Intrathecal bradykinin acts presynaptically on spinal noradrenergic terminals to produce antinociception in the rat

In the awake restrained rat the intrathecal (i.th.) administration of 8.1 pmol-8.1 nmol of bradykinin (BK) and kallidin (KD) enhanced the reaction time (RT) to a noxious radiant heat stimulus in a dose-dependent manner. The fragments BK-(1–8) and BK-(1–7) were active only at doses higher than 10 nmol and the following rank order of potency was observed: BK > KD ⪢ BK-(1–8) > BK-(1–7). The increment of tail-flick latency was greatest at 1 (BK) or 6 (KD) min and the RT returned to basal levels within 15 min post-administration. The effect of BK (81 pmol) was unaffected by the prior i.th. administration of propanolol and naloxone but was significantly potentiated by prazosin (P < 0.05). In contrast, the response to BK was significantly blocked (P < 0.001) by phentolamine, idazoxan and yohimbine as well as by treatment with 6-hydroxydopamine (6-OHDA) at a dose of 20 μg (i.th.) 1 week earlier. The latter pretreatment reduced the antinociceptive effect of i.th. tyramine (7 μ mol) and potentiated that to noradrenaline (NA) (0.6 nmol) (P < 0.01) while it preserved both the antinociceptive effect of neurokinin B (8 nmol) and the hyperalgesic effect of substance P (6.5 nmol). A biochemical analysis revealed that 6-OHDA treatment reduced the NA content in the lumbar spinal cord by 60% without affecting the levels of serotonin, dopamine, adrenaline or their main metabolites. There were also significant reductions in NA content in cervical (44%) and thoracic (55%) spinal cord. Pretreatment with 6-OHDA for a longer survival period (2 weeks) caused a further decrease of NA in the lumbar spinal cord (88%); however, the serotonin and dopamine levels were reduced in all regions examined. These results suggest that BK (kinins) may inhibit spinal nociceptive sensory transmission and produce analgesia by acting presynaptically on terminals of bulbospinal NA-containing fibers.