Transient Receptor Potential Ankyrin 1 Ion Channel Contributes to Guarding Pain and Mechanical Hypersensitivity in a Rat Model of Postoperative Pain

Background The transient receptor potential ankyrin 1 (TRPA1) ion channel is expressed on nociceptive primary afferent nerve fibers. On the distal ending, it is involved in transduction of noxious stimuli, and on the proximal ending (within the spinal dorsal horn), it regulates transmission of nociceptive signals. Here we studied whether the cutaneous or spinal TRPA1 ion channel contributes to mechanical hypersensitivity or guarding, an index of spontaneous pain, in an experimental model of postoperative pain in the rat. Methods A skin plus deep-tissue incision was performed under general anesthesia in the plantar skin of one hind paw, after which the incised skin was closed with sutures. Postoperative pain and hypersensitivity were assessed 24-48 h after the operation. Guarding pain was assessed by scoring the hind-paw position. Mechanical hypersensitivity was assessed with a calibrated series of monofilaments applied to the wound area in the operated paw or the contralateral control paw. Chembridge-5861528, a TRPA1 channel antagonist, was administered intaperitoneally (10-30 mg/kg), intraplantarly (10-30 μg), or intrathecally (10 μg) in attempts to suppress guarding and hypersensitivity. Results Intraperitoneal or ipsi- but not contralateral intraplantar treatment with Chembridge-5861528 reduced mechanical hypersensitivity and guarding in the operated limb. Intrathecal treatment attenuated hypersensitivity but not guarding. Intraplantar Chembridge-5861528 suppressed preferentially mechanical hyperalgesia and intrathecal Chembridge-5861528 tactile allodynia. Conclusions The TRPA1 channel in the skin contributes to sustained as well noxious mechanical stimulus-evoked postoperative pain, whereas the spinal TRPA1 channel contributes predominantly to innocuous mechanical stimulus-evoked postoperative pain.

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Peripheral Mechanobiology of Touch—Studies on Vertebrate Cutaneous Sensory Corpuscles

International Journal of Molecular Sciences ◽

10.3390/ijms21176221 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6221 ◽

Cited By ~ 1

Author(s):

Ramón Cobo ◽

Jorge García-Piqueras ◽

Yolanda García-Mesa ◽

Jorge Feito ◽

Olivia García-Suárez ◽

...

Keyword(s):

Ion Channels ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Transient Receptor Potential Channel ◽

Mechanical Stimulus ◽

Nerve Fibers ◽

Current Data ◽

Acid Sensing Ion Channels ◽

Low Threshold ◽

Transient Receptor

The vertebrate skin contains sensory corpuscles that are receptors for different qualities of mechanosensitivity like light brush, touch, pressure, stretch or vibration. These specialized sensory organs are linked anatomically and functionally to mechanosensory neurons, which function as low-threshold mechanoreceptors connected to peripheral skin through Aβ nerve fibers. Furthermore, low-threshold mechanoreceptors associated with Aδ and C nerve fibers have been identified in hairy skin. The process of mechanotransduction requires the conversion of a mechanical stimulus into electrical signals (action potentials) through the activation of mechanosensible ion channels present both in the axon and the periaxonal cells of sensory corpuscles (i.e., Schwann-, endoneurial- and perineurial-related cells). Most of those putative ion channels belong to the degenerin/epithelial sodium channel (especially the family of acid-sensing ion channels), the transient receptor potential channel superfamilies, and the Piezo family. This review updates the current data about the occurrence and distribution of putative mechanosensitive ion channels in cutaneous mechanoreceptors including primary sensory neurons and sensory corpuscles.

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Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

The Open Pain Journal ◽

10.2174/1876386301306010127 ◽

2013 ◽

Vol 6 (1) ◽

pp. 127-136 ◽

Cited By ~ 4

Author(s):

Romina Nassini ◽

Silvia Benemei ◽

Camilla Fusi ◽

Gabriela Trevisan ◽

Serena Materazzi

Keyword(s):

Oxidative Stress ◽

Peripheral Neuropathy ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Nerve Fibers ◽

Transient Receptor Potential Channels ◽

In Vivo Studies ◽

Spontaneous Pain ◽

Transient Receptor ◽

Thermal Hypersensitivity

Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common dose-limiting side effect of many chemotherapeuticdrugs, including platinum-based compounds (e.g., cisplatin and oxaliplatin), taxanes (e.g., paclitaxel), vinca alkaloids (e.g., vincristine), and the first-in-class proteasome inhibitor, bortezomib. Among the various sensory symptoms of CIPN, paresthesia, dysesthesia, spontaneous pain, and mechanical and thermal hypersensitivity are prominent. Inflammation, oxidative stress, loss of intraepidermal nerve fibers, modifications of mitochondria, and various ion channels alterations are part of the several mechanisms contributing to CIPN. Because attempts to mitigate chemotherapeutic- induced acute neuronal hyperexcitability and the subsequent peripheral neuropathy have yielded unsatisfactory results, a more in-depth understanding of the mechanism(s) responsible for the neurotoxic action of anticancer drugs is required. Some members of the transient receptor potential (TRP) family of channels, as the TRPV1 and TRPV4 (vanilloid), TRPA1 (ankyrin) and TRPM8 (melastatin) are expressed on the plasma membrane of primary sensory neurons (nociceptors), where they are activated by an unprecedented series of physical and chemical stimuli. There is evidence that TRPV1, TRPV4, TRPA1 and TRPM8 are prominent contributors of mechanical and thermal hypersensitivity in models of CIPN. In particular, in vitro and in vivo studies have pointed out the unique role of TRPA1 and oxidative stress in the mechanism responsible for cold and mechanical hyperalgesia in rodent models of CIPN.

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Transient receptor potential canonical 5 mediates inflammatory mechanical and spontaneous pain in mice

Science Translational Medicine ◽

10.1126/scitranslmed.abd7702 ◽

2021 ◽

Vol 13 (595) ◽

pp. eabd7702

Author(s):

Katelyn E. Sadler ◽

Francie Moehring ◽

Stephanie I. Shiers ◽

Lauren J. Laskowski ◽

Alexander R. Mikesell ◽

...

Keyword(s):

Mechanical Allodynia ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Skin Incision ◽

Spontaneous Pain ◽

Cell Disease ◽

Mechanical Hypersensitivity ◽

Transient Receptor Potential Canonical ◽

Pain Models ◽

Transient Receptor

Tactile and spontaneous pains are poorly managed symptoms of inflammatory and neuropathic injury. Here, we found that transient receptor potential canonical 5 (TRPC5) is a chief contributor to both of these sensations in multiple rodent pain models. Use of TRPC5 knockout mice and inhibitors revealed that TRPC5 selectively contributes to the mechanical hypersensitivity associated with CFA injection, skin incision, chemotherapy induced peripheral neuropathy, sickle cell disease, and migraine, all of which were characterized by elevated concentrations of lysophosphatidylcholine (LPC). Accordingly, exogenous application of LPC induced TRPC5-dependent behavioral mechanical allodynia, neuronal mechanical hypersensitivity, and spontaneous pain in naïve mice. Lastly, we found that 75% of human sensory neurons express TRPC5, the activity of which is directly modulated by LPC. On the basis of these results, TRPC5 inhibitors might effectively treat spontaneous and tactile pain in conditions characterized by elevated LPC.

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Transient receptor potential canonical 5 (TRPC5) mediates inflammatory mechanical pain

10.1101/2020.07.13.201186 ◽

2020 ◽

Author(s):

Katelyn E. Sadler ◽

Francie Moehring ◽

Stephanie I. Shiers ◽

Lauren J. Laskowski ◽

Alexander R. Mikesell ◽

...

Keyword(s):

Sensory Neurons ◽

Dorsal Root ◽

Mechanical Allodynia ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Spontaneous Pain ◽

Rodent Models ◽

Mechanical Hypersensitivity ◽

Transient Receptor

AbstractPersistent tactile pain is a poorly managed symptom of inflammatory and neuropathic injury. To develop therapies for this maladaptive sensation, the underlying molecular mediators must be identified. Using knockout mice and pharmacological inhibitors, we identified transient receptor canonical 5 (TRPC5) as a key contributor to the persistent tactile pain that occurs in many inflammatory and neuropathic preclinical rodent models. TRPC5 inhibition was effective in injuries associated with elevated levels of the bioactive phospholipid lysophosphatidylcholine (LPC). Exogenous application of LPC induced TRPC5-dependent behavioral mechanical allodynia, neuronal mechanical hypersensitivity, and spontaneous pain. In vitro, LPC activated both homomeric mouse and human TRPC5 channels, which upon examination of human dorsal root ganglia tissue, were expressed in 75% of human sensory neurons. Based on these results, TRPC5 inhibitors should be pursued as personalized therapy for spontaneous and tactile pain in conditions where elevated LPC is a biomarker.

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