Intact subepidermal nerve fibers mediate mechanical hypersensitivity via the activation of protein kinase C gamma in spared nerve injury.
BACKGROUND
Spared nerve injury is an important neuropathic pain model for investigating the role of intact primary afferents in the skin on pain hypersensitivity. However, potential cellular mechanisms remain poorly understood. In phosphoinositide-3 kinase pathway, pyruvate dehydrogenase kinase 1 (PDK1) participates in the regulation of neuronal plasticity for central sensitization. The downstream cascades of PDK1 include: (1) protein kinase C gamma (PKCg) controls the trafficking and phosphorylation of ionotropic glutamate receptor; (2) protein kinase B (Akt)/the mammalian target of rapamycin (mTOR) signaling is responsible for local protein synthesis. Under these statements, we therefore hypothesized that an increase of PKCg activation and mTOR-dependent PKCg synthesis in intact primary afferents after SNI might contribute to pain hypersensitivity.


RESULTS
The variants of spared nerve injury were performed in Sprague-Dawley rats by transecting any two of the three branches of the sciatic nerve, leaving only one branch intact. Following SNIt (spared tibial branch), mechanical hyperalgesia and mechanical allodynia, but not thermal hyperalgesia, were significantly induced. In the first footpad, normal epidermal innervations were verified by the protein gene product 9.5 (PGP9.5)- and growth-associated protein 43 (GAP43)-immunoreactive (IR) intraepidermal nerve fibers (IENFs) densities. Furthermore, the rapid increases of phospho-PKCg- and phosphomTOR-IR subepidermal nerve fibers (SENFs) areas were distinct gathered from the results of PGP9.5-, GAP43-, and neurofilament 200 (NF200)-IR SENFs areas. The efficacy of PKC inhibitor (GF 109203X) or mTOR complex 1 inhibitor (rapamycin) for attenuating mechanical hyperalgesia and mechanical allodynia by intraplantar injection was dose-dependent.


CONCLUSIONS
From results obtained in this study, we strongly recommend that the intact SENFs persistently increase PKCg activation and mTOR-dependent PKCg synthesis participate in the initiation and maintenance of mechanical hypersensitivity in spared nerve injury, which represents as a novel insight into the therapeutic strategy of pain in the periphery.
Miau-Hwa
MH
Ko
Ming-Ling
ML
Yang
Su-Chung
SC
Youn
Chyn-Tair
CT
Lan
To-Jung
TJ
Tseng
D000818:Animals; D001522:Behavior, Animal; D020405:Dermis / Q000473:pathology; D004789:Enzyme Activation; D004817:Epidermis / Q000294:innervation* / Q000601:surgery; D006930:Hyperalgesia / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D018862:Merkel Cells / Q000473:pathology; D009412:Nerve Fibers / Q000473:pathology*; D010146:Pain / Q000150:complications / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000201:enzymology* / Q000293:injuries* / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
C087857:protein kinase C gamma; D058570:TOR Serine-Threonine Kinases; D011493:Protein Kinase C