Sensitization of TRPV1 and TRPA1 via peripheral mGluR5 signaling contributes to thermal and mechanical hypersensitivity

Abstract

Peripheral tissue inflammation or injury causes glutamate release from nociceptive axons, keratinocytes, and Schwann cells, resulting in thermal hypersensitivity. However, the detailed molecular mechanisms underlying glutamate-induced thermal hypersensitivity are unknown. The aim of this study was to clarify the involvement of peripheral transient receptor potential (TRP) TRP vanilloid 1 (TRPV1), TRP ankyrin 1 (TRPA1), and protein kinase C epsilon (PKCε) in glutamate-induced pain hypersensitivity. The amount of glutamate in the facial tissue was significantly increased 3 days after facial Complete Freund's adjuvant injection. The head-withdrawal reflex threshold to heat, cold, or mechanical stimulation was significantly decreased on day 7 after continuous glutamate or metabotropic glutamate receptor 5 (mGluR5) agonist (CHPG) injection into the facial skin compared with vehicle-injected rats, and glutamate-induced hypersensitivity was significantly recovered by mGluR5 antagonist MTEP, TRPA1 antagonist HC-030031, TRPV1 antagonist SB366791, or PKCε translocation inhibitor administration into the facial skin. TRPV1 and TRPA1 were expressed in mGluR5-immunoreactive (IR) trigeminal ganglion (TG) neurons innervating the facial skin, and mGluR5-IR TG neurons expressed PKCε. There was no significant difference in the number of GluR5-IR TG neurons among glutamate-injected, saline-injected, and naive rats, whereas that of TRPV1- or TRPA1-IR TG neurons was significantly increased 7 days after continuous glutamate injection into the facial skin compared with vehicle injection. PKCε phosphorylation in TG was significantly enhanced following glutamate injection into the facial skin. Moreover, neuronal activity of TG neurons was significantly increased following facial glutamate treatment. The present findings suggest that sensitization of TRPA1 and/or TRPV1 through mGluR5 signaling via PKCε is involved in facial thermal and mechanical hypersensitivity.

Reciprocal Regulatory Interaction between TRPV1 and Kinin B1 Receptor in a Rat Neuropathic Pain Model

“…TRPV1 is commonly recognized as a main noxious heat sensor, being involved in thermal hyperalgesia [22,23,45], inflammatory pain [46], notably facial pain [47,48]. Our study suggests that TRPV1 could also be involved in mechanical and cold hypersensitivity during NP as shown for facial pain [47,48], yet its role appears shorter lasting than in heat hyperalgesia. The TRPV1 antagonist SB366791 dose-dependently alleviated heat and mechanical sensitivity in the model of chronic constriction injury of the sciatic nerve in mice when injected into the injured paw [49].…”

<p>Electroacupuncture Regulates Pain Transition by Inhibiting the mGluR5-PKCϵ Signaling Pathway in the Dorsal Root Ganglia</p>

“…27,47 A previous study found that PKCε contributes to the process by which mGluR5 causes hyperalgesia. 22 In this study, glutamate and MTEP were chosen to examine whether mGluR5 is involved in the process of hyperalgesic priming and PKCε activation. Our study found that glutamate can mimic hyperalgesic priming and increase PKCε expression in the DRGs.…”

“…Metabotropic glutamate receptor 5 (mGluR5) is one of the glutamate receptors expressed in small-diameter neurons in the DRGs. 19,20 Previous studies have found that damaged peripheral tissue can release glutamate 21,22 and activate primary afferent neurons that express mGluR5, causing hyperalgesia. 23,24 The use of selective inhibitors of mGluR5 can significantly reduce hyperalgesia.…”

Group I metabotropic glutamate receptor plasticity after peripheral inflammation alters nociceptive transmission in the dorsal horn of the spinal cord in adult rats

“… 34 This pronociceptive role is due to the activation of peripheral mGluR5 rather than spinal ones. 34 – 36 Therefore, we cannot rule out the spatial and functional segregation of mGluR5. Finally, a recent study emphasized the role of intracellular mGluR5 in the DH in a mononeuropathy model.…”