Regulatory Role Of Hemokinin-1, Mammalian Tachykinins, On Pain And And Its Impacts On Proliferation And Differentiation Of Human Leukemia Cells In Vitro

Human hemokinin-1(h HK-1) is a mammalian tachykinin peptide encoded by the recently identified TAC4 gene in human,and the biological functions of this peptide have not been well investigated.In the present study,an attempt has been made to investigate the effect and mechanism of action of h HK-1 on pain modulation at the supraspinal level in mice using the tail immersion test.Intracerebroventricular(i.c.v.) administration of h HK-1(0.3,1,3 and 6 nmol/mouse) produced a dose- and time-related antinociceptive effect.This effect was significantly antagonized by the NK₁ receptor antagonist SR140333,but not by the NK₂ receptor antagonist SR48968,indicating that the analgesic effect induced by i.c.v,h HK-1 is mediated through the activation of NK₁ receptors.Interestingly,naloxone,b-funaltrexamine and naloxonazine,but not naltrindole and nor-binaltorphimine,could also block the analgesic effect markedly,suggesting that this effect is related to descendingμopioidergic neurons (primaryμ₁ subtype).These findings suggested that h HK-1 might play an important role in pain modulation at supraspinal level in mice and the effect was elicited through the activation of NK₁ receptor,and related to descendingμopioidergic neurons.In the second section we studied the effects of human hemokinin-1(h HK-1) on the proliferation and differentiation of human leukemia cells in vitro.The tachykinins have shown immuno-regulatory activities in humans.In the present study,we investigated the effects of h HK-1 on the proliferation and differentiation of a human promyelocyte leukemia cell line,HL-60.It is noteworthy that h HK-1(1-300μM) displayed inhibitory effects on the proliferation of HL-60 cells in a dose- and time-dependent manner.The effect of suppressing proliferation induced by thise peptide was accompanied by an accumulation of cell cycle in the S phase.Moreover,this peptide induced differentiation of HL-60 cells by significantly increasing the NBT-reduction activity.However the effect induced by h HK-1 was not antagonized by the NK₁ receptor antagonist SR140333 or the NK₂ receptor antagonist SR48968.All the results indicated that h HK-1 was able to significantly inhibit proliferation and induce differentiation and S phase arrest of a human promyelocyte leukemia cell line HL-60,which may not be mediated through the activation of classical tachykinin NK₁ receptors and tachykinin NK₂ receptors.Our observations also implied that h HK-1 could act as an immunomodulatory factor in cancer chemotherapy.