The TRPV3 Receptor as a Pain Target: A Therapeutic Promise or Just Some More New Biology?!2009-12-02!2010-02-25!2010-07-26! (original) (raw)
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TRPV1 Antagonists and Chronic Pain: Beyond Thermal Perception
Pharmaceuticals, 2012
In the last decade, considerable evidence as accumulated to support the development of Transient Receptor Potential Vanilloid 1 (TRPV1) antagonists for the treatment of various chronic pain conditions. Whereas there is a widely accepted rationale for the development of TRPV1 antagonists for the treatment of various inflammatory pain conditions, their development for indications of chronic pain, where conditions of tactical, mechanical and spontaneous pain predominate, is less clear. Preclinical localization and expression studies provide a firm foundation for the use of molecules targeting TRPV1 for conditions of bone pain, osteoarthritis and neuropathic pain. Selective TRPV1 antagonists weakly attenuate tactile and mechanical hypersensivity and are partially effective for behavioral and electrophysiological endpoints that incorporate aspects of spontaneous pain. While initial studies with TRPV1 antagonist in normal human subjects indicate a loss of warm thermal perception, clinical studies assessing allelic variants suggests that TRPV1 may mediate other sensory modalities under certain conditions. The focus of this review is to summarize the current perspectives of TRPV1 for the treatment of conditions beyond those with a primary thermal sensitivity.
ThermoTRP Channels in Nociceptors: Taking a Lead from Capsaicin Receptor TRPV1
Current Neuropharmacology, 2008
Nociceptors with peripheral and central projections express temperature sensitive transient receptor potential (TRP) ion channels, also called thermoTRP's. Chemosensitivity of thermoTRP's to certain natural compounds eliciting pain or exhibiting thermal properties has proven to be a good tool in characterizing these receptors. Capsaicin, a pungent chemical in hot peppers, has assisted in the cloning of the first thermoTRP, TRPV1. This discovery initiated the search for other receptors encoding the response to a wide range of temperatures encountered by the body. Of these, TRPV1 and TRPV2 encode unique modalities of thermal pain when exposed to noxious heat. The ability of TRPA1 to encode noxious cold is presently being debated. The role of TRPV1 in peripheral inflammatory pain and central sensitization during chronic pain is well known. In addition to endogenous agonists, a wide variety of chemical agonists and antagonists have been discovered to activate and inhibit TRPV1. Efforts are underway to determine conditions under which agonistmediated desensitization of TRPV1 or inhibition by antagonists can produce analgesia. Also, identification of specific second messenger molecules that regulate phosphorylation of TRPV1 has been the focus of intense research, to exploit a broader approach to pain treatment. The search for a role of TRPV2 in pain remains dormant due to the lack of suitable experimental models. However, progress into TRPA1's role in pain has received much attention recently. Another ther-moTRP, TRPM8, encoding for the cool sensation and also expressed in nociceptors, has recently been shown to reduce pain via a central mechanism, thus opening a novel strategy for achieving analgesia. The role of other thermoTRP's (TRPV3 and TRPV4) encoding for detection of warm temperatures and expressed in nociceptors cannot be excluded. This review will discuss current knowledge on the role of nociceptor thermoTRPs in pain and therapy and describes the activator and inhibitor molecules known to interact with them and modulate their activity.
Polypeptide Modulators of TRPV1 Produce Analgesia without Hyperthermia
Marine Drugs, 2013
Transient receptor potential vanilloid 1 receptors (TRPV1) play a significant physiological role. The study of novel TRPV1 agonists and antagonists is essential. Here, we report on the characterization of polypeptide antagonists of TRPV1 based on in vitro and in vivo experiments. We evaluated the ability of APHC1 and APHC3 to inhibit TRPV1 using the whole-cell patch clamp approach and single cell Ca2+ imaging. In vivo tests were performed to assess the biological effects of APHC1 and APHC3 on temperature sensation, inflammation and core body temperature. In the electrophysiological study, both polypeptides partially blocked the capsaicin-induced response of TRPV1, but only APHC3 inhibited acid-induced (pH 5.5) activation of the receptor. APHC1 and APHC3 showed significant antinociceptive and analgesic activity in vivo at reasonable doses (0.01-0.1 mg/kg) and did not cause hyperthermia. Intravenous administration of these polypeptides prolonged hot-plate latency, blocked capsaicin- and formalin-induced behavior, reversed CFA-induced hyperalgesia and produced hypothermia. Notably, APHC3's ability to inhibit the low pH-induced activation of TRPV1 resulted in a reduced behavioural response in the acetic acid-induced writhing test, whereas APHC1 was much less effective. The polypeptides APHC1 and APHC3 could be referred to as a new class of TRPV1 modulators that produce a significant analgesic effect without hyperthermia.
Neurophysiology, 2013
Transient receptor potential channels (TRP) have been extensively investigated over the past few years. Recent findings in the field of pain have established a family of six thermoTRP channels (TRPA1, TRPM8, TRPV1, TRPV2, TRPV3, and TRPV4) that exhibits sensitivity to increases or decreases in temperature, as well as to chemical substances eliciting the respective hot or cold sensations. Such irritants include menthol, cinnamaldehyde, gingerol, mustard oil, capsaicin, camphor, eugenol, and others. In this study, we used behavioral and electrophysiological methods to investigate if mustard oil (allyl isothiocyanate, AITC) and capsaicin affect the sensitivity to thermal, innocuous cold, and mechanical stimuli in male rats. Unilateral intraplantar injection of AITC and capsaicin induced significant decreases in the latency for ipsilateral paw withdrawal from a noxious heat stimulus, i.e., heat hyperalgesia. These agents also significantly reduced the mechanical withdrawal thresholds of the injected paw, i.e., mechanical allodynia. Bilateral intraplantar injections of AITC resulted in a two-phase effect on cold avoidance (thermal preference test). A low concentration of AITC (5%) did not change cold avoidance similarly to the vehicle control, while higher AITC concentrations (10 and 15%) significantly reduced cold avoidance, i.e., induced cold hypoalgesia. Capsaicin acted in almost the same manner. These results indicate that TRPA1 channels are clearly involved in pain reactions, and the TRPA1 agonist AITC enhances the heat pain sensitivity, possibly by indirectly modulating TRPV1 channels, which are co-expressed in nociceptors with TRPA1s. In electrophysiological experiments, neuronal responses to electrical and graded mechanical and noxious thermal stimulations were tested before and after cutaneous application of AITC. Repetitive application of AITC initially increased the firing rate of spinal wide-dynamic range neurons; this was followed by rapid desensitization that persisted when AITC application was reapplied 30 min later. The responses to noxious thermal (but not to mechanical) stimuli were significantly enhanced irrespective of whether the neuron was directly activated by AITC. These findings indicate that AITC produced peripheral sensitization of heat nociceptors. Overall, our data support the role of hermosensitive TRPA1 and TRPV1 channels in pain modulation and show that these thermoTRP channels are promising targets for the development of a new group of analgesic drugs.
Neurophysiology, 2011
Transient receptor potential channels (TRP) have been extensively investigated over the past few years. Recent findings in the field of pain have established a family of six thermoTRP channels (TRPA1, TRPM8, TRPV1, TRPV2, TRPV3, and TRPV4) that exhibits sensitivity to increases or decreases in temperature, as well as to chemical substances eliciting the respective hot or cold sensations. Such irritants include menthol, cinnamaldehyde, gingerol, mustard oil, capsaicin, camphor, eugenol, and others. In this study, we used behavioral and electrophysiological methods to investigate if mustard oil (allyl isothiocyanate, AITC) and capsaicin affect the sensitivity to thermal, innocuous cold, and mechanical stimuli in male rats. Unilateral intraplantar injections of AITC and capsaicin induced significant decreases in the latency for ipsilateral paw withdrawal from a noxious heat stimulus, i.e., heat hyperalgesia. These agents also significantly reduced the mechanical withdrawal thresholds of the injected paw, i.e., mechanical allodynia. Bilateral intraplantar injections of AITC resulted in a twophase effect on cold avoidance (thermal preference test). A low concentration of AITC (5%) did not change cold avoidance similarly to the vehicle control, while higher AITC concentrations (10 and 15%) significantly reduced cold avoidance, i.e., induced cold hypoalgesia. Capsaicin acted in almost the same manner. These results indicate that TRPA1 channels are clearly involved in pain reactions, and the TRPA1 agonist AITC enhances the heat pain sensitivity, possibly by indirectly modulating TRPV1 channels co-expressed in nociceptors with TRPA1s. In electrophysiological experiments, neuronal responses to electrical and graded mechanical and noxious thermal stimulations were tested before and after cutaneous application of AITC. Repetitive application of AITC initially increased the firing rate of spinal wide-dynamic range neurons; this was followed by rapid desensitization that persisted when AITC application was reapplied 30 min later. The responses to noxious thermal (but not to mechanical) stimuli were significantly enhanced irrespective of whether the neuron was directly activated by AITC. These findings indicate that AITC produced peripheral sensitization of heat nociceptors. Overall, our data support the role of hermosensitive TRPA1 and TRPV1 channels in pain modulation and show that these thermoTRP channels are promising targets for the development of a new group of analgesic drugs.
TRPV1: a therapeutic target for novel analgesic drugs?
Trends in Molecular Medicine, 2006
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 wildtype 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.
Contributions of different modes of TRPV1 activation to TRPV1 antagonist-induced hyperthermia
2010
Transient receptor potential vanilloid-1 (TRPV1) antagonists are widely viewed as next-generation pain therapeutics. However, these compounds cause hyperthermia, a serious side effect. TRPV1 antagonists differentially block three modes of TRPV1 activation: by heat, protons, and chemical ligands (e.g., capsaicin). We asked what combination of potencies in these three modes of TRPV1 activation corresponds to the lowest potency of a TRPV1 antagonist to cause hyperthermia. We studied hyperthermic responses of rats, mice, and guinea pigs to eight TRPV1 antagonists with different pharmacological profiles and used mathematical modeling to find a relative contribution of the blockade of each activation mode to the development of hyperthermia. We have found that the hyperthermic effect has the highest sensitivity to the extent of TRPV1 blockade in the proton mode (0.43 to 0.65) with no to moderate sensitivity in the capsaicin mode (-0.01 to 0.34) and no sensitivity in the heat mode (0.00 to 0.01). We conclude that hyperthermia-free TRPV1 antagonists do not block TRPV1 activation by protons, even if they are potent blockers of the heat mode, and that decreasing the potency to block the capsaicin mode may further decrease the potency to cause hyperthermia.
TRPV1: On the Road to Pain Relief
Current Molecular Pharmacology, 2008
Historically, drug research targeted to pain treatment has focused on trying to prevent the propagation of action potentials in the periphery from reaching the brain rather than pinpointing the molecular basis underlying the initial detection of the nociceptive stimulus: the receptor itself. This has now changed, given that many receptors of nociceptive stimuli have been identified and/or cloned. Transient Receptor Potential (TRP) channels have been implicated in several physiological processes such as mechanical, chemical and thermal stimuli detection. Ten years after the cloning of TRPV1, compelling data has been gathered on the role of this channel in inflammatory and neuropathic states. TRPV1 activation in nociceptive neurons, where it is normally expressed, triggers the release of neuropeptides and transmitters resulting in the generation of action potentials that will be sent to higher CNS areas where they will often be perceived as pain. Its activation also will evoke the peripheral release of pro-inflammatory compounds that may sensitize other neurons to physical, thermal or chemical stimuli. For these reasons as well as because its continuous activation causes analgesia, TRPV1 has become a viable drug target for clinical use in the management of pain. This review will provide a general picture of the physiological and pathophysiological roles of the TRPV1 channel and of its structural, pharmacological and biophysical properties. Finally, it will provide the reader with an overall view of the status of the discovery of potential therapeutic agents for the management of chronic and neuropathic pain.