42 Current Pharmaceutical Design, 2008, 14, 42-54 1381-6128/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. TRPV1 Receptors in the Central Nervous System: Potential for Previously Unforeseen Therapeutic Applications Katarzyna Starowicz 1 , Luigia Cristino 2 and Vincenzo Di Marzo 1, * 1,2 Endocannabinoid Research Group, 1 Institute of Biomolecular Chemistry and 2 Institute of Cybernetics, C.N.R., Pozzuoli (Naples), Italy Abstract: Increasing evidence exists to support the presence of functional transient receptor potential vanilloid type 1 (TRPV1) channels in the brain, where these receptors are unlikely to be activated by high temperature and low pH. Here we review this evidence as well as the literature data pointing to the potential role of endovanilloid-activated brain TRPV1 channels not only in the supraspinal control of pain, body temperature, cardiovascular and respiratory functions and emesis, but also in anxiety and locomotion. This literature provides the first bases for the possible future development of new therapeutic approaches that, by specifically targeting brain TRPV1 receptors, might be used for the treatment of pain as well as affective and motor disorders. Key Words: TRPV1, brain, central nervous system, anandamide, endovanilloid, capsaicin, vanilloid. INTRODUCTION AND PHARMACOLOGICAL TOOLS TO STUDY THE PHARMACOLOGY OF TRPV1 The transient receptor potential vanilloid type 1 (TRPV1) chan- nel, also known as capsaicin vanilloid receptor-1 (VR1), is best known as a molecular sensor for both chemical (capsaicin, res- iniferatoxin, low pH) and physical (>42° temperatures) nociceptive stimuli in primary sensory neurons [1]. Indeed, consistent with its role in pain, nociception and heat sensing, TRPV1 expression has been confirmed in small to medium diameter primary afferent fibers [1], which are characteristic peptidergic sensory neuronal compo- nents of unmyelinated nociceptive A- and C-fibers [1, 2]. Also non-neuronal cells, such as skin and epidermal cells [3], bladder epithelial (urothelial) cells [4], liver hepatocytes [5], polymor- phonuclear granulocytes [6], pancreatic -cells [7], endothelial cells [8], lymphocytes [9] and macrophages [10] express TRPV1, whose physiological role therein still remains to be established. Resiniferatoxin (RTX) (Fig. 1), a phorbol-related diterpene, affects thermoregulation and neurogenic inflammation via TRPV1 with 3-4 orders of magnitude greater potency than capsaicin [11, 12]. Although RTX mimics capsaicin, it shows differential selectiv- ity in various TRPV1-mediated effects in vivo. It is equipotent to capsaicin for the induction of pain in the rat, as its ED 50 for desensi- tization of neurogenic inflammation is two orders of magnitude lower than that for induction of respiratory distress, whereas cap- saicin causes this latter effect at the same ED 50 necessary for desen- sitization [13]. Although RTX, either unmodified or tritiated, has been widely used as a tool to identify and study vanilloid receptors [14], it is now clear that this compound binds to TRPV1 receptors at binding sites not entirely overlapping with those necessary for capsaicin binding [15]. Structure-activity relationship studies on capsaicin analogs (“capsaicinoids”) [16-19] provided other impor- tant TRPV1 ligands used as tools to investigate the pharmacology of TRPV1 receptors, such as olvanil [20] (Fig. 1). Moreover, the recognition of the chemical similarity between the endocannabinoid anandamide (AEA) and capsaicin, and, even more, between olvanil and the inhibitor of AEA cellular uptake, AM404 [21], led to the identification of other N-acyl-vanillamide TRPV1 agonists that were also cannabinoid CB 1 receptor agonists [22]. The prototypical such compound is arvanil (N-arachidonoyl-vanillylamide), which was synthesized and characterized pharmacologically in our *Address correspondence to this author at the Institute of Biomolecular Chemistry, C.N.R., Via dei Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli (Naples), Italy; Tel: +39-081-8675093; Fax: +39-081-8041770; E-mail: vdimarzo@icmib.na.cnr.it laboratory [22, 23], and represents a “chimeric” ligand combining structural features of capsaicin and AEA and capable of acting as a partial agonist at CB 1 receptors (Fig. 1). Chemical modification of arvanil led to more potent CB 1 /TRPV1 hybrids as well as to selec- tive TRPV1 agonists [24, 25] (Fig. 1), whereas SAR studies on N- ricinoleoyl-vanillamide ended with the development of the most potent “capsaicinoid” TRPV1 agonist ever synthesised, phenyl- acetyl-rinvanil [26] (Fig. 1), whose activity at TRPV1 is compara- ble to that of RTX. Importantly, it was also thanks to SAR studies that a putative endogenous ligand of TRPV1 receptors, N-arachi- donoyl-dopamine (NADA), was first synthesized [27] and then identified in the brain [28], and shown to be capable of activating, like AEA, both CB 1 and TRPV1 receptors. The diminished pain response observed in TRPV1 knockout mice [29, 30], along with the beneficial effect of an anti-TRPV1 antiserum on thermal allodynia and hyperalgesia in diabetic mice [31], suggested the potential therapeutic value for TRPV1 antago- nists in the treatment of pain and hyperalgesia, recently extended also to chronic cough or irritable bowel syndrome [32]. Since the lack of specificity of capsazepine [33, 34], perhaps the most widely used TRPV1 antagonist in pharmacological studies [35, 36] (Fig. 1), might limit its clinical use, a large effort has been dedicated to develop more selective antagonists (see 32, 37, 38 for reviews). Although the list of such compounds is ever increasing, certainly worth of mention are the following selective TRPV1 antagonists: 5’-iodoresiniferatoxin [39, 40], 6’-iodo-nor-dihydro-capsaicin [41], SB-366791 [42], 4-(3-trifluoromethylpyridin-2-yl)piperazine-1-car- boxylic acid (5-trifluoromethylpyridin- 2-yl)amide [43], and (E)-3- (4-tert-butylphenyl)-N-(2,3-dihydrobenzo(b) (1,4)dioxin-6-yl)acryl- amide [44]. Interestingly, some other TRPV1 antagonists have been characterized for their pharmacological profiles, i.e. SB-705498 [45], which successfully completed phase I clinical trials; A- 425619, 1-isoquinolin-5-yl-3-(4-trifluoromethylbenzyl)-urea) [46], which reverses mechanical hyperalgesia in rats [47]; AMG-9810 ((E)-3-(4-t-butylphenyl) - N - (2,3 - dihydrobenzo(b)(1,4)dioxin - 6 - yl) acrylamide), which reverses both thermal and mechanical hyperal- gesia induced by complete Freund’s Adjuvant (CFA) [44], an ani- mal model of arthritis; BCTC (N-(4-Tertiarybutylphenyl) - 4 - (3 - cholorphyridin - 2 - yl)tetrahydropryazine - 1(2H) -carbox-amide), which attenuates the symptoms of both neuropathic and CFA- induced inflammatory pain [48]; GRC 6127, an orally active TRPV1 antagonist against CFA-induced and sciatic nerve ligation- induced hyperalgesia [49]; and, finally, JNJ-17203212, which is efficient at reducing bone pain and blocking citric-acid-induced cough in guinea pigs [50]. A significant effort has been made to develop competitive capsaicin antagonists [51], though most of the