Contribution of Piezo2 to endothelium-dependent pain.

BackgroundWe evaluated the role of a mechanically-gated ion channel, Piezo2, in mechanical stimulation-induced enhancement of hyperalgesia produced by the pronociceptive vasoactive mediator endothelin-1, an innocuous mechanical stimulus-induced enhancement of hyperalgesia that is vascular endothelial cell dependent. We also evaluated its role in a preclinical model of a vascular endothelial cell dependent painful peripheral neuropathy.ResultsThe local administration of oligodeoxynucleotides antisense to Piezo2 mRNA, at the site of nociceptive testing in the rat's hind paw, but not intrathecally at the central terminal of the nociceptor, prevented innocuous stimulus-induced enhancement of hyperalgesia produced by endothelin-1 (100 ng). The mechanical hyperalgesia induced by oxaliplatin (2 mg/kg. i.v.), which was inhibited by impairing endothelial cell function, was similarly attenuated by local injection of the Piezo2 antisense. Polymerase chain reaction analysis demonstrated for the first time the presence of Piezo2 mRNA in endothelial cells.ConclusionsThese results support the hypothesis that Piezo2 is a mechano-transducer in the endothelial cell where it contributes to stimulus-dependent hyperalgesia, and a model of chemotherapy-induced painful peripheral neuropathy

Perturbations in neuroinflammatory pathways are associated with paclitaxel-induced peripheral neuropathy in breast cancer survivors.

Paclitaxel is a common chemotherapy drug associated with the development of chronic paclitaxel-induced peripheral neuropathy (PIPN). PIPN is associated with neuroinflammatory mechanisms in pre-clinical studies. Here, we evaluated for differential gene expression (DGE) in peripheral blood between breast cancer survivors with and without PIPN and for neuroinflammatory (NI) related signaling pathways and whole-transcriptome profiles from other experiments. Pathway impact analysis identified 8 perturbed NI related pathways. Expression profile analysis found 15 experiments having similar whole-transcriptome profiles of DGE related to neuroinflammation and PIPN. These findings suggest that perturbations in pathways associated with neuroinflammation are found in cancer survivors with PIPN

Expression of a novel versican variant in dorsal root ganglia from spared nerve injury rats

The size and modular structure of versican and its gene suggest the existence of multiple splice variants. We have identified, cloned, and sequenced a previously unknown exon located within the noncoding gene sequence downstream of exon 8. This exon, which we have named exon 8β, specifies two stop-codons. mRNAs of the versican gene with exon 8β are predicted to be constitutively degraded by nonsense-mediated RNA decay. Here, we tested the hypothesis that these transcripts become expressed in a model of neuropathic pain

Ionic basis of a mechanotransduction current in adult rat dorsal root ganglion neurons

Sensory mechanical transduction – necessary for hearing, proprioception, and the senses of touch and pain – remains poorly understood. In somatosensation, even the basic properties of the mechanically sensitive excitatory ionic currents that are assumed to mediate mechanical transduction are largely undescribed. We have recorded, from the soma of rat dorsal root ganglion (DRG) neurons in vitro, whole-cell ionic currents induced by the impact of a piezo-electrically driven glass probe. This transient mechanically activated current was observed in virtually all DRG neurons tested. In ion substitution experiments the current could be carried nonselectively by most cations, including divalent and organic cations, but not by chloride or sulfate ions. In addition, the mechanically activated current carried by monovalent cations was consistently blocked by millimolar concentrations of external calcium or magnesium. Based on these results, the transient mechanical transduction current observed in somatosensory neurons in vitro is mediated by large-pore mechanically gated channels nonselective for cations but impermeable to anions

Plasma Membrane Mechanisms in a Preclinical Rat Model of Chronic Pain

UnlabelledWe have recently shown that the prolongation of prostaglandin E2 hyperalgesia in a preclinical model of chronic pain-hyperalgesic priming-is mediated by release of cyclic adenosine monophosphate from isolectin B4-positive nociceptors and its metabolism by ectonucleotidases to produce adenosine. The adenosine, in turn, acts in an autocrine mechanism at an A1 adenosine receptor whose downstream signaling mechanisms in the nociceptor are altered to produce nociceptor sensitization. We previously showed that antisense against an extracellular matrix molecule, versican, which defines the population of nociceptors involved in hyperalgesic priming, eliminated the prolongation of prostaglandin E2 hyperalgesia. To further evaluate the mechanisms at the interface between the extracellular matrix and the nociceptor's plasma membrane involved in hyperalgesia prolongation, we interrupted a plasma membrane molecule involved in versican signaling, integrin β1, with an antisense oligodeoxynucleotide. Integrin β1 antisense eliminated mechanical hyperalgesia induced by an adenosine A1 receptor agonist, cyclopentyladenosine, in the primed rat. We also disrupted a molecular complex of signaling molecules that contains integrin β1, lipid rafts, with methyl-β-cyclodextrin, which attenuated the prolongation without affecting the acute phase of prostaglandin E2 hyperalgesia, while having no effect on cyclopentyladenosine hyperalgesia. Our findings help to define the plasma membrane mechanisms involved in a preclinical model of chronic pain.PerspectiveThe present study contributes to a further understanding of mechanisms involved in the organization of messengers at the plasma membrane that participate in the transition from acute to chronic pain

Marked attenuation of inflammatory mediator-induced C-fiber sensitization for mechanical and hypotonic stimuli in TRPV4-/- mice

Inflammatory mediators can directly sensitize primary afferent nociceptors to mechanical and osmotic stimuli. Sensitized nociceptors have a lowered threshold of activation and increased spontaneous activity, which result in symptoms of hyperalgesia and pain, respectively. The transient receptor potential vanilloid 4 (TRPV4) ligand-gated ion channel has been implicated in the hyperalgesia for mechanical and osmotic stimuli associated with inflammatory states. To investigate whether TRPV4 directly contributes to the mechanisms of inflammatory mediator sensitization of C-fiber nociceptors, we compared the effect of the injection of simplified inflammatory soup (prostaglandin E2 and serotonin) into the mechanical receptive fields of C-fibers in TRPV4+/+ and TRPV4-/- mice in vivo. Following the injection of the soup, the percentage of C-fibers responding to a hypotonic stimulus and the magnitude of the response was significantly greater in TRPV4+/+ mice compared to TRPV4-/- mice. Moreover, in response to simplified inflammatory soup only C-fibers from TRPV4+/+ mice exhibited increased spontaneous activity and decreased mechanical threshold. These marked impairments in the response of C-fibers in TRPV4-/- mice demonstrate the importance of TRPV4 in nociceptor sensitization; we suggest that TRPV4, as TRPV1, underlies the nociceptive effects of multiple inflammatory mediators on primary afferent

Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain

The primary afferent nociceptor was used as a model system to study mechanisms of pain induced by chronic opioid administration. Repeated intradermal injection of the selective mu-opioid receptor (MOR) agonist DAMGO induced mechanical hyperalgesia and marked prolongation of prostaglandin E2 (PGE2) hyperalgesia, a key feature of hyperalgesic priming. However, in contrast to prior studies of priming induced by receptor-mediated (i.e., TNFα, NGF, or IL-6 receptor) or direct activation of protein kinase Cε (PKCε), the pronociceptive effects of PGE2 in DAMGO-treated rats demonstrated the following: (1) rapid induction (4 h compared with 3 d); (2) protein kinase A (PKA), rather than PKCε, dependence; (3) prolongation of hyperalgesia induced by an activator of PKA, 8-bromo cAMP; (4) failure to be reversed by a protein translation inhibitor; (5) priming in females as well as in males; and (6) lack of dependence on the isolectin B4-positive nociceptor. These studies demonstrate a novel form of hyperalgesic priming induced by repeated administration of an agonist at the Gi-protein-coupled MOR to the peripheral terminal of the nociceptor. Significance statement: The current study demonstrates the molecular mechanisms involved in the sensitization of nociceptors produced by repeated activation of mu-opioid receptors and contributes to our understanding of the painful condition observed in patients submitted to chronic use of opioids

Three red suns in the sky: A transiting, terrestrial planet in a triple M-dwarf system at 6.9 pc

We present the discovery from Transiting Exoplanet Survey Satellite (TESS) data of LTT 1445Ab. At a distance of 6.9 pc, it is the second nearest transiting exoplanet system found to date, and the closest one known for which the primary is an M dwarf. The host stellar system consists of three mid-to-late M dwarfs in a hierarchical configuration, which are blended in one TESS pixel. We use MEarth data and results from the Science Processing Operations Center data validation report to determine that the planet transits the primary star in the system. The planet has a radius of ${1.38}_{-0.12}^{+0.13}$ ${R}_{\oplus }$, an orbital period of ${5.35882}_{-0.00031}^{+0.00030}$ days, and an equilibrium temperature of ${433}_{-27}^{+28}$ K. With radial velocities from the High Accuracy Radial Velocity Planet Searcher, we place a 3σ upper mass limit of 8.4 ${M}_{\oplus }$ on the planet. LTT 1445Ab provides one of the best opportunities to date for the spectroscopic study of the atmosphere of a terrestrial world. We also present a detailed characterization of the host stellar system. We use high-resolution spectroscopy and imaging to rule out the presence of any other close stellar or brown dwarf companions. Nineteen years of photometric monitoring of A and BC indicate a moderate amount of variability, in agreement with that observed in the TESS light-curve data. We derive a preliminary astrometric orbit for the BC pair that reveals an edge-on and eccentric configuration. The presence of a transiting planet in this system hints that the entire system may be co-planar, implying that the system may have formed from the early fragmentation of an individual protostellar core.Accepted manuscrip