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Item Activin acutely sensitizes dorsal root ganglion neurons and induces hyperalgesia via PKC-mediated potentiation of transient receptor potential vanilloid I(Society for Neuroscience, 2007-12-12) Zhu, Weiguo; Xu, Pin; Cuascut, Fernando X.; Hall, Alison K.; Oxford, Gerry S.; Pharmacology and Toxicology, School of MedicinePain hypersensitivity is a cardinal sign of tissue damage, but how molecules from peripheral tissues affect sensory neuron physiology is incompletely understood. Previous studies have shown that activin A increases after peripheral injury and is sufficient to induce acute nociceptive behavior and increase pain peptides in sensory ganglia. This study was designed to test the possibility that the enhanced nociceptive responsiveness associated with activin involved sensitization of transient receptor potential vanilloid I (TRPV1) in primary sensory neurons. Activin receptors were found widely distributed among adult sensory neurons, including those that also express the capsaicin receptor. Whole-cell patch-clamp recording from sensory neurons showed that activin acutely sensitized capsaicin responses and depended on activin receptor kinase activity. Pharmacological studies revealed that the activin sensitization of capsaicin responses required PKCepsilon signaling, but not PI3K (phosphoinositide 3-kinase), ERK (extracellular signal-regulated protein kinase), PKA, PKCalpha/beta, or Src. Furthermore, activin administration caused acute thermal hyperalgesia in wild-type mice, but not in TRPV1-null mice. These data suggest that activin signals through its own receptor, involves PKCepsilon signaling to sensitize the TRPV1 channel, and contributes to acute thermal hyperalgesia.Item The cAMP transduction cascade mediates the prostaglandin E2 enhancement of the capsaicin-elicited current in rat sensory neurons: whole-cell and single-channel studies(Society for Neuroscience, 1998-08-15) Lopshire, John C.; Nicol, Grant D.; Pharmacology and Toxicology, School of MedicineTreatment with proinflammatory prostaglandin E2 (PGE2) produced a transient sensitization of whole-cell currents elicited by the vanilloid capsaicin. The intracellular signaling pathways that mediate the initiation of this PGE2-induced sensitization of the capsaicin-elicited current in rat sensory neurons are not well established. Treatment with either forskolin (100 nM to 10 microM) or membrane-permeant analogs of cAMP, 8-bromo-cAMP (8-Br-cAMP) and chlorphenylthio-cAMP (10 microM to 1 mM), transiently sensitized neuronal responses elicited by capsaicin in a manner analogous to that produced by PGE2. The duration of sensitization was lengthened with increasing concentrations of forskolin; however, higher concentrations of 8-Br-cAMP or chlorphenylthio-cAMP led to a shortening of sensitization. The inactive analog of forskolin, dideoxy-forskolin, had no effect on capsaicin responses. Inclusion of the inhibitor of protein kinase A in the recording pipette completely suppressed the sensitization produced by PGE2 or forskolin. In recordings from membrane patches in the cell-attached configuration, the bath application of capsaicin evoked single-channel currents in which the level of channel activity was concentration-dependent and had an EC50 of 1.4 microM. These single-channel currents evoked by capsaicin exhibited an apparent reversal potential of +4 mV and were blocked by the capsaicin antagonist capsazepine. Exposure of the sensory neuron to either PGE2 or forskolin produced a large and transient increase in the mean channel activity (NPo) elicited by capsaicin, although the unitary conductance remained unaltered. Taken together, these observations suggest that modulation of the capsaicin-gated channel by the cAMP-protein kinase A signaling pathway enhanced the gating of these channels and consequently resulted in the sensitization of the whole-cell currents.Item Dihydroceramides Derived from Bacteroidetes Species Sensitize TRPV1 Channels(MDPI, 2023-01-03) Ludwig, Nora; Demaree, Isaac S.; Yamada, Chiaki; Nusbaum, Amilia; Nichols, Frank C.; White, Fletcher A.; Movila, Alexandru; Obukhov, Alexander G.; Anatomy, Cell Biology and Physiology, School of MedicineBacterial colonization of open wounds is common, and patients with infected wounds often report significantly elevated pain sensitivity at the wound site. Transient Receptor Potential Vanilloid Type 1 (TRPV1) channels are known to play an important role in pain signaling and may be sensitized under pro-inflammatory conditions. Bacterial membrane components, such as phosphoethanolamine dihydroceramide (PEDHC), phosphoglycerol dihydroceramide (PGDHC), and lipopolysaccharide (LPS), are released in the environment from the Gram-negative bacteria of the Bacteroidetes species colonizing the infected wounds. Here, we used intracellular calcium imaging and patch-clamp electrophysiology approaches to determine whether bacterially derived PEDHC, PGDHC, or LPS can modulate the activity of the TRPV1 channels heterologously expressed in HEK cells. We found that PEDHC and PGDHC can sensitize TRPV1 in a concentration-dependent manner, whereas LPS treatment does not significantly affect TRPV1 activity in HEK cells. We propose that sensitization of TRPV1 channels by Bacteroidetes-derived dihydroceramides may at least in part underlie the increased pain sensitivity associated with wound infections.Item Long-Term Diabetic Microenvironment Augments the Decay Rate of Capsaicin-Induced Currents in Mouse Dorsal Root Ganglion Neurons(MDPI, 2019-02-21) Chen, Xingjuan; Duan, Yaqian; Riley, Ashley M.; Welch, Megan A.; White, Fletcher A.; Grant, Maria B.; Obukhov, Alexander G.; Cellular and Integrative Physiology, School of MedicineIndividuals with end-stage diabetic peripheral neuropathy present with decreased pain sensation. Transient receptor potential vanilloid type 1 (TRPV1) is implicated in pain signaling and resides on sensory dorsal root ganglion (DRG) neurons. We investigated the expression and functional activity of TRPV1 in DRG neurons of the Ins2+/Akita mouse at 9 months of diabetes using immunohistochemistry, live single cell calcium imaging, and whole-cell patch-clamp electrophysiology. 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence assay was used to determine the level of Reactive Oxygen Species (ROS) in DRGs. Although TRPV1 expressing neuron percentage was increased in Ins2+/Akita DRGs at 9 months of diabetes compared to control, capsaicin-induced Ca2+ influx was smaller in isolated Ins2+/Akita DRG neurons, indicating impaired TRPV1 function. Consistently, capsaicin-induced Ca2+ influx was decreased in control DRG neurons cultured in the presence of 25 mM glucose for seven days versus those cultured with 5.5 mM glucose. The high glucose environment increased cytoplasmic ROS accumulation in cultured DRG neurons. Patch-clamp recordings revealed that capsaicin-activated currents decayed faster in isolated Ins2+/Akita DRG neurons as compared to those in control neurons. We propose that in poorly controlled diabetes, the accelerated rate of capsaicin-sensitive TRPV1 current decay in DRG neurons decreases overall TRPV1 activity and contributes to peripheral neuropathy.Item Primary Erythromelalgia Treated With 10% Capsaicin Cream: A Case Report and a 10-Year Follow-Up(Springer Nature, 2022-08-24) Tolley, James A.; Walsh, Laurence E.; Anesthesia, School of MedicineIn this case report, we describe the difficulty in finding a suitable treatment for a nine-year-old girl with erythromelalgia. Initially, she could only find pain relief through immersion of her hands and feet in buckets of cool water. Her pain did not respond to outpatient treatments, and she was ultimately admitted to the hospital for pain management. Many different medications and modalities were tried over the course of several weeks in the hospital. Finally, she received the most benefit from 10% compounded capsaicin cream administered under general anesthesia with regional analgesia for post-application pain. Over the course of several years, exacerbations of her pain were treated with additional applications of 10% capsaicin cream, with each application providing relief for an increased duration. Her severe pain flares eventually went into remission after several years. Today, after more than a decade following her initial presentation, she is a successful college student and is taking no medications for her erythromelalgia.Item Regulation of the PGE₂-induced sensitization of capsaicin-elicited currents in rat sensory neurons(1998) Lopshire, John ChristopherItem Tumor necrosis factor enhances the capsaicin sensitivity of rat sensory neurons(Society for Neuroscience, 1997-02-01) Nicol, Grant D.; Lopshire, John C.; Pafford, Carl M.; Pharmacology and Toxicology, School of MedicineThe capacity of the proinflammatory cytokines, tumor necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL-1 beta), to modulate the sensitivity of isolated sensory neurons grown in culture to the excitatory chemical agent capsaicin was examined. Alterations in capsaicin sensitivity were assessed by quantifying the number of neurons labeled with cobalt after exposure to capsaicin and by recording the whole-cell response from a single neuron to the focal application of capsaicin. A 24 hr pretreatment of the neuronal cultures with TNF alpha (10 or 50 ng/ml), but not IL-1 beta (10 or 50 ng/ml), produced a concentration-dependent increase in the number of cobalt-labeled neurons after exposure to 100 nM capsaicin. The peak increase in the number of labeled neurons was attained after a 4 hr treatment with 10 ng/ml TNF alpha. Similarly, pretreatment with TNF alpha (10 ng/ml for 4, 12, and 24 hr) produced a greater than twofold increase in the average peak amplitude of the inward current evoked by 100 nM capsaicin. Both the TNF alpha-induced increase in labeling and current amplitude were blocked by treating the neuronal cultures with indomethacin before the addition of TNF alpha. Enhancement of the capsaicin-evoked current also was blocked by the specific cyclo-oxygenase-2 inhibitor SC-236. These results indicate that TNF alpha can enhance the sensitivity of sensory neurons to the excitation produced by capsaicin and that this enhancement likely is mediated by the neuronal production of prostaglandins. Isolated sensory neurons grown in culture may prove to be a useful model system in which to explore how prolonged exposure to mediators associated with chronic inflammation alter the regulatory pathways that modulate the excitability of the nervous system.