Hot off the presses! Apr 01 Brain Res Rev

The Apr 01 issue of the Brain Res Rev is now up on Pubget (About Brain Res Rev): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Spring Pain Research Conference 2008
  - Brain Res Rev 60(1):1 (2009)
  
• Roles of transient receptor potential channels in pain
  - Brain Res Rev 60(1):2-23 (2009)
  Pain perception begins with the activation of primary sensory nociceptors. Over the past decade, flourishing research has revealed that members of the Transient Receptor Potential (TRP) ion channel family are fundamental molecules that detect noxious stimuli and transduce a diverse range of physical and chemical energy into action potentials in somatosensory nociceptors. Here we highlight the roles of TRP vanilloid 1 (TRPV1), TRP melastatin 8 (TRPM8) and TRP ankyrin 1 (TRPA1) in the activation of nociceptors by heat and cold environmental stimuli, mechanical force, and by chemicals including exogenous plant and environmental compounds as well as endogenous inflammatory molecules. The contribution of these channels to pain and somatosensation is discussed at levels ranging from whole animal behavior to molecular modulation by intracellular signaling proteins. An emerging theme is that TRP channels are not simple ion channel transducers of one or two stimuli, but instead! serve multidimensional roles in signaling sensory stimuli that are exceptionally diverse in modality and in their environmental milieu.
• Nucleotide signaling and cutaneous mechanisms of pain transduction
  - Brain Res Rev 60(1):24-35 (2009)
  Sensory neurons that innervate the skin provide critical information about physical contact between the organism and the environment, including information about potentially-damaging stimuli that give rise to the sensation of pain. These afferents also contribute to the maintenance of tissue homeostasis, inflammation and wound healing, while sensitization of sensory afferents after injury results in painful hypersensitivity and protective behavior. In contrast to the traditional view of primary afferent terminals as the sole site of sensory transduction, recent reports have lead to the intriguing idea that cells of the skin play an active role in the transduction of sensory stimuli. The search for molecules that transduce different types of sensory stimuli (mechanical, heat, chemical) at the axon terminal has yielded a wide range of potential effectors, many of which are expressed by keratinocytes as well as neurons. Emerging evidence underscores the importance of nucl! eotide signaling through P2X ionotropic and P2Y metabotropic receptors in pain processing, and implicates nucleotide signaling as a critical form of communication between cells of the skin, immune cells and sensory neurons. It is of great interest to determine whether pathological changes in these mechanisms contribute to chronic pain in human disease states such as complex regional pain syndrome (CRPS). This review discusses recent advances in our understanding of communication mechanisms between cells of the skin and sensory axons in the transduction of sensory input leading to pain.
• Nociceptive sensitization by endothelin-1
  - Brain Res Rev 60(1):36-42 (2009)
  The endogenous peptide endothelin-1 (ET-1), originally identified as a potent vasoconstrictor, plays a role in a number of painful conditions. In this review article we discuss the mechanisms that are essential for local sensitization by subcutaneously administered ET-1, and report evidence of ET-1's ability to sensitize distant regions of the body, through the central nervous system and, likely, coupling through the spinal cord. In addition, we will review the latest information on the role of ET-1 in cancerous and non-cancerous conditions. Cancer pain has indeed been shown to be attenuated by antagonists of endothelin receptors, and ET-1 is known to be secreted by cancer cells of many different histologic types. Furthermore, a growing body of evidence links increased expression and secretion of ET-1 to the occurrence of non-cancer related pain syndromes, such as inflammatory and neuropathic pain syndromes.
• Metabotropic receptors for glutamate and GABA in pain
  - Brain Res Rev 60(1):43-56 (2009)
  Glutamate and γ-amino butyric acid (GABA) are respectively two major excitatory and inhibitory neurotransmitters of the adult mammalian central nervous system. These neurotransmitters exert their action through two types of receptors: ionotropic and metabotropic receptors. While ionotropic receptors are ligand gated ion channels involved in fast synaptic transmission, metabotropic receptors belong to the superfamily of G-protein coupled receptors (GPCRs) and are responsible for the neuromodulatory effect of glutamate and GABA. Metabotropic glutamate receptors (mGluRs) and metabotropic GABA receptors (GABA-B) are present at different levels of the pain neuraxis where they regulate nociceptive transmission and pain. The present review will focus on the role of these receptors in the modulation of pain perception.
• Role of interleukin-1β during pain and inflammation
  - Brain Res Rev 60(1):57-64 (2009)
  The cytokine cascade in pain and inflammatory processes is a tremendously complex system, involving glial, immune, and neuronal cell interactions. IL-1β is a pro-inflammatory cytokine that has been implicated in pain, inflammation and autoimmune conditions. This review will focus on studies that shed light on the critical role of IL-1β in various pain states, including the role of the intracellular complex, the inflammasome, which regulates IL-1β production. Evidence will be presented demonstrating the importance of IL-1β in both the induction of pain and in the maintenance of pain in chronic states, such as after nerve injury. Additionally, the involvement of IL-1β as a key mediator in the interaction between glia and neurons in pain states will be discussed. Taken together, the evidence presented in the current review showing the importance of IL-1β in animal and human pain states, suggests that blockade of IL-1β be considered as a therapeutic opportunity.
• Voltage-gated sodium channels in pain states: Role in pathophysiology and targets for treatment
  - Brain Res Rev 60(1):65-83 (2009)
  Pain is a major unmet medical need which has been causally linked to changes in sodium channel expression, modulation, or mutations that alter channel gating properties or current density in nociceptor neurons. Voltage-gated sodium channels activate (open) then rapidly inactivate in response to a depolarization of the plasma membrane of excitable cells allowing the transient flow of sodium ions thus generating an inward current which underlies the generation and conduction of action potentials (AP) in these cells. Activation and inactivation, as well as other gating properties, of sodium channel isoforms have different kinetics and voltage-dependent properties, so that the ensemble of channels that are present determine the electrogenic properties of specific neurons. Biophysical and pharmacological studies have identified the peripheral-specific sodium channels Nav1.7, Nav1.8 and Nav1.9 as particularly important in the pathophysiology of different pain syndromes, and ! isoform-specific blockers of these channels or targeting their modulators hold the promise of a future effective therapy for treatment of pain.
• Role of voltage-gated calcium channels in ascending pain pathways
  - Brain Res Rev 60(1):84-89 (2009)
  Voltage gated calcium channels (VGCCs) are well established mediators of pain signals in primary afferent neurons. N-type calcium channels are localized to synaptic nerve terminals in laminae 1 and 2 of the dorsal horn where their opening results in the release of neurotransmitters such as glutamate and substance P. The contribution of N-type channels to the processing of pain signals is regulated by alternate splicing of the N-type channel gene, with unique N-type channel splice variants being expressed in small nociceptive neurons. In contrast, T-type VGCCs of the Cav3.2 subtype are likely localized to nerve endings where they regulate cellular excitability. Consequently, inhibition of N-type and Cav3.2 T-type VGCCs has the propensity to mediate analgesia. T-type channel activity is regulated by redox modulation, and can be inhibited by a novel class of small organic blockers. N-type VGCC activity can be potently inhibited by highly selective peptide toxins that are ! delivered intrathecally, and the search for small organic blockers with clinical efficacy is ongoing. Here, we provide a brief overview of recent advances in this area, as presented at the Spring Pain Research conference (Grand Cayman, 2008).
• Peripheral mechanisms of pain and analgesia
  - Brain Res Rev 60(1):90-113 (2009)
  This review summarizes recent findings on peripheral mechanisms underlying the generation and inhibition of pain. The focus is on events occurring in peripheral injured tissues that lead to the sensitization and excitation of primary afferent neurons, and on the modulation of such mechanisms. Primary afferent neurons are of particular interest from a therapeutic perspective because they are the initial generator of noxious impulses traveling towards relay stations in the spinal cord and the brain. Thus, if one finds ways to inhibit the sensitization and/or excitation of peripheral sensory neurons, subsequent central events such as wind-up, sensitization and plasticity may be prevented. Most importantly, if agents are found that selectively modulate primary afferent function and do not cross the blood–brain-barrier, centrally mediated untoward side effects of conventional analgesics (e.g. opioids, anticonvulsants) may be avoided. This article begins with the periphera! l actions of opioids, turns to a discussion of the effects of adrenergic co-adjuvants, and then moves on to a discussion of pro-inflammatory mechanisms focusing on TRP channels and nerve growth factor, their signaling pathways and arising therapeutic perspectives.
• Rapid pain modulation with nuclear receptor ligands
  - Brain Res Rev 60(1):114-124 (2009)
  We discuss and present new data regarding the physiological and molecular mechanisms of nuclear receptor activation in pain control, with a particular emphasis on non-genomic effects of ligands at peroxisome proliferator-activated receptor (PPAR), GPR30, and classical estrogen receptors. PPARα agonists rapidly reduce both acute and chronic pain in a number of pain assays. These effects precede transcriptional anti-inflammatory actions, and are mediated in part by IKca and BKca channels on DRG neurons. In contrast to the peripheral site of action of PPARα ligands, the dorsal horn supports the expression of PPARγ. Intrathecal administration of PPARγ ligands rapidly (≤ 5 min) attenuated mechanical and thermal hypersensitivity associated with nerve injury in a dose-dependent manner that could be blocked with PPARγ antagonists. By contrast, a PPARγ antagonist itself rapidly increased the mechanical allodynia associated with nerve injury. These data suggest that liga! nd-dependent, non-genomic activation of spinal PPARγ decreases behavioral signs of inflammatory and neuropathic pain. We also report that the GPR30 is expressed on cultured sensory neurons, that activation of the receptor elicits signaling to increase calcium accumulation. This signaling may contribute to increased neuronal sensitivity as treatment with the GPR30 agonist induces hyperalgesia. Finally, application of the membrane-impermeable 17β-E2-BSA rapidly (within 15 min) enhanced BK-stimulated inositol phosphate (IP) accumulation and PGE2-mediated cAMP accumulation in trigeminal ganglion cultures. We conclude that nuclear receptor ligands may operate through rapid, non-genomic mechanisms to modulate inflammatory and neuropathic pain.
• Chemokines and pain mechanisms
  - Brain Res Rev 60(1):125-134 (2009)
  The development of new therapeutic approaches to the treatment of painful neuropathies requires a better understanding of the mechanisms that underlie the development of these chronic pain syndromes. It is now well established that astrocytic and microglial cells modulate the neuronal mechanisms of chronic pain in spinal cord and possibly in the brain. In animal models of neuropathic pain following peripheral nerve injury, several changes occur at the level of the first pain synapse between the central terminals of sensory neurons and second order neurons. These neuronal mechanisms can be modulated by pro-nociceptive mediators released by non neuronal cells such as microglia and astrocytes which become activated in the spinal cord following PNS injury. However, the signals that mediate the spread of nociceptive signaling from neurons to glial cells in the dorsal horn remain to be established. Herein we provide evidence for two emerging signaling pathways between injure! d sensory neurons and spinal microglia: chemotactic cytokine ligand 2 (CCL2)/CCR2 and cathepsin S/CX3CL1 (fractalkine)/CX3CR1. We discuss the plasticity of these two chemokine systems at the level of the dorsal root ganglia and spinal cord demonstrating that modulation of chemokines using selective antagonists decrease nociceptive behavior in rodent chronic pain models. Since up-regulation of chemokines and their receptors may be a mechanism that directly and/or indirectly contributes to the development and maintenance of chronic pain, these molecular molecules may represent novel targets for therapeutic intervention in sustained pain states.
• MAP kinase and pain
  - Brain Res Rev 60(1):135-148 (2009)
  Mitogen-activated protein kinases (MAPKs) are important for intracellular signal transduction and play critical roles in regulating neural plasticity and inflammatory responses. The MAPK family consists of three major members: extracellular signal-regulated kinases (ERK), p38, and c-Jun N-terminal kinase (JNK), which represent three separate signaling pathways. Accumulating evidence shows that all three MAPK pathways contribute to pain sensitization after tissue and nerve injury via distinct molecular and cellular mechanisms. Activation (phosphorylation) of MAPKs under different persistent pain conditions results in the induction and maintenance of pain hypersensitivity via non-transcriptional and transcriptional regulation. In particular, ERK activation in spinal cord dorsal horn neurons by nociceptive activity, via multiple neurotransmitter receptors, and using different second messenger pathways plays a critical role in central sensitization by regulating the activi! ty of glutamate receptors and potassium channels and inducing gene transcription. ERK activation in amygdala neurons is also required for inflammatory pain sensitization. After nerve injury, ERK, p38, and JNK are differentially activated in spinal glial cells (microglia vs astrocytes), leading to the synthesis of proinflammatory/pronociceptive mediators, thereby enhancing and prolonging pain. Inhibition of all three MAPK pathways has been shown to attenuate inflammatory and neuropathic pain in different animal models. Development of specific inhibitors for MAPK pathways to target neurons and glial cells may lead to new therapies for pain management. Although it is well documented that MAPK pathways can increase pain sensitivity via peripheral mechanisms, this review will focus on central mechanisms of MAPKs, especially ERK.
• Chloride regulation in the pain pathway
  - Brain Res Rev 60(1):149-170 (2009)
  Melzack and Wall's Gate Control Theory of Pain laid the theoretical groundwork for a role of spinal inhibition in endogenous pain control. While the Gate Control Theory was based on the notion that spinal inhibition is dynamically regulated, mechanisms underlying the regulation of inhibition have turned out to be far more complex than Melzack and Wall could have ever imagined. Recent evidence indicates that an exquisitely sensitive form of regulation involves changes in anion equilibrium potential (Eanion), which subsequently impacts fast synaptic inhibition mediated by GABAA, and to a lesser extent, glycine receptor activation, the prototypic ligand gated anion channels. The cation-chloride co-transporters (in particular NKCC1 and KCC2) have emerged as proteins that play a critical role in the dynamic regulation of Eanion which in turn appears to play a critical role in hyperalgesia and allodynia following peripheral inflammation or nerve injury. This review summarize! s the current state of knowledge in this area with particular attention to how such findings relate to endogenous mechanisms of hyperalgesia and allodynia and potential applications for therapeutics based on modulation of intracellular Cl− gradients or pharmacological interventions targeting GABAA receptors.
• Development, plasticity and modulation of visceral afferents
  - Brain Res Rev 60(1):171-186 (2009)
  Visceral pain is the most common reason for doctor visits in the US. Like somatic pain, virtually all visceral pain sensations begin with the activation of primary sensory neurons innervating the viscera and/or the blood vessels associated with these structures. Visceral afferents also play a central role in tissue homeostasis. Recent studies show that in addition to monitoring the state of the viscera, they perform efferent functions through the release of small molecules (e.g. peptides like CGRP) that can drive inflammation, thereby contributing to the development of visceral pathologies (e.g. diabetes Razavi, R., Chan, Y., Afifiyan, F.N., Liu, X.J., Wan, X., Yantha, J., Tsui, H., Tang, L., Tsai, S., Santamaria, P., Driver, J.P., Serreze, D., Salter, M.W., Dosch, H.M., 2006. TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes, Cell 127 1123–1135). Visceral afferents are heterogeneous with respect to their anatomy, neurochem! istry and function. They are also highly plastic in that their cellular environment continuously influences their response properties. This plasticity makes them susceptible to long-term changes that may contribute significantly to the development of persistent pain states such as those associated with irritable bowel syndrome, pancreatitis, and visceral cancers. This review examines recent insights into visceral afferent anatomy and neurochemistry and how neonatal insults can affect the function of these neurons in the adult. New approaches to the treatment of visceral pain, which focus on primary afferents, will also be discussed.
• New advances in musculoskeletal pain
  - Brain Res Rev 60(1):187-201 (2009)
  Non-malignant musculoskeletal pain is the most common clinical symptom that causes patients to seek medical attention and is a major cause of disability in the world. Musculoskeletal pain can arise from a variety of common conditions including osteoarthritis, rheumatoid arthritis, osteoporosis, surgery, low back pain and bone fracture. A major problem in designing new therapies to treat musculoskeletal pain is that the underlying mechanisms driving musculoskeletal pain are not well understood. This lack of knowledge is largely due to the scarcity of animal models that closely mirror the human condition which would allow the development of a mechanistic understanding and novel therapies to treat this pain. To begin to develop a mechanism-based understanding of the factors involved in generating musculoskeletal pain, in this review we present recent advances in preclinical models of osteoarthritis, post-surgical pain and bone fracture pain. The models discussed appear to! offer an attractive platform for understanding the factors that drive this pain and the preclinical screening of novel therapies to treat musculoskeletal pain. Developing both an understanding of the mechanisms that drive persistent musculoskeletal pain and novel mechanism-based therapies to treat these unique pain states would address a major unmet clinical need and have significant clinical, economic and societal benefits.
• Mechanisms of chronic central neuropathic pain after spinal cord injury
  - Brain Res Rev 60(1):202-213 (2009)
  Not all spinal contusions result in mechanical allodynia, in which non-noxious stimuli become noxious. The studies presented use the NYU impactor at 12.5 mm drop or the Infinite Horizons Impactor (150 kdyn, 1 s dwell) devices to model spinal cord injury (SCI). Both of these devices and injury parameters, if done correctly, will result in animals with above level (forelimb), at level (trunk) and below level (hindlimb) mechanical allodynia that model the changes in evoked somatosensation experienced by the majority of people with SCI. The sections are as follows: 1) Mechanisms of remote microglial activation and pain signaling in "below-level" central pain 2) Intracellular signaling mechanisms in central sensitization in "at-level" pain 3) Peripheral sensitization contributes to "above level" injury pain following spinal cord injury and 4) Role of reactive oxygen species in central sensitization in regional neuropathic pain following SCI. To summarize, differ! ential regional mechanisms contribute to the regional chronic pain states. We propose the importance of understanding the mechanisms in the differential regional pain syndromes after SCI in the chronic condition. Targeting regional mechanisms will be of enormous benefit to the SCI population that suffer chronic pain, and will contribute to better treatment strategies for other chronic pain syndromes.
• Descending control of nociception: Specificity, recruitment and plasticity
  - Brain Res Rev 60(1):214-225 (2009)
  The dorsal horn of the spinal cord is the location of the first synapse in pain pathways, and as such, offers a very powerful target for regulation of nociceptive transmission by both local segmental and supraspinal mechanisms. Descending control of spinal nociception originates from many brain regions and plays a critical role in determining the experience of both acute and chronic pain. The earlier concept of descending control as an "analgesia system" is now being replaced with a more nuanced model in which pain input is prioritized relative to other competing behavioral needs and homeostatic demands. Descending control arises from a number of supraspinal sites, including the midline periaqueductal gray-rostral ventromedial medulla (PAG-RVM) system, and the more lateral and caudal dorsal reticular nucleus (DRt) and ventrolateral medulla (VLM). Inhibitory control from the PAG-RVM system preferentially suppresses nociceptive inputs mediated by C-fibers, preserving! sensory-discriminative information conveyed by more rapidly conducting A-fibers. Analysis of the circuitry within the RVM reveals that the neural basis for bidirectional control from the midline system is two populations of neurons, ON-cells and OFF-cells, that are differentially recruited by higher structures important in fear, illness and psychological stress to enhance or inhibit pain. Dynamic shifts in the balance between pain inhibiting and facilitating outflows from the brainstem play a role in setting the gain of nociceptive processing as dictated by behavioral priorities, but are also likely to contribute to pathological pain states.
• Forebrain pain mechanisms
  - Brain Res Rev 60(1):226-242 (2009)
  Emotional–affective and cognitive dimensions of pain are less well understood than nociceptive and nocifensive components, but the forebrain is believed to play an important role. Recent evidence suggests that subcortical and cortical brain areas outside the traditional pain processing network contribute critically to emotional–affective responses and cognitive deficits related to pain. These brain areas include different nuclei of the amygdala and certain prefrontal cortical areas. Their roles in various aspects of pain will be discussed. Biomarkers of cortical dysfunction are being identified that may evolve into therapeutic targets to modulate pain experience and improve pain-related cognitive impairment. Supporting data from preclinical studies in neuropathic pain models will be presented. Neuroimaging analysis provides evidence for plastic changes in the pain processing brain network. Results of clinical studies in neuropathic pain patients suggest that neuroi! maging may help determine mechanisms of altered brain functions in pain as well as monitor the effects of pharmacologic interventions to optimize treatment in individual patients. Recent progress in the analysis of higher brain functions emphasizes the concept of pain as a multidimensional experience and the need for integrative approaches to determine the full spectrum of harmful or protective neurobiological changes in pain.
• Predicting therapeutic efficacy — Experimental pain in human subjects
  - Brain Res Rev 60(1):243-254 (2009)
  The pharmaceutical industry faces tough times. Despite tremendous advances in the science and technology of new lead identification and optimization, attrition rates for novel drug candidates making it into the clinic remain unacceptably high. A seamless boundary between basic preclinical and clinical arms of the discovery process, embodying the concept of 'translational research' is viewed by many as the way forward. The rational application of human experimental pain models in early clinical development is reviewed. Capsaicin, UV-irradiation and electrical stimulation methods have each been used to establish experimental hyperalgesia in Phase-I human volunteers and the application of these approaches is discussed in the context of several pharmacological examples. However, data generated from such studies must be integrated into a well-conceived and executed series of Phase-II efficacy trials in patients in order to derive maximal benefit. The challenges involved! in optimal Phase-II/III trial design are reviewed with specific attention to the issues of sample size and placebo response. Finally, the application and potential of cortical EEG studies are discussed as an objective alternative to more conventional pain assessment tools with specific examples of how this technique has been applied to the study of NSAID and opiate-based therapeutics.
• Targeting CB2 receptors and the endocannabinoid system for the treatment of pain
  - Brain Res Rev 60(1):255-266 (2009)
  The endocannabinoid system consists of the cannabinoid (CB) receptors, CB1 and CB2, the endogenous ligands anandamide (AEA, arachidonoylethanolamide) and 2-arachidonoylglycerol (2-AG), and their synthetic and metabolic machinery. The use of cannabis has been described in classical and recent literature for the treatment of pain, but the potential for psychotropic effects as a result of the activation of central CB1 receptors places a limitation upon its use. There are, however, a number of modern approaches being undertaken to circumvent this problem, and this review represents a concise summary of these approaches, with a particular emphasis upon CB2 receptor agonists. Selective CB2 agonists and peripherally restricted CB1 or CB1/CB2 dual agonists are being developed for the treatment of inflammatory and neuropathic pain, as they demonstrate efficacy in a range of pain models. CB2 receptors were originally described as being restricted to cells of immune origin, but t! here is evidence for their expression in human primary sensory neurons, and increased levels of CB2 receptors reported in human peripheral nerves have been seen after injury, particularly in painful neuromas. CB2 receptor agonists produce antinociceptive effects in models of inflammatory and nociceptive pain, and in some cases these effects involve activation of the opioid system. In addition, CB receptor agonists enhance the effect of μ-opioid receptor agonists in a variety of models of analgesia, and combinations of cannabinoids and opioids may produce synergistic effects. Antinociceptive effects of compounds blocking the metabolism of anandamide have been reported, particularly in models of inflammatory pain. There is also evidence that such compounds increase the analgesic effect of non-steroidal anti-inflammatory drugs (NSAIDs), raising the possibility that a combination of suitable agents could, by reducing the NSAID dose needed, provide an efficacious treatment stra! tegy, while minimizing the potential for NSAID-induced gastroi! ntestinal and cardiovascular disturbances. Other potential "partners" for endocannabinoid modulatory agents include α2-adrenoceptor modulators, peroxisome proliferator-activated receptor α agonists and TRPV1 antagonists. An extension of the polypharmacological approach is to combine the desired pharmacological properties of the treatment within a single molecule. Hopefully, these approaches will yield novel analgesics that do not produce the psychotropic effects that limit the medicinal use of cannabis.
• Therapeutic potential of vanilloid receptor TRPV1 agonists and antagonists as analgesics: Recent advances and setbacks
  - Brain Res Rev 60(1):267-277 (2009)
  The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibers). TRPV1 is considered as a highly validated pain target because, i) its agonists such as capsaicin cause desensitization of TRPV1 channels that relieves pain behaviors in preclinical species, and ii) its antagonists relieve pain behaviors in rodent models of inflammation, osteoarthritis, and cancer. Hence, both agonists and antagonists of TRPV1 are being evaluated as potential analgesics in clinical trials. Clinical trial results of TRPV1 agonists such as resiniferatoxin in interstitial cystitis, NGX 4010 in post-herpetic neuralgia, and 4975 (Adlea™) in osteoarthritis, bunionectomy, and Morton's neuroma have been reported. Similarly, clinical trial results of TRPV1 antagonists such as SB-705498 and AMG 517 have also been published recently. Overall, some molecules (e.g., capsaicin) demonstrated potential analgesia in certain conditions (pos! tsurgical pain, postherpetic neuralgia, pain in diabetic neuropathy, osteoarthritis, bunionectomy, and Morton's neuroma), whereas others fell out of the clinic due to on-target liabilities or failed to demonstrate efficacy. This review summarizes recent advances and setbacks of TRPV1 agonists and antagonists in the clinic and predicts future directions.