Review
TRPV1: a therapeutic target for novel analgesic drugs?

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The vanilloid receptor TRPV1 is now recognized as a molecular integrator of painful stimuli ranging from noxious heat to endovanilloids in inflammation. Pharmacological blockade of TRPV1 represents a new strategy in pain relief. TRPV1 antagonists are expected to prevent pain by silencing receptors where pain is generated rather than stopping the propagation of pain, as most-traditional pain killers do. This hypothesis has already being tested in the clinic by administering small molecule TRPV1 antagonists (e.g. GlaxoSmithKline SB-705498) for migraine and dental pain. Paradoxically, in some murine models of chronic pain, TRPV1-deficient mice exhibit more pain-related behavior than their wild-type littermates, indicating that the understanding of TRPV1 in pain is still incomplete. Moreover, there is mounting evidence to suggest the existence of functional TRPV1 both in the brain and in various non-neuronal tissues. The biological role of these receptors remains elusive, but their tissue distribution clearly indicates that they are involved in many more functions than just pain perception. Here, we review the potential therapeutic indications and adverse effects of TRPV1 antagonists.

Section snippets

The transient receptor potential vanilloid subfamily member 1, TRPV1

It is an exciting time in pain research. The past ten years have seen the emergence of specific small molecule antagonists targeting receptors on sensory neurons that detect painful stimuli. Among these new therapeutic targets, TRPV1 has attracted the most attention [1]. TRPV1 (formerly known as the vanilloid receptor VR1) is probably still best recognized as the receptor for capsaicin, which is responsible for the piquancy of hot chili peppers [2]. Capsaicin is unique among naturally occurring

TRPV1 and its family

Ironically, the founding member of the TRPV vanilloid receptor subfamily TRPV1 remains the only vanilloid receptor that is a target for capsaicin and other vanilloids. Up to date, the TRPV subfamily has six members, TRPV1–TRPV6. TRPV5 and TRPV6 seem to be constitutively active and are thought to have a role in vitamin D-dependent Ca2+ uptake in the kidney and intestine, respectively 8, 9. TRPV4 was originally identified as an osmotic receptor detecting decreased osmolarity [10]. Interestingly,

The broad tissue distribution of TRPV1 and its implications for therapy and side effects

Functional TRPV1 is expressed both in the brain (from the olfactory bulb to the cortex and from the basal ganglia to the cerebellum) [17] and in various non-neuronal tissues. From a pharmacological point of view, this phenomenon might be considered as a double-edged sword: TRPV1 in these tissues might represent a novel therapeutic target and/or mediate unforeseen adverse effects. Either way, these findings place TRPV1 in a much broader context than simply a polymodal pain sensor on primary

TRPV1 is regulated at multiple levels providing opportunities for pharmacological intervention

TRPV1 is now recognized as a molecular integrator of various noxious stimuli, both physical (noxious heat) and chemical (e.g. capsaicin analogs, protons and lipid derivative endovanilloids) (Figure 1). This last group of molecules includes diverse agents such as cannabimimetic lipids (e.g. anandamide 19, 20, 35, N-arachidonoyl dopamine [36] and other endogenous unsaturated C18 N-acetylethanolamines [37]), eicosanoid precursors (e.g. 12- and 5-hydroperoxy-eicosatetraeonic acids) [38] and the

Disease-specific regulation of TRPV1

Disease-related changes in TRPV1 expression are bi-directional. As discussed earlier, increased TRPV1-immunoreactive fiber innervation was demonstrated in inflamed human skin [56], vulva [55] and gastrointestinal tract [54], in addition to tooth pulp with caries [57]. This increase in TRPV1 expression was suggested to contribute to the pathogenesis of various disease states (e.g. reflux esophagitis, inflammatory bowel disease, irritable bowel syndrome, vulvar allodynia and prurigo nodularis),

TRPV1 in bladder disorders

From a theoretical point of view, TRPV1 antagonists are of special interest in bladder disorders because TRPV1, whether overexpressed or not, might be activated by endogenous ligands that can accumulate in the diseased tissue (Figure 2). Therefore, the most-obvious clinical application for TRPV1 antagonists is in the treatment of pain and bladder hyperactivity that accompanies interstitial cystitis, a chronic inflammatory condition of the bladder of unknown etiology. This notion has gained

Migraine and other types of pain or inflammatory conditions

The ability to reduce thermal, but more importantly mechanical, hyperalgesia is a paramount feature of analgesic compounds. Studies in TRPV1-deficient mice clearly showed the role of TRPV1 in thermal, but not mechanical, hyperalgesia 6, 7. The old-generation antagonist capsazepine confirmed this anti-hyperalgesic profile in the rat but, surprisingly, it reduced also mechanical hyperalgesia in the guinea pig [77]. Recently developed antagonists associated the ability to inhibit thermal and

TRPV1-deficient mice predict adverse effects for antagonist

Generally, TRPV1-deficient mice have a benign phenotype, including altered bladder function (high-frequency non-voiding contractions) [25]. Recent findings, however, indicate that such animals might fare much worse than their wild-type littermates under pathological conditions such as post-ischemic recovery of the heart [83]. The well-known French Paradox – that is the protective action of alcoholic beverages on coronary artery disease – might be in part explained with the recent finding that

Future directions

The TRPV1 literature is vast and suffers from many unconfirmed and/or conflicting results. For example, recently both the presence [89] and absence [90] of TRPV1 in mouse dendritic cells have been reported. Such discrepant results need to be resolved. The function of TRPV1 in physiological functions remains poorly understood. There is a clear gap between the unremarkable phenotype of TRPV1-deficient mice and the broad interference of TRPV1 antagonists with physiological functions, ranging from

Concluding remarks

Endovanilloids that act on TRPV1, which is a molecular integrator of noxious stimuli, are believed to have a pivotal role in certain pain conditions. Indeed, desensitization of TRPV1 to the agonist capsaicin and RTX is a powerful approach to relieve inflammatory, post-operative and chronic neuropathic pain [2]. TRPV1 agonists, however, are doing much more than simply desensitizing TRPV1: they render the whole neuron unresponsive to a large series of stimuli unrelated to TRPV1 [2]. Mechanisms

Acknowledgements

We thank Marcello Trevisani for preparing the figures. Furthermore, we apologize to those authors whose work could not be cited owing to length restrictions.

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