Discomfort and pain encountered during orthodontic treatment are major problems for patients, but the details of the underlying neural processes and molecular mechanisms are not well-understood. Here we show that noxious tooth mechanical pressure induced by orthodontic elastics resulted in a rapid and transient activation of extracellular signal-regulated protein kinase (ERK) in the trigeminal spinal subnucleus interpolaris and caudalis transition zone (Vi/Vc), trigeminal spinal subnucleus caudalis (Vc), and upper cervical spinal cord (Vc/C2). The phosphorylated ERK (pERK) was observed in neurons but not in astroglia and microglia. Single-plane scanning analysis indicated that the pERK was localized to the nucleus of Vc neurons. In addition, the tooth mechanical pressure led to Fos expression in the pERK-positive Vc neurons that would be suppressed by intrathecal administration of an MEK1/2 inhibitor (PD98059). Taken together, these findings suggest that activation of the ERK signaling cascade following noxious mechanical pressure on the teeth regulates Fos expression in Vc neurons and may thereby contribute to pain associated with orthodontic treatment.
BadingHGreenbergME (1991). Stimulation of protein tyrosine phosphorylation by NMDA receptor activation. Science253:912-914.
2.
BalamTAYamashiroTZhengLMurshid AhmedSFujiyoshiYTakano-YamamotoT (2005). Experimental tooth movement upregulates preproenkephalin mRNA in the rat trigeminal nucleus caudalis and oralis. Brain Res1036:196-201.
3.
BergiusMKiliaridisSBerggrenU (2000). Pain in orthodontics. A review and discussion of the literature. J Orofac Orthop61:125-137.
4.
CoggeshallRE (2005). Fos, nociception and the dorsal horn. Prog Neurobiol. 77:299-352.
5.
CruzCDCruzF (2007). The ERK 1 and 2 pathway in the nervous system: from basic aspects to possible clinical applications in pain and visceral dysfunction. Curr Neuropharmacol5:244-252.
6.
FurstmanLBernickS (1972). Clinical considerations of the periodontium. Am J Orthod61:138-155.
7.
HattoriYWatanabeMIwabeTTanakaENishiMAoyamaJ. (2004). Administration of MK-801 decreases c-Fos expression in the trigeminal sensory nuclear complex but increases it in the midbrain during experimental movement of rat molars. Brain Res1021:183-191.
8.
HerdegenTWaetzigV (2001). AP-1 proteins in the adult brain: facts and fiction about effectors of neuroprotection and neurodegeneration. Oncogene20:2424-2437.
JiRRBabaHBrennerGJWoolfCJ (1999). Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci2:1114-1119.
11.
JiRRBefortKBrennerGJWoolfCJ (2002). ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity. J Neurosci22:478-485.
12.
JiRRGereauRWMalcangioMStrichartzGR (2009). MAP kinase and pain. Brain Res Rev60:135-148.
13.
KatoJWakisakaSTabataMJSasakiYKurisuK (1994). Induction of Fos protein in the rat trigeminal nucleus complex during an experimental tooth movement, Arch Oral Biol39:723-726.
14.
KatoJWakisakaSTabataMJItotagawaTKurisuK (1995). Appearance of dynorphin in the spinal trigeminal nucleus complex following experimental tooth movement in the rat. Arch Oral Biol40:79-81.
15.
KaufmanMPRybickiKJKozlowskiGPIwamotoGA (1986). Immunoneutralization of substance P attenuates the reflex pressor response to muscular contraction. Brain Res377:199-203.
16.
KrishnanV (2007). Orthodontic pain: from causes to management—a review. Eur J Orthod29:170-179.
17.
MagdalenaCMNavarroVPParkDMStuaniMBRochaMJ (2004). c-fos expression in rat brain nuclei following incisor tooth movement. J Dent Res83:50-54.
18.
NomaNTsuboiYKondoMMatsumotoMSessleBJKitagawaJ. (2008). Organization of pERK-immunoreactive cells in trigeminal spinal nucleus caudalis and upper cervical cord following capsaicin injection into oral and craniofacial regions in rats. J Comp Neurol507:1428-1440.
19.
PlotnikovAZehoraiEProcacciaSSegerR. (2011). The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim Biophys Acta1813:1619-1633.
20.
PrzewłockiRPrzewłockaB (2001). Opioids in chronic pain. Eur J Pharmacol429:79-91.
21.
SgambatoVPagèsCRogardMBessonMJCabocheJ (1998). Extracellular signal-regulated kinase (ERK) controls immediate early gene induction on cortico-striatal stimulation. J Neurosci18:8814-8825.
22.
ShimizuKAsanoMKitagawaJOgisoBRenKOkiH. (2006). Phosphorylation of extracellular signal-regulated kinase in medullary and upper cervical cord neurons following noxious tooth pulp stimulation. Brain Res1072:99-109.
23.
ToddAJSpikeRCPolgarE (1998). A quantitative study of neurons which express neurokinin-1 or somatostatin sst2a receptor in rat spinal dorsal horn. Neuroscience85:459-473.
24.
WaldoCM (1953). Method for the study of tissue response to tooth movement. J Dent Res32:690-691.
25.
YamashiroTSatohKNakagawaKMoriyamaHYagiTTakadaK (1998). Expression of Fos in the rat forebrain following experimental tooth movement. J Dent Res77:1920–1925.
26.
ZhangYQiaoJTDafnyN (2005). c-Fos antisense oligodeoxynucleotide offsets behavioral nociceptive responses and both up-regulations of c-Fos protein and dynorphin A (1-8) in dorsal horn: a study using the formalin test in rats. Int J Neurosci115:935-948.
27.
ZhuangZYGernerPWoolfCJJiRR (2005). ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain114:149-159.
28.
ZimmermannM (1983). Ethical guidelines for investigations of experimental pain in conscious animals. Pain16:109-110.
