TY - JOUR
T1 - Sensitization of TRPV1 and TRPA1 via peripheral mGluR5 signaling contributes to thermal and mechanical hypersensitivity
AU - Honda, Kuniya
AU - Shinoda, Masamichi
AU - Kondo, Masahiro
AU - Shimizu, Kohei
AU - Yonemoto, Hisashi
AU - Otsuki, Katsuhiko
AU - Akasaka, Ryuta
AU - Furukawa, Akihiko
AU - Iwata, Koichi
N1 - Publisher Copyright:
© 2017 International Association for the Study of Pain.
PY - 2017/9/1
Y1 - 2017/9/1
N2 - 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.
AB - 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.
KW - Glutamate
KW - Mechanical hypersensitivity
KW - Metabotropic glutamate receptor 5
KW - Orofacial pain
KW - Thermal hypersensitivity
KW - Transient receptor potential ankyrin 1
KW - Transient receptor potential vanilloid 1
UR - http://www.scopus.com/inward/record.url?scp=85028307509&partnerID=8YFLogxK
U2 - 10.1097/j.pain.0000000000000973
DO - 10.1097/j.pain.0000000000000973
M3 - Article
C2 - 28621704
AN - SCOPUS:85028307509
SN - 0304-3959
VL - 158
SP - 1754
EP - 1764
JO - Pain
JF - Pain
IS - 9
ER -