TRP channel antagonists for pain--opportunities beyond TRPV1.
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Abstract:
There is emerging evidence that transient receptor potential (TRP) ion channels expressed in sensory neurons are important for the transduction of chemical, thermal and mechanical signals. Increasing research efforts are directed at understanding the roles of sensory TRP channels in acute and chronic pain. Studies using RNAi techniques to reduce the levels of individual TRP channels or genetically modified mice lacking specific channels are being complemented with pharmacological studies using newly discovered investigational compounds. These studies are providing evidence that drugs that interfere with the function of TRPA1, TRPM8, TRPV4 or TRPV3 may be useful in treating pain.Keywords:
TRPM8
TRPV4
Transduction (biophysics)
TRPV
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TRPM8
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Capsaicin
Cold sensitivity
Sensory neuron
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The cloning of the first sensory Transient Receptor Potential (TRP) channel, TRPVanilloid 1 (TRPV1) in 1997, initiated a new era of pain research and coincided with the Decade of Pain Control and Research promulgated by the United States Congress. When cloned, TRPV1 channel was shown to be predominantly expressed in nociceptors (C- and A -fibers) and are activated by physical and chemical stimuli. Channel function can be amplified by transcriptional upregulation and posttranslational modification by proinflammatory agents. Indeed, TRPV1 gene disruption confirms that it is involved in transmitting inflammatory thermal hypersensitivity, but not acute thermal or mechanical pain sensitivity. Based on its distribution and functions, TRPV1 is considered as an ideal target for developing small molecule antagonists. Now, there is a growing body of evidence that TRPV1 is expressed in non-sensory neurons and non-neuronal cells. This raises the possibility of unwanted effects that may result from targeting TRPV1. A major consequence of TRPV1 blockade that has come to light in clinical trials following administration of antagonists is hyperthermia. This observation has threatened the abandonment of TRPV1 antagonists, although they are proven to be useful in certain modalities of pain. In this review, we will discuss the expression and functions of TRPV1 in various organ systems and highlight the consequences that might be associated with blocking the receptor.
Resiniferatoxin
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Capsazepine
Capsaicin
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Transient receptor potential (TRP) channels are a group of membrane proteins involved in the transduction of a plethora of chemical and physical stimuli. These channels modulate ion entry, mediating a variety of neural signaling processes implicated in the sensation of temperature, pressure, and pH, as well as smell, taste, vision, and pain perception. Many diseases involve TRP channel dysfunction, including neuropathic pain, inflammation, and respiratory disorders. In the pursuit of new treatments for these disorders, it was discovered that cannabinoids can modulate a certain subset of TRP channels. The TRP vanilloid (TRPV), TRP ankyrin (TRPA), and TRP melastatin (TRPM) subfamilies were all found to contain channels that can be modulated by several endogenous, phytogenic, and synthetic cannabinoids. To date, six TRP channels from the three subfamilies mentioned above have been reported to mediate cannabinoid activity: TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8. The increasing data regarding cannabinoid interactions with these receptors has prompted some researchers to consider these TRP channels to be "ionotropic cannabinoid receptors." Although CB1 and CB2 are considered to be the canonical cannabinoid receptors, there is significant overlap between cannabinoids and ligands of TRP receptors. The first endogenous agonist of TRPV1 to be discovered was the endocannabinoid, anandamide (AEA). Similarly, N-arachidonyl dopamine (NADA) and AEA were the first endogenous TRPM8 antagonists discovered. Additionally, Δ9-tetrahydrocannabinol (Δ9-THC), the most abundant psychotropic compound in cannabis, acts most potently at TRPV2, moderately modulates TRPV3, TRPV4, TRPA1, and TRPM8, though Δ9-THC is not reported to modulate TRPV1. Moreover, TRP receptors may modulate effects of synthetic cannabinoids used in research. One common research tool is WIN55,212-2, a CB1 agonist that also exerts analgesic effects by desensitizing TRPA1 and TRPV1. In this review article, we aim to provide an overview and classification of the cannabinoid ligands that have been reported to modulate TRP channels and their therapeutic potential.
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Preclinical research has identified an array of ion channels in sensory neurons involved in the generation and transduction of pain as potential targets for pharmacological intervention. Paramount among these new targets is the family of thermosensitive transient receptor potential channels, referred to as "thermoTRPs". We detect a wide range of noxious stimuli via a limited number (as of today, six) of thermoTRP channels, four of which (TRPV1-TRPV4) respond to heat and two (TRPA1 and TRPM8) are sensitive to cold. Targeting these thermoTRP channels represents a new and logical strategy in pain relief. Unlike traditional analgesic drugs that either suppress inflammation (e.g. NSAIDs and COX-2 inhibitors) or block pain transmission (e.g. opiates), TRP channel inhibitors aim to prevent pain by blocking a receptor where pain is generated. The archetypal thermoTRP is the vanilloid (capsaicin) receptor TRPV1. TRPV1 has a dynamic threshold of activation. Agents in inflammatory soup, including endogenous TRPV1 agonists (so-called "endovanilloids"), act in concert to reduce the heat activation threshold of TRPV1. In patients, the expression of TRPV1 is up-regulated in a number of painful inflammatory disorders. TRPV1 as a pain target has been validated by genetic deletion and pharmacological inhibition experiments. This area of drug development has been moving rapidly. It took less than a decade from the cloning of TRPV1 to clinical trials with potent small molecule TRPV1 antagonists. This review evaluates current evidence that supports particular TRP channels as targets for novel analgesic drugs, along with potential adverse effects that may limit drug development.
TRPM8
Capsaicin
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Transient receptor potential (TRP) receptors are ion channels that mediate pain and inflammation. We provide evidence for the distinct roles of TRPV1 and TRPA1 in arthritis.
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The transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) channels are members of the TRP superfamily of structurally related, non-selective cation channels. It is rapidly becoming clear that the functions of TRPV1 and TRPA1 interlink with each other to a considerable extent. This is especially clear in relation to pain and neurogenic inflammation where TRPV1 is coexpressed on the vast majority of TRPA1-expressing sensory nerves and both integrate a variety of noxious stimuli. The more recent discovery that both TRPV1 and TRPA1 are expressed on a multitude of non-neuronal sites has led to a plethora of research into possible functions of these receptors. Non-neuronal cells on which TRPV1 and TRPA1 are expressed vary from vascular smooth muscle to keratinocytes and endothelium. This review will discuss the expression, functionality and roles of these non-neuronal TRP channels away from sensory nerves to demonstrate the diverse nature of TRPV1 and TRPA1 in addition to a direct role in pain and neurogenic inflammation.
mechanosensation
Neurogenic inflammation
Ankyrin
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Capsaicin
Nociceptor
Neurogenic inflammation
Resiniferatoxin
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Transient receptor potential ion channels in primary sensory neurons as targets for novel analgesics
The last decade has witnessed an explosion in novel findings relating to the molecules involved in mediating the sensation of pain in humans. Transient receptor potential (TRP) ion channels emerged as the greatest group of molecules involved in the transduction of various physical stimuli into neuronal signals in primary sensory neurons, as well as, in the development of pain. Here, we review the role of TRP ion channels in primary sensory neurons in the development of pain associated with peripheral pathologies and possible strategies to translate preclinical data into the development of effective new analgesics. Based on available evidence, we argue that nociception-related TRP channels on primary sensory neurons provide highly valuable targets for the development of novel analgesics and that, in order to reduce possible undesirable side effects, novel analgesics should prevent the translocation from the cytoplasm to the cell membrane and the sensitization of the channels rather than blocking the channel pore or binding sites for exogenous or endogenous activators.
Nociceptor
Sensation
Transduction (biophysics)
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Pungency
Allyl isothiocyanate
Capsaicin
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