Evidence from pharmacological studies has implicated
substance P (SP), a natural
ligand of
tachykinin NK(1) receptors which can also interact with
NK(2) receptors, in the generation of pressor and tachycardic responses to stress. Using selective blockade of brain NK(1) and
NK(2) receptors, we tested in conscious rats the hypothesis that SP initiates, within the neuronal brain circuits, the sympathoadrenal, hypothalamic-pituitary-adrenal (HPA) and behavioural responses to noxious stimuli.
Formalin injected s.c. through a chronically implanted
catheter in the area of the lower leg was used as a
pain stimulus. Rats were pretreated i.c.v. with vehicle or the selective, nonpeptide antagonists of
tachykinin NK(1) and
NK(2) receptors,
RP 67580 and
SR 48968, respectively. Ten minutes thereafter,
formalin was injected s.c. and the cardiovascular responses were recorded, plasma concentrations of
catecholamines,
adrenocorticotrophic hormone (
ACTH) and
corticosterone were determined and the expression of the inducible
transcription factor c-Fos in the paraventricular (PVN) and supraoptic nuclei was detected to identify neurones which were activated during
pain stimulation. Blockade of NK(1) and
NK(2) receptors attenuated the
formalin-induced increases in mean arterial pressure and heart rate,
adrenaline and
ACTH concentrations in plasma, and completely abolished the
pain-induced c-Fos expression in
corticotrophin-releasing
hormone neurones localised in the parvocellular division of the PVN. The results obtained provide pharmacological evidence that
tachykinins, most probably SP, act as mediators within the neuronal circuits linked to the initiation and control of the cardiovascular, sympathoadrenal, HPA and behavioural responses to
pain stimuli and provide an excitatory input to
corticotrophin-releasing
hormone neurones in the PVN to activate the HPA axis. Our data demonstrating the inhibition of the complex response pattern to noxious stimuli and stress are consistent with the proposed
anxiolytic and
antidepressant activity of NK(1) and
NK(2) receptor antagonists.