Activation of the RAS/B‐RAF‐MEK‐ERK pathway in satellite glial cells contributes to substance p‐mediated orofacial pain
Authors: Jiu Lin
Yan-Yan Zhang
Fei Liu
Ning Song
Da-Qing Liao
Jie-Fei Shen
Hang Wang
Chao-Lan Huang
Meng-Ke Liu
Cheng Zhou
Journal: European Journal of Neuroscience (2020)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: SD rat; extracellular signal-regulated kinase; inflammatory pain; neurokinin-I receptor; satellite glial cell
Affiliations: State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China., Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Center, West China Hospital of Sichuan University, Chengdu, China.

Abstract:  The cross talk between trigeminal ganglion (TG) neurons and satellite glial cells (SGCs) is crucial for the regulation of inflammatory orofacial pain. Substance P (SP) plays an important role by activating neurokinin (NK)-I receptors in this cross talk. The activation of extracellular signal-regulated kinase (ERK) 1/2, protein kinase A (PKA) and protein kinase C (PKC) in neurons and SGCs of peripheral ganglions by peripheral inflammation is associated with inflammatory hypersensitivity. This study tested the hypothesis that SP evoked SP-NK-I receptor positive feedback via the Renin-Angiotensin System/B-Protein Kinase A-Rapidly Accelerates Fibrosarcoma-MEK-Extracellular Signal-Regulated Kinase (RAS/PKA-RAF-MEK-ERK) pathway, which is involved in pain hypersensitivity. Inflammatory models were induced in vivo by injecting Complete Freund's adjuvant (CFA) into the whisker pad of rats. SP was administrated to SGCs in vitro for investigating, whether SP regulates the expression of NK-I receptor in the SGC nucleus. The effects of RAS-RAF-MEK, PKA and PKC pathways in this process were measured by co-incubating SGCs with respective Raf, PKA, PKC and MEK inhibitors in vitro and by pre-injecting these inhibitors into the TG in vivo. SP significantly upregulated NK-I receptor, p-ERK1/2, Ras, B-Raf, PKA and PKC in SGCs under inflammatory conditions. In addition, L703,606 (NK-I receptor antagonist), U0126 (MEK inhibitor), Sorafenib (Raf inhibitor) and H892HCL (PKA inhibitor) but not chelerythrine chloride (PKC inhibitor) significantly decreased NK-I mRNA and protein levels induced by SP. The allodynia-related behavior evoked by CFA was inhibited by pre-injection of L703,606, U0126, Sorafenib and H892HCL into the TG. Overall, SP upregulates NK-I receptor in TG SGCs via PKA/RAS-RAF-MEK-ERK pathway activation, contributing to a positive feedback of SP-NK-I receptor in inflammatory orofacial pain. 

Retracted: No

PubPeer comments:
null, 
 Copy pasted from https: retractionwatch.com 2021 04 09 anesthesiologist-loses-50-more-papers-in-12-months  (....) In view of these inconsistencies and Dr. Boldtu2019s misconduct in this and many other aspects of scientific integrity, JLU recommends that journal editors retract all papers where Dr. Boldt is the responsible author even if there is no obvious indication of falsification. All articles by Dr. Boldt u2013 if still available u2013 should be read with great caution because they may contain falsified data. (....) ,