaicin exceeding 650–700 papers per year is a clear indication that this spicy pungent agent has become nowadays really a “hot” topic in neuroscience. In striking contrast during my fifteen year long “first capsaicin period” (1962–1976) altogether less than 40 papers were published from non-Hungarian sources and very few of them were related to neurobiology in its broadest sense. There are two reasons why the emerging interest is nowdays so high. First, in drug research capsaicin and its receptor have become generally accepted lead and target molecules, respectively. The promising perspective of this trend is to discover the first analgesic and antiinflammatory drug which acts not on cyclooxygenases or opioid receptors but selectively on nociceptors. The second reason is related to the new horizons of the neurohumoral regulatory role of mediators (neuropeptides) released from capsaicin-sensitive nociceptors. It is somehow rewarding for me that in the late sixties just these two reasons – what I formulated in my thesis, early publications and reviews – inspired me to devote all my scientific efforts with limited facilities to break through several burdens in this pathway (Szolcsányi, 1982, Szolcsányi, 1984a, Szolcsányi, 1984b, Szolcsányi, 1990, Szolcsányi, 1991, Szolcsányi, 1993, Szolcsányi, 1996a, Szolcsányi, 1996b, Szolcsányi, 2002, Szolcsányi et al., 1994, Szolcsányi et al., 2004).

Section snippets

Capsaicin desensitization and neurogenic inflammation

Nicholas (Miklós) Jancsó, my mentor with whom I worked together in Szeged until his demise in 1966, discovered around the late forties as an accidental observation that high doses of capsaicin applied topically or later also systemically to mice, rats or guinea-pigs elicit a novel type of analgesia. The so called capsaicin desensitized animals did not react with protective reflexes and inflammation to noxious chemicals although their responsiveness to physical stimuli remained intact (

Actions of capsaicin on thermoregulation

Systemic application of capsaicin or its pungent congeners elicited a pronounced fall in body temperature and this response was also absent in capsaicin desensitized animals. The hypothermic effect of the agent was due to a coordinated heat loss response accompanied by vasodilatation, salivation, fall in metabolic rate at cool ambient temperature and in cats also by panting. Heat loss responses to heating the preoptic area or to intrahypothalamic microinjection of capsaicin were also diminished

Postulation of a capsaicin receptor on polymodal nociceptors

The uniqueness of these pharmacological effects of capsaicin was challenging for further research, but the mechanism behind the extremely long-term capsaicin-induced blockade of chemonociception against such diverse structures as xylene, formaldehyde, veratridine or mustard oil remained enigmatic and seemed to favour some kind of neurotoxicity. Beyond the selective ultrastructural impairment restricted to one set of neurons mentioned before (Szolcsányi et al., 1975), results of three sets of

Dual sensory-efferent function of capsaicin-sensitive nociceptors

Our proposal of “dual sensory-efferent function” for a nerve ending is against the classical works of Bayliss, Bruce and Thomas Lewis on antidromic vasodilatation and axon reflex flare. According to the views of these pioneers signals from sensors are conducted through axonal arborization to nerve terminals specialized for mediator releasing functions (Szolcsányi, 1984b, Szolcsányi, 1988, Szolcsányi, 1996a, Szolcsányi, 1996b). Taking the advantage of the neuroselective action of capsaicin we

The TRPV1/VR1 capsaicin receptor

From the late eighties conclusive evidence has accumulated for the existence of a capsaicin receptor and a novel capsaicin-gated cation channel was identified in patch clamp studies (Bevan and Szolcsányi, 1990). Thus, strong efforts were made to isolate, identify and clone this membrane protein. Finally, it was succeeded by the group of David Julius in 1997 (Caterina et al., 1997). It was named by the authors both as “capsaicin receptor” or as “vanilloid receptor 1” (VR1) and recently renamed

Sensocrine function of capsaicin-sensitive nociceptors

It was serendipity, an unexpected observation made by my coworker Erika Pintér that in the course of rat experiments for mapping neurogenic inflammation in visceral organs by antidromic stimulation of dorsal roots, the cutaneous blueing response to the first stimulation was obviously more pronounced than the effect evoked by a subsequent stimulation of another pair of dorsal roots (Pintér and Szolcsányi, 1995, Pintér and Szolcsányi, 1996). Thus, the paradigm was changed and only single

Acknowledgements

Supported by the Hungarian Academy of Sciences and by research Grants of NRDP 1A/021/2002, OTKA TS-040753 and T-034911.

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