Review
Targeting TRP channels for pain relief

https://doi.org/10.1016/j.ejphar.2013.03.003Get rights and content

Abstract

Preclinical research has recently uncovered new molecular mechanisms underlying the generation and transduction of pain, many of which represent opportunities for pharmacological intervention. Manipulating temperature-sensitive Transient Receptor Potential (TRP) channels (so-called “thermoTRPs”) on nociceptive neurons is a particularly attractive strategy in that it targets the beginning of the pain pathway. In the focus of current drug development efforts are the heat-sensitive TRPV1, warm-activated TRPV3, cold-responsive TRPA1, and cool-activated TRPM8 channels. TRPV1 desensitization by topical agonists (e.g. high concentration capsaicin creams and patches) has been in clinical use for decades to alleviate chronic painful conditions like diabetic neuropathy. Currently, site-specific resiniferatoxin (an ultrapotent capsaicin analogue) injections are being evaluated as “molecular scalpels” to achieve permanent analgesia in cancer patients with chronic, intractable pain. In the past few years a number of potent, small molecule TRPV1, TRPV3 and TRPA1 antagonists have been advanced into clinical trials for the treatment of inflammatory, neuropathic and visceral pain. TRPM8 antagonists are following closely behind for cold allodynia. Early TRPV1 antagonists in the clinic, however, showed worrisome adverse effects including hyperthermia and impaired noxious heat sensation. These adverse effects placed the patients at risk for scalding injury and prompted their withdrawal from the clinical trials. Second generation TRPV1 antagonists that do not cause core body temperature elevation have been reported, although the therapeutic utility of this class of compounds is not yet known. This review discusses the promise and challenges of developing TRP channel antagonists as a new generation of pain therapeutics.

Introduction

Chronic pain affects a large segment of the population, an estimated 50 million Americans, and costs the country billions of dollars in health care costs and lost productivity. Although the Decade of Pain Control and Research has given new impetus to pain research, the translation of preclinical research into clinical practice is slow to occur. This is evident by the limited number of mechanistically novel therapeutic agents that have entered into the clinic for the treatment of pain in recent years. Consequently, agents that have been around for decades such as opiates and non-steroidal anti-inflammatory drugs (NSAID) still represent a mainstay in the current pain therapy. However, NSAIDs have only modest effects on moderate to severe pain and their use is limited by a combination of gastro-intestinal and cardiovascular side effects. Opiates are effective pain killers but their use is complicated by sedation, constipation and itch, as well as concerns regarding tolerance and abuse. Clearly, new potent analgesic drugs with an acceptable safety profile are needed.

Preclinical research has identified an array of new molecular mechanisms that are involved in the development and maintenance of chronic pain and may represent attractive targets for pharmacological intervention. A key discovery was the molecular cloning of the vanilloid (capsaicin) receptor TRPV1 (transient receptor potential, vanilloid subfamily member 1) (Caterina et al., 1997). TRPV1 functions as a heat-sensitive, non-selective cation channel with a preference for Ca2+ whose heat-activation threshold is lowered by inflammatory agents (reviewed in Caterina and Julius, 2001, Szallasi et al., 2007). TRPV1 can be both up-regulated and sensitized during inflammation and injury (Bishnoi and Premkumar, 2012). Indeed, TRPV1 was suggested to play a central role in peripheral sensitization (Immke and Gavva, 2006). In keeping with this concept, mice whose TRPV1 gene has been deleted by genetic manipulation are devoid of the thermal hyperalgesia that develops following inflammation (Caterina et al., 2000, Davis et al., 2000).

TRPV1 belongs to the TRP superfamily of ion channels which, in humans, constitutes a diverse family of 28 cation channels with varied physiological functions (reviewed in Wu et al. (2010)). Their name stems from sequence similarities to the original trp gene from Drosophila which, when mutated, resulted in a transient receptor potential in the presence of continued exposure to light. Overall, few generalizations can be made about TRP channels. Consistent with their diverse structure, TRP channels serve diverse afferent (transduction of mechanical, chemical, thermal stimuli) and efferent (e.g. growth control, cellular differentiation, thermoregulation, vasoregulation and mediator release) functions (reviewed in Wu et al. (2010)). These TRP channel properties may be exploited therapeutically but can also pose problems for drug development in terms of on-target adverse effects (reviewed in Patapoutian et al., 2009, Moran et al., 2011).

Of the 28 TRP channels discovered to date, seven sense hot or warm temperatures (TRPV1, TRPV2, TRPV3, TRPV4, TRPM2, TRPM4, and TRPM5) whereas two are activated by cold or cool (TRPA1 and TRPM8) (reviewed in Patapoutian et al., 2003, Mandadi and Roufogalis, 2008). Together, these channels, referred to as “thermoTRPs”, cover a wide temperature range with extremes that fall between 10 °C (TRPA1) and 53 °C (TRPV2) (Numazaki and Tominaga, 2004). Animal data and human genetic studies have shown that TRP channel dysfunction (“TRP channelopathy”) can cause various pathological conditions (reviewed in Nilius et al. (2007)). Given the pivotal role of TRP channels in nociceptive transduction (Patapoutian et al., 2009), it is a bit unexpected that so far only a somewhat obscure human pain condition, Familial Episodic Pain Syndrome, has been linked to a TRP channelopathy, namely a gain-of-function mutation in TRPA1 (Kremeyer et al., 2010).

Section snippets

The vanilloid (capsaicin) receptor as a “hot” pain target

A subset of nociceptive sensory neurons is distinguished by its unique sensitivity to capsaicin, responsible for the piquancy of hot chilli peppers (reviewed in Szallasi and Blumberg (1999)). A specific receptor for capsaicin was identified as TRPV1 (Caterina et al., 1997). The initial TRPV1-mediated stimulation of these neurons by capsaicin (perceived in humans as a burning sensation) is followed by a lasting refractory state, traditionally referred to as desensitization, in which the

Therapeutic potential of TRPV3 antagonists

TRPV3 is the third member of the transient receptor potential vanilloid (TRPV) family. TRPV3 functions as a non-selective cation channel (with permeability to Ca2+ and Na+) following activation by thermal or chemical stimuli (Peier et al., 2002a, Smith et al., 2002, Xu et al., 2002). As a thermoreceptor, TRPV3 is activated in vitro by temperatures in the warm range (33–39 °C) with an activation threshold of 33 and 34 °C (Peier et al., 2002a, Xu et al., 2002). A non-selective activator of TRPV3,

Targeting TRPM8 to relieve cold allodynia

Hypersensitivity to cold (manifested as cold hyperalgesia or allodynia) is often noted in patients with neuropathic pain and can be disabling with unsatisfactory treatment options. TRPM8 is a cold-sensitive receptor (McKemy et al., 2002, Peier et al., 2002b) and genetic deletion has identified TRPM8 as a potential therapeutic target for the relief of cold hypersensitivity (Bautista et al., 2007, Colburn et al., 2007, Dhaka et al., 2007). For example, wild-type mice with sciatic nerve injury

TRPA1 antagonists

TRPA1 is the first and only member of the mammalian transient receptor potential ankyrin family of proteins. Like other TRP channels, TRPA is non-selectively permeable to small cations. Structurally TRPA1 has a large N-terminus with multiple ankyrin repeats, suggestive of a role in mechanosensation. TRPA1 functions as a polymodal receptor, as it can be activated in vitro by mechanical, osmotic, thermal and chemical stimuli (Story et al., 2003, Jordt et al., 2004, Corey et al., 2004, Zhang et

Perspective

Nearly 15 years of research has provided preclinical evidence for the involvement of thermoTRP channels in nociceptive transmission and sensitization, and the identification of potent and subtype selective chemical matter that demonstrates attractive preclinical pharmacological activity. Widespread pharmaceutical interest in these targets will create the opportunity to test these mechanisms clinically in chronic pain patients over the next few years. First generation TRPV1 antagonists that

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