Opinion
TRPV1 antagonists: the challenges for therapeutic targeting

https://doi.org/10.1016/j.molmed.2008.11.004Get rights and content

The capsaicin receptor TRPV1 (transient receptor potential cation channel, subfamily V, member 1) is a polymodal nociceptor whose expression is upregulated in several painful disorders. At present, potent small molecule TRPV1 antagonists are undergoing clinical trials in patients with chronic pain. Clinical development of TRPV1 antagonists is, however, facing new challenges. Many drug candidates evoke a febrile reaction that varies among patients. We speculate that TRPV1 gene polymorphism might be an underlying cause of the inter-subject variability in pain sensation and response to TRPV1 antagonists. This newly understood and yet to be fully validated aspect of pain suggests that pain management based on regulating the TRPV1 receptor might require a personalized approach for effective clinical outcome. Here, we provide our perspectives on current progress in targeting TRPV1.

Section snippets

The TRPV1 receptor – strategically positioned at the root of the problem

The vanilloid (capsaicin) receptor TRPV1 (transient receptor potential cation channel, subfamily V, member 1) is the oldest and best-characterized member of the transient receptor potential (TRP) family of receptors and is activated by various unrelated stimuli (hence the term ‘polymodal’) [1]. The cloning and characterization of TRPV1 by Julius and coworkers in 1997 [2] generated a huge upsurge in research interest among scientists in investigating several aspects of TRPV1 receptor biology,

The TRPV1 receptor: also present in non-neuronal cells

Although TRPV1 is expressed predominantly in primary sensory (dorsal root and trigeminal ganglion) neurons, it is also present (albeit at much lower levels compared with sensory neurons) in various non-neuronal cells, such as keratinocytes [19], urothelial cells [20], smooth muscle cells [21], endothelial cells [22] and cells of the immune system, including mast cells, lymphocytes and dendritic cells (reviewed in [23]). The biological role of the receptors in each of these cells remains

TRPV1: a ‘polymodal’ receptor with complex regulation

TRPV1 is a heat-sensitive channel (a ‘thermoTRP’) that serves as a target for several noxious xenobiotics, including both plant products (e.g. capsaicin, resiniferatoxin) and animal venoms (from spiders and jellyfish) (reviewed in [1]). Various inflammatory mediators (including protons, NGF and prostaglandin metabolites) and signaling components are also believed to be involved in sensitization and/or activation of peripheral TRPV1 receptors (reviewed in 1, 29, 51). Activated peripheral TRPV1

TRPV1 gene polymorphism: pain and beyond

Humans report strikingly variable pain experience in response to similar noxious stimuli. There is a growing speculation that part of this inter-individual variability in pain response and therapy could be associated with genetic polymorphism [67]. Gene polymorphism might impede on the generation, transmission and processing of nociceptive information or increase the local availability of active analgesic or its pharmaco-dynamic properties. Investigations at the gene level have commenced to

TRPV1 antagonists in clinical development: soothing the pain but lighting a fire?

Given the crucial role of TRPV1-mediated signaling in the pain-transmission process, therapeutic intervention into TRPV1 signaling is being attempted by pharmaceutical companies via many different approaches, some of which have shown promising signs at various stages of discovery, preclinical or clinical research. Investigators at Grünenthal demonstrated that TRPV1 blockade using siRNA and antisense oligonucleotide platforms represents a valid approach for developing new pain therapeutics 81, 82

Concluding remarks

Targeting TRPV1 represents a new strategy in pain relief. Many pharmaceutical companies have focused their discovery efforts on developing TRPV1 antagonists for the treatment of human pain disorders. Of the several TRPV1 receptor antagonists reported in the literature, a number have entered into clinical trials successfully (e.g. NGD8243, SB-705498, AMG 517, AMG 986, AMG 628, AZD1386, GRC 6211, SAR-115740, M68008, AZD1386 and JTS-653) (Table 1). Most of the trial drugs are still under clinical

Disclosure statement

N.K-J. was involved in the preclinical development of GRC 6211, a TRPV1 antagonist that was subsequently licensed to Eli Lilly. A.S. is a member of the Scientific Advisory Board to Glenmark.

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