Human
hemokinin-1 (h HK-1) and its truncated form h HK-1(4-11) are mammalian
tachykinin peptides encoded by the recently identified TAC4 gene in human, and the
biological functions of these
peptides have not been well investigated. In the present study, an attempt has been made to investigate the effects and mechanisms of action of h HK-1 and h HK-1(4-11) in
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
NK(1) receptor antagonist
SR140333, but not by the
NK(2) receptor antagonist
SR48968, indicating that the
analgesic effect induced by i.c.v. h HK-1 is mediated through the activation of
NK(1) receptors. Interestingly,
naloxone,
beta-funaltrexamine and
naloxonazine, but not
naltrindole and
nor-binaltorphimine, could also block the
analgesic effect markedly, suggesting that this effect is related to descending mu opioidergic neurons (primary mu(1) subtype). Human HK-1(4-11) could also induce a dose- and time-dependent
analgesic effect after i.c.v. administration, however, the potency of
analgesia was less than h HK-1. Surprisingly,
SR140333 could not modify this
analgesic effect, suggesting that this effect is not mediated through the
NK(1) receptors like h HK-1.
SR48968 could modestly enhance the
analgesic effect induced by h HK-1(4-11), indicating that a small amount of h HK-1(4-11) may bind to
NK(2) receptors. Furthermore, none of the
opioid receptor (OR) antagonists could markedly block the
analgesia of h HK-1(4-11), suggesting that the
analgesic effect is not mediated through the descending opioidergic neurons. Blocking of delta
ORs significantly enhanced the
analgesia, indicating that delta OR is a negatively modulatory factor in the
analgesic effect of h HK-1(4-11). It is striking that
bicuculline (a competitive antagonist at
GABA(A) receptors) effectively blocked the
analgesia induced by h HK-1(4-11), suggesting that this
analgesic effect is mediated through the descending inhibitory GABAergic neurons. The novel mechanism involved in the
analgesic effect of h HK-1(4-11), which is different from that of h HK-1, may pave the way for a new strategy for the investigation and control of
pain.