Recent pharmacological evidence has implicated
substance P and
neurokinin A, natural
ligands for neurokinin-1 and
neurokinin-2 receptors, respectively, as
neurotransmitters in brain neuronal circuits activated upon noxious stimulation. The expression of the inducible
transcription factor, c-Fos, was used to identify areas in the brain activated by a noxious stimulus (the
subcutaneous injection of
formalin), and to investigate the effects of intracerebroventricular administration of selective, nonpeptide antagonists for neurokinin-1 and neurokinin-2
tachykinin receptors on the neural activity in these areas and on the behavioural response to
formalin-induced
pain.
Formalin (5%, 50 microl), injected subcutaneously through a chronically implanted
catheter in the region of the lower hindlimb, increased c-Fos expression in a number of brain areas related to nociceptive transmission or the integration of stress responses. Grooming behaviour, licking and biting directed to the injected site, was the most frequent behavioural response. Intracerebroventricular pretreatment of rats with either
RP 67580 (500 pmol), the active enantiomer of a
neurokinin-1 receptor antagonist, or with
SR 48968 (500 pmol), the active enantiomer of a
neurokinin-2 receptor antagonist, reduced the
formalin-induced c-Fos staining in the prefrontal cortex, dorsomedial and ventromedial nuclei of the hypothalamus, the locus coeruleus and the periaqueductal gray. The neurokinin-1, but not the
neurokinin-2, receptor antagonist attenuated the
formalin-induced activation of c-Fos in the paraventricular nucleus of the hypothalamus. Simultaneous intracerebroventricular pretreatment with both neurokinin-1 and
neurokinin-2 receptor antagonists did not produce any additional inhibitory effect on the post-
formalin c-Fos expression. None of the
tachykinin receptor antagonists had an effect on the
formalin-induced c-Fos expression in the septohypothalamic nucleus, medial thalamus, parabrachial nucleus and central amygdaloid nucleus, indicating that
neurotransmitters other than neurokinins are most probably responsible for the activation of these areas in response to noxious stimulation. While both
tachykinin receptor antagonists reduced the grooming behaviour to
formalin, the
neurokinin-1 receptor antagonist was clearly more effective than the
neurokinin-2 receptor antagonist. Intracerebroventricular pretreatment of rats with the inactive enantiomers of the
tachykinin receptor antagonists,
RP 68651 and
SR 48965, was without effect. Our results show that (i) the modified
formalin test elicited an intense grooming behaviour and expression of c-Fos in numerous forebrain and brainstem areas, (ii) both
tachykinin receptor antagonists were able to attenuate the behavioural response to
pain and to reduce the
formalin-induced c-Fos expression in some, but not all, brain areas, and (iii) the neurokinin-1 antagonist,
RP 67580, was more effective in inhibiting the behavioural response to
formalin and the
pain-induced activation of c-Fos than the antagonist for
neurokinin-2 receptors,
SR 48968, indicating that
neurokinin-1 receptors are preferentially activated in neurokinin-containing pathways responding to noxious stimuli. Our results demonstrate that blockade of brain
tachykinin receptors, especially of the
neurokinin-1 receptor, reduces the behavioural response to
pain and the
pain-induced c-Fos activation in distinct brain areas which are intimately linked with nociceptive neurotransmission and the initiation and integration of central stress responses. Together with the previous findings of the inhibition of hypertensive and tachycardic responses to
pain, the present data indicate that
tachykinin receptor antagonists can effectively inhibit the generation of an integrated cardiovascular and behavioural response pattern to noxious stimuli.