Biology subjects

Cabanero, D.

Publications and source records attributed to Cabanero, D..

4 recordsLinked to original sources

bioRxiv2025

Druggability of Phospholipase C-β Isoforms with Small Peptides Patterned after the Autoinhibitory XY Linker

The phospholipase C-{beta} (PLC{beta}) signaling pathway plays a pivotal role in peripheral nociception, particularly during inflammation and pain transduction. Despite their validation as important therapeutic targets, PLC{beta} isoforms are yet undruggable due to the difficulties to identify potent and selective modulators. Here, we addressed this question and used the autoinhibitory XY linker present in these enzymes as a source of peptide inhibitors of PLC{beta} activity. We report that peptides patterned after this motif inhibited PIP2 hydrolysis and the consequent calcium release from endoplasmic reticulum. In primary nociceptor cultures, active peptides notably attenuated bradykinin-induced electrogenesis and TRPV1 sensitization, thus reducing nociceptor hyperexcitability. Noteworthy, intraplantar administration of a lead peptide prevented inflammation and hypersensitivity in a mouse model of inflammatory pain. Collectively, our findings indicate that peptides patterned after the autoinhibitory XY linker act as selective PLC{beta} inhibitors with in vivo anti-inflammatory and antinociceptive activity, providing pharmacological tools for this enzyme family. SIGNIFICANCEPhospholipases C (PLC) are intracellular signaling proteins, with PLC{beta} isoforms crucial in somatosensory neuron signaling. These enzymes interact with G-protein coupled receptors for pro-inflammatory and algesic agents, sensitizing nociceptors by increasing their excitability. Despite their importance, selective PLC{beta} modulators remain limited; U73122 is widely used, though it lacks specificity and has off-target effects. Here, we introduce peptide inhibitors based on the XY autoinhibitory motif that selectively block PLC{beta} activity, reduce bradykinin-induced neuronal responses and TRPV1 sensitization, and do not affect other PLC isoforms. In a murine inflammatory pain model, local administration of our lead peptide showed both anti-inflammatory and antinociceptive effects, highlighting its therapeutic potential. This approach expands the toolkit of PLC-isoform selective modulators for drug development.

molecular biology↗

bioRxiv2025

Cold Receptor TRPM8 as a target for Migraine-associated Pain and Affective Comorbidities

BackgroundGenetic variations in the Trpm8 gene that encodes the cold receptor TRPM8 have been linked to protection against polygenic migraine, a disabling condition primarily affecting women. Noteworthy, TRPM8 has been recently found in brain areas related to emotional processing, suggesting an unrecognized role in migraine comorbidities. Here, we use mouse behavioural models to investigate the role of Trpm8 in migraine-related phenotypes. Subsequently, we test the efficacy of rapamycin, a clinically relevant TRPM8 agonist, in these behavioural traits and in human induced pluripotent stem cell (iPSC)-derived sensory neurons. FindingsWe report that Trpm8 null mice exhibited impulsive and depressive-like behaviours, while also showing frequent pain-like facial expressions detected by an artificial intelligence algorithm. In a nitroglycerin-induced migraine model, Trpm8 knockout mice of both sexes developed anxiety and mechanical hypersensitivity, whereas wild-type females also displayed depressive-like phenotype and hypernociception. Notably, rapamycin alleviated pain-related behaviour through both TRPM8-dependent and independent mechanisms but lacked antidepressant activity, consistent with a peripheral action. The macrolide ionotropically activated TRPM8 signalling in human sensory neurons, emerging as a new candidate for intervention. SignificanceTogether, our findings underscore the potential of TRPM8 for migraine relief and its involvement in affective comorbidities, emphasizing the importance of addressing emotional symptoms to improve clinical outcomes for migraine sufferers, especially in females.

neuroscience↗

bioRxiv2020

Protective role of neuronal and lymphoid cannabinoid CB2 receptors in neuropathic pain

Cannabinoid CB2 receptor (CB2r) agonists are potential painkillers void of psychotropic effects. Peripheral immune cells, neurons and glia express CB2r, however the involvement of CB2r from these cells in neuropathic pain remains unresolved. We explored spontaneous neuropathic pain through on-demand self-administration of the selective CB2r agonist JWH133 in wild-type and knockout mice lacking CB2r in neurons, monocytes or constitutively. Operant self-administration reflected drug-taking to alleviate spontaneous pain, nociceptive and affective manifestations. While constitutive deletion of CB2r disrupted JWH133-taking behavior, this behavior was not modified in monocyte-specific CB2r knockouts and was increased in mice defective in neuronal CB2r knockouts suggestive of increased spontaneous pain. Interestingly, CB2r-positive lymphocytes infiltrated the injured nerve and possible CB2r transfer from immune cells to neurons was found. Lymphocyte CB2r depletion also exacerbated JWH133 self-administration and inhibited antinociception. This work identifies a simultaneous activity of neuronal and lymphoid CB2r that protects against spontaneous and evoked neuropathic pain.

physiology↗

bioRxiv2019

Disease-modifying effects of natural Δ9-tetrahydrocannabinol in endometriosis-associated pain

Endometriosis is a chronic painful disease highly prevalent in women that is defined by growth of endometrial tissue outside the uterine cavity and lacks adequate treatment. Medical use of cannabis derivatives is a current hot topic and it is unknown whether phytocannabinoids may modify endometriosis symptoms and development. Here we evaluate the effects of repeated exposure to {Delta}9-tetrahydrocannabinol (THC) in a mouse model of surgically-induced endometriosis. In this model, female mice develop pelvic mechanical hypersensitivity, anxiety-like behavior and sharp memory deficits associated to the presence of extrauterine endometrial cysts. Interestingly, chronic THC (2 mg/kg/day) provides sustained alleviation of pelvic hypersensitivity without altering the anxiogenic phenotype, modifies uterine innervation and restores cognitive function, an effect correlated with neuroinflammatory changes in prefrontal cortex. Strikingly, THC also inhibits the development of endometrial cysts. These data highlight the interest of scheduled clinical trials designed to investigate possible benefits of THC for women with endometriosis.

physiology↗