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

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.

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

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.

scholarly journals Transient receptor potential vanilloid 1 mediates pain in mice with severe sickle cell disease

Blood ◽  
2011 ◽  
Vol 118 (12) ◽  
pp. 3376-3383 ◽  
Author(s):  
Cheryl A. Hillery ◽  
Patrick C. Kerstein ◽  
Daniel Vilceanu ◽  
Marie E. Barabas ◽  
Dawn Retherford ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Emergency Department Visits ◽  
Transient Receptor Potential Vanilloid ◽  
Cell Disease ◽  
Primary Afferent ◽  
Mechanical Hypersensitivity ◽  
Transient Receptor

Abstract Pain is the leading cause of emergency department visits, hospitalizations, and daily suffering in individuals with sickle cell disease (SCD). The pathologic mechanisms leading to the perception of pain during acute RBC sickling episodes and development of chronic pain remain poorly understood and ineffectively treated. We provide the first study that explores nociceptor sensitization mechanisms that contribute to pain behavior in mice with severe SCD. Sickle mice exhibit robust behavioral hypersensitivity to mechanical, cold, and heat stimuli. Mechanical hypersensitivity is further exacerbated when hypoxia is used to induce acute sickling. Behavioral mechanical hypersensitivity is mediated in part by enhanced excitability to mechanical stimuli at both primary afferent peripheral terminal and sensory membrane levels. In the present study, inhibition of the capsaicin receptor transient receptor potential vanilloid 1 (TRPV1) with the selective antagonist A-425619 reversed the mechanical sensitization at both primary afferent terminals and isolated somata, and markedly attenuated mechanical behavioral hypersensitivity. In contrast, inhibition of TRPA1 with HC-030031 had no effect on mechanical sensitivity. These results suggest that the TRPV1 receptor contributes to primary afferent mechanical sensitization and a substantial portion of behavioral mechanical hypersensitivity in SCD mice. Therefore, TRPV1-targeted compounds that lack thermoregulatory side effects may provide relief from pain in patients with SCD.

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

2012 ◽  
Vol 117 (1) ◽  
pp. 137-148 ◽  
Author(s):  
Hong Wei ◽  
Mari Karimaa ◽  
Timo Korjamo ◽  
Ari Koivisto ◽  
Antti Pertovaara
Keyword(s):  
Postoperative Pain ◽  
Ion Channel ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Mechanical Stimulus ◽  
Nerve Fibers ◽  
Spontaneous Pain ◽  
Mechanical Hypersensitivity ◽  
Afferent Nerve Fibers ◽  
Transient Receptor

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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