Thermoregulation and heat dissipation by sweat production and evaporation are vital for human sur... more Thermoregulation and heat dissipation by sweat production and evaporation are vital for human survival. However, hyperhidrosis or excessive perspiration might affect people's quality of life by causing discomfort and stress. The prolonged use of classical antiperspirants, anticholinergic medications or botulinum toxin injections for persistent hyperhidrosis might produce diverse side effects that limit their clinical use. Inspired by botox molecular mode of action, we used an in silico molecular modelling approach to design novel peptides to target neuronal acetylcholine exocytosis by interfering with the Snapin‐SNARE complex formation. Our exhaustive design rendered the selection of 11 peptides that decreased calcium‐dependent vesicle exocytosis in rat DRG neurons, reducing αCGRP release and TRPV1 inflammatory sensitization. The most potent peptides were palmitoylated peptides SPSR38‐4.1 and SPSR98‐9.1 that significantly suppressed acetylcholine release in vitro in human LAN‐2 ...
Abstract: One approach to develop successful pain therapies is the modulation of dysfunctional io... more Abstract: One approach to develop successful pain therapies is the modulation of dysfunctional ion channels that contribute to the detection of thermal, mechanical and chemical painful stimuli. These ion channels, known as thermoTRPs, promote the sensitization and activation of primary sensory neurons known as nociceptors. Pharmacological blockade and genetic deletion of thermoTRP have validated these channels as therapeutic targets for pain intervention. Several thermoTRP modulators have progressed towards clinical development, although most failed because of the appearance of unpredicted side effects. Thus, there is yet a need to develop novel channel modulators with improved therapeutic index. Here, we review the current state-of-the art and illustrate new pharmacological paradigms based on TRPV1 that include: (i) the identification of activity-dependent modulators of this thermoTRP channel; (ii) the design of allosteric modulators that interfere with protein-protein interaction ...
ThermoTRP channels (thermoTRPs) define a subfamily of the transient receptor potential (TRP) chan... more ThermoTRP channels (thermoTRPs) define a subfamily of the transient receptor potential (TRP) channels that are activated by changes in the environmental temperature, from noxious cold to injurious heat. Acting as integrators of several stimuli and signalling pathways, dysfunction of these channels contributes to several pathological states. The surface expression of thermoTRPs is controlled by both, the constitutive and regulated vesicular trafficking. Modulation of receptor surface density during pathological processes is nowadays considered as an interesting therapeutic approach for management of diseases, such as chronic pain, in which an increased trafficking is associated with the pathological state. This review will focus on the recent advances trafficking of the thermoTRP channels, TRPV1, TRPV2, TRPV4, TRPM3, TRPM8 and TRPA1, into/from the plasma membrane. Particularly, regulated membrane insertion of thermoTRPs channels contributes to a fine tuning of final channel activity, and indeed, it has resulted in the development of novel therapeutic approaches with successful clinical results such as disruption of SNARE-dependent exocytosis by botulinum toxin or botulinomimetic peptides.
TLRs may contribute to the progression of rheumatoid arthritis through recognition of microbial o... more TLRs may contribute to the progression of rheumatoid arthritis through recognition of microbial or hostderived ligands found in arthritic joints. Here, we show that TLR2 and TLR4, but not TLR9, are involved in the pathogenesis of autoimmune arthritis and play distinct roles in the regulation of T cells and cytokines. We investigated the involvement of TLR2, TLR4, and TLR9 in the progression of arthritis using IL-1 receptor antagonist-knockout (IL1rn-/-) mice, which spontaneously develop an autoimmune T cell-mediated arthritis. Spontaneous onset of arthritis was dependent on TLR activation by microbial flora, as germ-free mice did not develop arthritis. Clinical and histopathological evaluation of IL1rn-/-Tlr2-/mice revealed more severe arthritis, characterized by reduced suppressive function of Tregs and substantially increased IFN-γ production by T cells. IL1rn-/-Tlr4-/mice were, in contrast, protected against severe arthritis and had markedly lower numbers of Th17 cells and a reduced capacity to produce IL-17. A lack of Tlr9 did not affect the progression of arthritis. While any therapeutic intervention targeting TLR2 still seems complicated, the strict position of TLR4 upstream of a number of pathogenic cytokines including IL-17 provides an interesting potential therapeutic target for rheumatoid arthritis.
ObjectiveInterleukin‐1 receptor antagonist–deficient (IL‐1Ra−/−) mice spontaneously develop an in... more ObjectiveInterleukin‐1 receptor antagonist–deficient (IL‐1Ra−/−) mice spontaneously develop an inflammatory and destructive arthritis due to unopposed excess IL‐1 signaling. In this study, the role of Th17 cells and the effect of neutralization of IL‐17, IL‐1, and tumor necrosis factor α (TNFα) were investigated in this IL‐1–driven murine arthritis model.MethodsT cells isolated from IL‐1Ra−/− and wild‐type (WT) mice were stained for IL‐17 and interferon‐γ, with results assessed by fluorescence‐activated cell sorting analysis. To investigate the contribution of IL‐1 and IL‐17 in further progression of arthritis in this model, mice were treated with neutralizing antibodies after the onset of arthritis.ResultsCompared with WT mice, IL‐1Ra−/− mice had similar levels of Th1 cells but clearly enhanced levels of Th17 cells; this increase in the number of Th17 cells was evident even before the onset of arthritis, in young, nonarthritic IL‐1Ra−/− mice. The percentage of Th17 cells increased ...
Proceedings of the National Academy of Sciences, 2014
Significance Pain is a societal burden with enormous economic and social costs. More than 50% of ... more Significance Pain is a societal burden with enormous economic and social costs. More than 50% of pain patients find current therapies unsatisfactory. A major reason for this pharmacological failure is our limited understanding of the cellular processes underlying pain. Algesic sensitization of nociceptors is a complex event in pain transduction that involves the potentiation of thermosensory channels. The molecular mechanisms remain controversial because of nociceptor heterogeneity that suggests the existence of cell-type–specific strategies. We show that algesic sensitization of transient receptor potential vanilloid 1 (TRPV1) involves the exocytotic recruitment of new receptors in peptidergic nociceptors and the modulation of channel gating in nonpeptidergic sensory neurons. Furthermore, algesic delivery of TRPV1 channels is concomitant with pro-inflammatory neuropeptide secretion, ensuring rapid modulation of pain transduction.
Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the gene... more Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and slightly effective, so there is a need of developing more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA1) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA1 agonists among which derivative (S)-17 (UCM-05194) stands out as the most potent and selective LPA1 receptor agonist described so far (Emax=118%, EC50=0.24 µM, KD=19.6 nM; inactive at autotaxin and LPA2-6 receptors). This compound induces characteristic LPA1-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an in vivo model of NP.
Despite being an old molecule, capsaicin is still a hot topic in the scientific community, and th... more Despite being an old molecule, capsaicin is still a hot topic in the scientific community, and the development of new capsaicinoids is a promising pharmacological approach in the management of skin disorders related to inflammation and pruritus. Here we report the synthesis and the evaluation of capsaicin soft drugs that undergo deactivation by the hydrolyzing activity of skin esterases. The implanting of an ester group in the lipophilic moiety of capsaicinoids by the Passerini multicomponent reaction affords both agonists and antagonists that retain transient receptor potential vanilloid 1 channel (TRPV1) modulating activity and, at the same time, are susceptible to hydrolysis. The most promising antagonist identified shows in vivo anti-nociceptive activity on pruritus and hyperalgesia without producing hyperthermia, thus validating it as novel treatment for dermatological conditions that implicate TRPV1 channel dysfunction.
Transient receptor potential vanilloid I (TRPV1) sensitization in peripheral nociceptors is a pro... more Transient receptor potential vanilloid I (TRPV1) sensitization in peripheral nociceptors is a prominent phenomenon that occurs in inflammatory pain conditions. Pro-algesic agents can potentiate TRPV1 activity in nociceptors through both stimulation of its channel gating and mobilization of channels to the neuronal surface in a context dependent manner. A recent study reported that ATP-induced TRPV1 sensitization in peptidergic nociceptors involves the exocytotic release of channels trafficked by large dense core vesicles (LDCVs) that cargo alpha-calcitonin gene related peptide alpha (αCGRP). We hypothesized that, similar to ATP, bradykinin may also use different mechanisms to sensitize TRPV1 channels in peptidergic and non-peptidergic nociceptors. We found that bradykinin notably enhances the excitability of peptidergic nociceptors, and sensitizes TRPV1, primarily through the bradykinin receptor 2 pathway. Notably, bradykinin sensitization of TRPV1 in peptidergic nociceptors was significantly blocked by inhibiting Ca 2+-dependent neuronal exocytosis. In addition, silencing αCGRP gene expression, but not substance P, drastically reduced bradykinin-induced TRPV1 sensitization in peptidergic nociceptors. Taken together, these findings indicate that bradykinin-induced sensitization of TRPV1 in peptidergic nociceptors is partially mediated by the exocytotic mobilization of new channels trafficked by αCGRPloaded LDCVs to the neuronal membrane. Our findings further imply a central role of αCGRP peptidergic nociceptors in peripheral algesic sensitization, and substantiate that inhibition of LDCVs exocytosis is a valuable therapeutic strategy to treat pain, as it concurrently reduces the release of pro-inflammatory peptides and the membrane recruitment of thermoTRP channels.
Advances in Experimental Medicine and Biology, 2016
ThermoTRPs are unique channels that mediate Na(+) and Ca(2+) currents in response to changes in a... more ThermoTRPs are unique channels that mediate Na(+) and Ca(2+) currents in response to changes in ambient temperature. In combination with their activation by other physical and chemical stimuli, they are considered key integrators of environmental cues into neuronal excitability. Furthermore, roles of thermoTRPs in non-neuronal tissues are currently emerging such as insulin secretion in pancreatic β-cells, and links to cancer. Calcium permeability through thermoTRPs appears a central hallmark for their physiological and pathological activities. Moreover, it is currently being proposed that beyond working as a second messenger, Ca(2+) can function locally by acting on protein complexes near the membrane. Interestingly, thermoTRPs can enhance and expand the inherent plasticity of signalplexes by conferring them temperature, pH and lipid regulation through Ca(2+) signalling. Thus, unveiling the local role of Ca(2+) fluxes induced by thermoTRPs on the dynamics of membrane-attached signalling complexes as well as their significance in cellular processes, are central issues that will expand the opportunities for therapeutic intervention in disorders involving dysfunction of thermoTRP channels.
Because drug discovery efforts have experienced a pronounced decline in productivity, novel appro... more Because drug discovery efforts have experienced a pronounced decline in productivity, novel approaches to the rational design of new drugs are being introduced and developed. An exciting solution is the use of natural or synthetic peptides and peptidomimetics targeting protein-protein interactions essential for signaling networks function. The combination of several bioinformatic approaches (docking, virtual screening, pharmacophore models, etc.) allows for the use of the vast amount of information on protein-protein interactions deposited in structural databases. In this respect, interacting peptides are susceptible of optimization in order to stabilize or disrupt protein-protein interactions, providing a promising use of peptides and derivatives as therapeutics. In this review we illustrate tools and strategies currently used in peptidomic drug discovery as well as trends in the area of molecular pharmacology
Because of the social and economic costs of chronic pain, there is a growing interest in unveilin... more Because of the social and economic costs of chronic pain, there is a growing interest in unveiling the cellular and molecular mechanisms underlying it with the aim of developing more effective medications. Pain signalling is a multicomponent process that involves the peripheral and central nervous systems. At the periphery, nociceptor sensitisation by pro-inflammatory mediators is a primary step in pain transduction. Although pain is multifactorial at cellular and molecular levels, it is widely accepted that neurotrophin (TrkA, p75NTR, Ret and GFRs), cannabinoid (CB1 and CB2), and thermo-transient receptor potential (TRPs; TRPV1, TRPA1 and TRPM8) receptors play a pivotal role. They form a threesome for which endocannabinoids appear to be a first line of defence against pain, while neurotrophins and thermoTRPs are the major generators of painful signals. However, endocannabinoids may exhibit nociceptive activity while some neurotrophins may display anti-nociception. Accordingly, a clear-cut knowledge of the modulation and context-dependent function of these signalling cascades, along with the molecular and dynamic details of their crosstalk, is critical for understanding and controlling pain transduction. Here, the recent progress in this fascinating topic, as well as the tantalizing questions that remain unanswered, will be discussed. Furthermore, we will underline the need for using a systems biology approach (referred to as systems pain) to uncover the dynamics and interplay of these intricate signalling cascades, taking into consideration the molecular complexity and cellular heterogeneity of nociceptor populations. Nonetheless, the available information confirms that pharmacological modulation of this signalling triad is a highly valuable therapeutic strategy for effectively treating pain syndromes.
Thermoregulation and heat dissipation by sweat production and evaporation are vital for human sur... more Thermoregulation and heat dissipation by sweat production and evaporation are vital for human survival. However, hyperhidrosis or excessive perspiration might affect people's quality of life by causing discomfort and stress. The prolonged use of classical antiperspirants, anticholinergic medications or botulinum toxin injections for persistent hyperhidrosis might produce diverse side effects that limit their clinical use. Inspired by botox molecular mode of action, we used an in silico molecular modelling approach to design novel peptides to target neuronal acetylcholine exocytosis by interfering with the Snapin‐SNARE complex formation. Our exhaustive design rendered the selection of 11 peptides that decreased calcium‐dependent vesicle exocytosis in rat DRG neurons, reducing αCGRP release and TRPV1 inflammatory sensitization. The most potent peptides were palmitoylated peptides SPSR38‐4.1 and SPSR98‐9.1 that significantly suppressed acetylcholine release in vitro in human LAN‐2 ...
Abstract: One approach to develop successful pain therapies is the modulation of dysfunctional io... more Abstract: One approach to develop successful pain therapies is the modulation of dysfunctional ion channels that contribute to the detection of thermal, mechanical and chemical painful stimuli. These ion channels, known as thermoTRPs, promote the sensitization and activation of primary sensory neurons known as nociceptors. Pharmacological blockade and genetic deletion of thermoTRP have validated these channels as therapeutic targets for pain intervention. Several thermoTRP modulators have progressed towards clinical development, although most failed because of the appearance of unpredicted side effects. Thus, there is yet a need to develop novel channel modulators with improved therapeutic index. Here, we review the current state-of-the art and illustrate new pharmacological paradigms based on TRPV1 that include: (i) the identification of activity-dependent modulators of this thermoTRP channel; (ii) the design of allosteric modulators that interfere with protein-protein interaction ...
ThermoTRP channels (thermoTRPs) define a subfamily of the transient receptor potential (TRP) chan... more ThermoTRP channels (thermoTRPs) define a subfamily of the transient receptor potential (TRP) channels that are activated by changes in the environmental temperature, from noxious cold to injurious heat. Acting as integrators of several stimuli and signalling pathways, dysfunction of these channels contributes to several pathological states. The surface expression of thermoTRPs is controlled by both, the constitutive and regulated vesicular trafficking. Modulation of receptor surface density during pathological processes is nowadays considered as an interesting therapeutic approach for management of diseases, such as chronic pain, in which an increased trafficking is associated with the pathological state. This review will focus on the recent advances trafficking of the thermoTRP channels, TRPV1, TRPV2, TRPV4, TRPM3, TRPM8 and TRPA1, into/from the plasma membrane. Particularly, regulated membrane insertion of thermoTRPs channels contributes to a fine tuning of final channel activity, and indeed, it has resulted in the development of novel therapeutic approaches with successful clinical results such as disruption of SNARE-dependent exocytosis by botulinum toxin or botulinomimetic peptides.
TLRs may contribute to the progression of rheumatoid arthritis through recognition of microbial o... more TLRs may contribute to the progression of rheumatoid arthritis through recognition of microbial or hostderived ligands found in arthritic joints. Here, we show that TLR2 and TLR4, but not TLR9, are involved in the pathogenesis of autoimmune arthritis and play distinct roles in the regulation of T cells and cytokines. We investigated the involvement of TLR2, TLR4, and TLR9 in the progression of arthritis using IL-1 receptor antagonist-knockout (IL1rn-/-) mice, which spontaneously develop an autoimmune T cell-mediated arthritis. Spontaneous onset of arthritis was dependent on TLR activation by microbial flora, as germ-free mice did not develop arthritis. Clinical and histopathological evaluation of IL1rn-/-Tlr2-/mice revealed more severe arthritis, characterized by reduced suppressive function of Tregs and substantially increased IFN-γ production by T cells. IL1rn-/-Tlr4-/mice were, in contrast, protected against severe arthritis and had markedly lower numbers of Th17 cells and a reduced capacity to produce IL-17. A lack of Tlr9 did not affect the progression of arthritis. While any therapeutic intervention targeting TLR2 still seems complicated, the strict position of TLR4 upstream of a number of pathogenic cytokines including IL-17 provides an interesting potential therapeutic target for rheumatoid arthritis.
ObjectiveInterleukin‐1 receptor antagonist–deficient (IL‐1Ra−/−) mice spontaneously develop an in... more ObjectiveInterleukin‐1 receptor antagonist–deficient (IL‐1Ra−/−) mice spontaneously develop an inflammatory and destructive arthritis due to unopposed excess IL‐1 signaling. In this study, the role of Th17 cells and the effect of neutralization of IL‐17, IL‐1, and tumor necrosis factor α (TNFα) were investigated in this IL‐1–driven murine arthritis model.MethodsT cells isolated from IL‐1Ra−/− and wild‐type (WT) mice were stained for IL‐17 and interferon‐γ, with results assessed by fluorescence‐activated cell sorting analysis. To investigate the contribution of IL‐1 and IL‐17 in further progression of arthritis in this model, mice were treated with neutralizing antibodies after the onset of arthritis.ResultsCompared with WT mice, IL‐1Ra−/− mice had similar levels of Th1 cells but clearly enhanced levels of Th17 cells; this increase in the number of Th17 cells was evident even before the onset of arthritis, in young, nonarthritic IL‐1Ra−/− mice. The percentage of Th17 cells increased ...
Proceedings of the National Academy of Sciences, 2014
Significance Pain is a societal burden with enormous economic and social costs. More than 50% of ... more Significance Pain is a societal burden with enormous economic and social costs. More than 50% of pain patients find current therapies unsatisfactory. A major reason for this pharmacological failure is our limited understanding of the cellular processes underlying pain. Algesic sensitization of nociceptors is a complex event in pain transduction that involves the potentiation of thermosensory channels. The molecular mechanisms remain controversial because of nociceptor heterogeneity that suggests the existence of cell-type–specific strategies. We show that algesic sensitization of transient receptor potential vanilloid 1 (TRPV1) involves the exocytotic recruitment of new receptors in peptidergic nociceptors and the modulation of channel gating in nonpeptidergic sensory neurons. Furthermore, algesic delivery of TRPV1 channels is concomitant with pro-inflammatory neuropeptide secretion, ensuring rapid modulation of pain transduction.
Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the gene... more Neuropathic pain (NP) is a complex chronic pain state with a prevalence of almost 10% in the general population. Pharmacological options for NP are limited and slightly effective, so there is a need of developing more efficacious NP attenuating drugs. Activation of the type 1 lysophosphatidic acid (LPA1) receptor is a crucial factor in the initiation of NP. Hence, it is conceivable that a functional antagonism strategy could lead to NP mitigation. Here we describe a new series of LPA1 agonists among which derivative (S)-17 (UCM-05194) stands out as the most potent and selective LPA1 receptor agonist described so far (Emax=118%, EC50=0.24 µM, KD=19.6 nM; inactive at autotaxin and LPA2-6 receptors). This compound induces characteristic LPA1-mediated cellular effects and prompts the internalization of the receptor leading to its functional inactivation in primary sensory neurons and to an efficacious attenuation of the pain perception in an in vivo model of NP.
Despite being an old molecule, capsaicin is still a hot topic in the scientific community, and th... more Despite being an old molecule, capsaicin is still a hot topic in the scientific community, and the development of new capsaicinoids is a promising pharmacological approach in the management of skin disorders related to inflammation and pruritus. Here we report the synthesis and the evaluation of capsaicin soft drugs that undergo deactivation by the hydrolyzing activity of skin esterases. The implanting of an ester group in the lipophilic moiety of capsaicinoids by the Passerini multicomponent reaction affords both agonists and antagonists that retain transient receptor potential vanilloid 1 channel (TRPV1) modulating activity and, at the same time, are susceptible to hydrolysis. The most promising antagonist identified shows in vivo anti-nociceptive activity on pruritus and hyperalgesia without producing hyperthermia, thus validating it as novel treatment for dermatological conditions that implicate TRPV1 channel dysfunction.
Transient receptor potential vanilloid I (TRPV1) sensitization in peripheral nociceptors is a pro... more Transient receptor potential vanilloid I (TRPV1) sensitization in peripheral nociceptors is a prominent phenomenon that occurs in inflammatory pain conditions. Pro-algesic agents can potentiate TRPV1 activity in nociceptors through both stimulation of its channel gating and mobilization of channels to the neuronal surface in a context dependent manner. A recent study reported that ATP-induced TRPV1 sensitization in peptidergic nociceptors involves the exocytotic release of channels trafficked by large dense core vesicles (LDCVs) that cargo alpha-calcitonin gene related peptide alpha (αCGRP). We hypothesized that, similar to ATP, bradykinin may also use different mechanisms to sensitize TRPV1 channels in peptidergic and non-peptidergic nociceptors. We found that bradykinin notably enhances the excitability of peptidergic nociceptors, and sensitizes TRPV1, primarily through the bradykinin receptor 2 pathway. Notably, bradykinin sensitization of TRPV1 in peptidergic nociceptors was significantly blocked by inhibiting Ca 2+-dependent neuronal exocytosis. In addition, silencing αCGRP gene expression, but not substance P, drastically reduced bradykinin-induced TRPV1 sensitization in peptidergic nociceptors. Taken together, these findings indicate that bradykinin-induced sensitization of TRPV1 in peptidergic nociceptors is partially mediated by the exocytotic mobilization of new channels trafficked by αCGRPloaded LDCVs to the neuronal membrane. Our findings further imply a central role of αCGRP peptidergic nociceptors in peripheral algesic sensitization, and substantiate that inhibition of LDCVs exocytosis is a valuable therapeutic strategy to treat pain, as it concurrently reduces the release of pro-inflammatory peptides and the membrane recruitment of thermoTRP channels.
Advances in Experimental Medicine and Biology, 2016
ThermoTRPs are unique channels that mediate Na(+) and Ca(2+) currents in response to changes in a... more ThermoTRPs are unique channels that mediate Na(+) and Ca(2+) currents in response to changes in ambient temperature. In combination with their activation by other physical and chemical stimuli, they are considered key integrators of environmental cues into neuronal excitability. Furthermore, roles of thermoTRPs in non-neuronal tissues are currently emerging such as insulin secretion in pancreatic β-cells, and links to cancer. Calcium permeability through thermoTRPs appears a central hallmark for their physiological and pathological activities. Moreover, it is currently being proposed that beyond working as a second messenger, Ca(2+) can function locally by acting on protein complexes near the membrane. Interestingly, thermoTRPs can enhance and expand the inherent plasticity of signalplexes by conferring them temperature, pH and lipid regulation through Ca(2+) signalling. Thus, unveiling the local role of Ca(2+) fluxes induced by thermoTRPs on the dynamics of membrane-attached signalling complexes as well as their significance in cellular processes, are central issues that will expand the opportunities for therapeutic intervention in disorders involving dysfunction of thermoTRP channels.
Because drug discovery efforts have experienced a pronounced decline in productivity, novel appro... more Because drug discovery efforts have experienced a pronounced decline in productivity, novel approaches to the rational design of new drugs are being introduced and developed. An exciting solution is the use of natural or synthetic peptides and peptidomimetics targeting protein-protein interactions essential for signaling networks function. The combination of several bioinformatic approaches (docking, virtual screening, pharmacophore models, etc.) allows for the use of the vast amount of information on protein-protein interactions deposited in structural databases. In this respect, interacting peptides are susceptible of optimization in order to stabilize or disrupt protein-protein interactions, providing a promising use of peptides and derivatives as therapeutics. In this review we illustrate tools and strategies currently used in peptidomic drug discovery as well as trends in the area of molecular pharmacology
Because of the social and economic costs of chronic pain, there is a growing interest in unveilin... more Because of the social and economic costs of chronic pain, there is a growing interest in unveiling the cellular and molecular mechanisms underlying it with the aim of developing more effective medications. Pain signalling is a multicomponent process that involves the peripheral and central nervous systems. At the periphery, nociceptor sensitisation by pro-inflammatory mediators is a primary step in pain transduction. Although pain is multifactorial at cellular and molecular levels, it is widely accepted that neurotrophin (TrkA, p75NTR, Ret and GFRs), cannabinoid (CB1 and CB2), and thermo-transient receptor potential (TRPs; TRPV1, TRPA1 and TRPM8) receptors play a pivotal role. They form a threesome for which endocannabinoids appear to be a first line of defence against pain, while neurotrophins and thermoTRPs are the major generators of painful signals. However, endocannabinoids may exhibit nociceptive activity while some neurotrophins may display anti-nociception. Accordingly, a clear-cut knowledge of the modulation and context-dependent function of these signalling cascades, along with the molecular and dynamic details of their crosstalk, is critical for understanding and controlling pain transduction. Here, the recent progress in this fascinating topic, as well as the tantalizing questions that remain unanswered, will be discussed. Furthermore, we will underline the need for using a systems biology approach (referred to as systems pain) to uncover the dynamics and interplay of these intricate signalling cascades, taking into consideration the molecular complexity and cellular heterogeneity of nociceptor populations. Nonetheless, the available information confirms that pharmacological modulation of this signalling triad is a highly valuable therapeutic strategy for effectively treating pain syndromes.
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Papers by Isabel Devesa