NMDA Receptor Mechanisms Of Sensitization Of Hypothalamic Arcuate Nucleus Neurons In Inflammation Rats

Objective: To explore the NMDA receptor mechanisms and signal transduction ofcentral sensitization in arcuate nucleus of hypothalamus (ARC) during peripheralinflammatory pain.Methods: The model of inflamed rats was induced by complete Freund’s adjuvant(CFA). The spontaneous discharge of ARC neurons and their response to noxiousstimulation were recorded extracellularly with three barrels glass microelectrode. Therole of ionotropic NMDA receptors and post-receptor kinase (Src, PKC) activation wasstudied by microiontophoretic administration of MK-801(non-competitive NMDAreceptor antagonist), PP2(Src protein tyrosine kinase inhibitor) and Chelerythrine(protein kinase C inhibitor).Results:(1) The spontaneous discharge frequency of ARC neurons in CFA ratswas significantly higher than that in Saline rats. The former is3.63±0.25Hz, the latter is2.17±0.22Hz and the difference was statistically significant (P<0.01).(2) Theresponses of PENs in ARC evoked by noxious stimulation in CFA rats wassignificantly higher than that in Saline rats. The former is3.92±0.19Hz, the later is4.95±0.29Hz and the difference was statistically significant (P<0.01).(3) Thespontaneous discharge of PENs in ARC was inhibited by microiontophoresis MK-801(3mM,+20~30nA,30s), PP2(1mM,+20~30nA,10~15min) and Chelerythrine (2mM,+20~30nA,10~15min) in CFA rats and reduced52.36%(P<0.001),25.5%(P<0.05)and25%(P<0.05) separately. The differences were statistically significant in CFA rats,but not in Saline rats.(4) The noxious discharge of PENs in ARC was inhibited bymicroiontophoresis MK-801(3mM,+20~30nA,30s), PP2(1mM,+20~30nA,10~15min) and Chelerythrine (2mM,+20~30nA,10~15min) in CFA rats, reduced89.15%(P<0.001),77.09%(P<0.001) and54.65%(P<0.001) separately. Thedifferences were statistically significant between groups. The pain-evoked discharge of PENs in ARC was also inhibited by the same drugs in Saline rats, reduced90.63%(P<0.001),79.18%(P<0.001) and47.06%(P<0.01) separately. The differences werestatistically significant between groups.Conclusions:(1) ARC neurons are sensitized under peripheral CFA conditions,specific performance: ARC neurons have higher spontaneous discharge frequency andPENs in ARC have higher discharge frequency evoked by peripheral noxiousstimulation.(2) NMDA receptor, Src and PKC of PENs in ARC involved in the centralsensitization in CFA rats, performance: the higher spontaneous discharge andpain-evoked discharge of PENs were inhibited by MK-801, PP2and Chelerythrine.(3)NMDA receptor, Src and PKC of PENs in ARC involved in the response to peripheralnoxious stimulation in Saline rats and CFA rats, performance: the pain-evokeddischarge of PENs was inhibited by MK-801, PP2and Chelerythrine.