molecules Review Capsaicin: Current Understanding of Its Mechanisms and Therapy of Pain and Other Pre-Clinical and Clinical Uses Victor Fattori †, Miriam S. N. Hohmann †, Ana C. Rossaneis, Felipe A. Pinho-Ribeiro and Waldiceu A. Verri Jr. * Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, Rodovia Celso Garcia Cid KM480 PR445, Caixa Postal 10.011, 86057-970 Londrina, Paraná, Brazil; [email protected] (V.F.); [email protected] (M.S.N.H.); [email protected] (A.C.R.); [email protected] (F.A.P.-R.) * Correspondence: [email protected] or [email protected]; Tel.: +55-43-3371-4979 † These authors contributed equally to this paper. Academic Editor: Pin Ju Chueh Received: 27 April 2016; Accepted: 27 April 2016; Published: 28 June 2016 Abstract: In this review, we discuss the importance of capsaicin to the current understanding of neuronal modulation of pain and explore the mechanisms of capsaicin-induced pain. We will focus on the analgesic effects of capsaicin and its clinical applicability in treating pain. Furthermore, we will draw attention to the rationale for other clinical therapeutic uses and implications of capsaicin in diseases such as obesity, diabetes, cardiovascular conditions, cancer, airway diseases, itch, gastric, and urological disorders. Keywords: analgesia; capsaicinoids; chili peppers; desensitization; TRPV1 1. Introduction Capsaicin is a compound found in chili peppers and responsible for their burning and irritant effect. In addition to the sensation of heat, capsaicin produces pain and, for this reason, is an important tool in the study of pain. Although our understanding of pain mechanisms has evolved greatly through the development of new techniques, experimental tools are still extremely necessary and widely used. Among these basic experimental tools for the study of pain mechanisms and development of novel analgesics, we can fairly consider capsaicin as one of the most important sources of knowledge in the pain field. Curiously, many recent studies have confirmed scientifically what was already known by some cultures: capsaicin can also be used to relieve pain [1]. This paradox can also be seen with opioids, which have an established clinical use as analgesics, but also induce hyperalgesia [2]. Therefore, the complexities of capsaicin-triggered responses as well as its therapeutic usefulness highlight the importance of understanding its mechanisms of action not only in pain modulation, but also in other pathological conditions. In this review, we will highlight the importance of capsaicin to the current understanding of neuronal modulation of pain and explore some mechanisms of capsaicin-induced pain. We will focus on the analgesic effects of capsaicin and its clinical applicability in treating pain. Furthermore, we will draw attention to the rationale for other clinical therapeutic uses and implications of capsaicin in diseases such as obesity, diabetes, cardiovascular conditions, cancer, airway diseases, itch, gastric, and urological disorders. 1.1. Discovery, Natural Sources, Role in Plants, Isolation, and Structure of Capsaicin Chili peppers contain capsaicin (8-methyl-N-vanillyl-6-nonenamide), a phenolic compound responsible for their characteristic taste and pungency. All plants from Capsicum genus produce varied Molecules 2016, 21, 844; doi:10.3390/molecules21070844 www.mdpi.com/journal/molecules Molecules 2016, 21, 844 2 of 31 1.1. Discovery, Natural Sources, Role in Plants, Isolation, and Structure of Capsaicin Molecules 2016, 21, 844 2 of 33 Chili peppers contain capsaicin (8-methyl-N-vanillyl-6-nonenamide), a phenolic compound responsible for their characteristic taste and pungency. All plants from Capsicum genus produce varied amountsamounts of capsaicin, exceptexceptCapsicum Capsicum annum annum, and, and all all of of them them have have been been used used as aas spice a spice ingredient ingredient and andconsumed consumed by humans by humans for overfor over 6000 6000 years years [3,4 [3,4].]. The The quantities quantities of capsaicinof capsaicin can can represent represent up up to 1%to 1% of theof themass mass of the of chilithe chili peppers peppers and, togetherand, together with salt,with represent salt, represent the most the consumed most consumed condiment condiment by humans. by humans.Capsaicin Capsaicin is an intriguing is an intriguing molecule molecule since the consumptionsince the consumption of chili peppers of chili evokes peppers opposing evokes sensationsopposing sensations(pleasant and(pleasant unpleasant) and unpleasant) depending ondepending the individual on the experience individual andexpe chilirience pepper and consumptionchili pepper consumptionhabits. The effectshabits. ofThe capsaicin effects of go capsaicin well beyond go well the beyond taste and the its taste role and in plants’its role healthin plants’ help health us to helpunderstand us to understand how its use how can its improve use can human improve health human [4]. health [4]. TheThe production production of of capsaicin capsaicin among among plants plants from from the the Capsicum Capsicum genus genus was was well well conserved, conserved, likely likely duedue to to its its roles roles in in seed germination and and protection protection from from parasites. In In fact, fact, capsaicin capsaicin is is not not equally equally distributeddistributed in in all all parts parts of of pepper pepper fruit. fruit. Its Its concentr concentrationation is is higher higher in in the the area area surrounding surrounding the the seeds seeds (placental(placental tissue) tissue) and and this this localization localization is is related related di directlyrectly to to the the role role of of capsaicin capsaicin in in protecting protecting seed seed germinationgermination [5]. [5]. The The aversion aversion to to eating eating large large am amountsounts of of capsaicin capsaicin keeps keeps rodents rodents and and other other mammals mammals awayaway and and this this represents represents an an important important mechanis mechanismm to to increase increase the the chances chances of of germination germination since since mammalsmammals can can grind grind and and digest digest the the seeds seeds making making them them unable unable to to germinate. germinate. Birds, Birds, on on the the other other hand, hand, cannotcannot feel feel this this unplea unpleasantsant taste taste of of peppers peppers [6]. [6]. Importantly, Importantly, pepper pepper seeds seeds re resistsist to to birds´ birds´ digestive tract,tract, making making them them the the perfect perfect consumers. consumers. Capsaicin Capsaicin also also protects protects plants plants from from parasites parasites such such as as insects insects andand mold, mold, and and humans humans have have been been using using this this property property to to treat treat infectious infectious di diseasesseases and and to to preserve preserve foodfood [7,8]. [7,8]. DespiteDespite the the unpleasant unpleasant sensation sensation that that occurs occurs when when large large quantities quantities of of chili chili peppers peppers are are consumed, consumed, capsaicincapsaicin promotes promotes pain pain relief relief when when used used in inthe the righ rightt dosage dosage and and frequency. frequency. These These properties properties caught caught the attentionthe attention of researchers of researchers long long ago ago and and still still do donowadays, nowadays, boosting boosting our our knowledge knowledge about about capsaicin. capsaicin. CapsaicinCapsaicin was was first first purified purified in in 1876 1876 [9] [9] but but its its stru structurecture started started to to be be described described only only in in 1919 1919 [10]. [10]. Currently,Currently, the structure structure and and properties properties of of capsaicin capsaicin are are well well defined defined (Figure (Figure 11).). Capsaicin presents a nonpolarnonpolar phenolic structurestructure and and thus thus cannot cannot be be solubilized solubilized in water. in water. The mainThe main solvents solvents used toused extract to extractand maintain and maintain capsaicin capsaicin properties properties are nonpolar are nonpol solventsar solvents such as ether,such as benzene, ether, benzene, dimethyl dimethyl sulfoxide sulfoxideand acetone, and butacetone, ethanol but can ethanol also be can used also as be a used solvent as duea solvent to its due mixed to its properties. mixed properties. BecauseBecause of of its its chemical chemical structur structure,e, capsaicin capsaicin can can be be well well absorbed absorbed when when administered administered topically topically oror orally, orally, reaching up to 94% of absorption [11]. [11]. Following Following its its discovery discovery and and characterization, characterization, it it was was observedobserved that that capsaicin capsaicin is is actually actually part part of of a a family family of of compounds compounds that that share share similar similar structural structural and and biologicbiologic char characteristics.acteristics. FigureFigure 1. 1. ChemicalChemical structure structure of of capsaicin capsaicin and and capsaicino capsaicinoids.ids. Molecules Molecules of of capsaicin capsaicin and and capsaicinoids capsaicinoids availableavailable in in PubChem PubChem database database [12–16]. [12–16]. Compound Compound identifier identifier (CID) (CID) number number is is provided provided in in parentheses. parentheses. MoleculesMolecules were were drawn