EFFECT OF TACHYKININ RECEPTOR INHIBITION IN THE BRAIN ON CARDIOVASCULAR AND BEHAVIORAL-RESPONSES TO STRESS

The neurokinins, substance P (SP) and neurokinin A (NKA) represent nat ural, nonspecific ligands of NK1 and NK2 receptors. In our study in co nscious rats, we tested the hypothesis that neurokinins, especially SP , are used by neuronal circuits to generate cardiovascular and behavio ral responses to stress by using the selective, high-affinity, nonpept ide: antagonists of NK1 and NK2 receptors, CP-96, 345, RP 67580 and SR 48968, respectively, Formalin injected s.c. through a chronically imp lanted catheter in the region of the lower leg was used as a stress st imulus, The antagonists and their inactive enantiomers, RP 68651 and S R 48965, as a control for nonspecific activity, were injected intracer ebroventricularly (i.c.v.) 10 min before the s.c. injection of formali n. Formalin (2.5%, 50 mu l, s.c.) induced a marked increase in mean ar terial pressure (MAP) and heart rate (HR) as well as hind limb groomin g/biting (HG) as the dominant behavioral manifestation. Pretreatment w ith the NK1 receptor antagonist, CP-96,345 (5 nmol, i.c.v.), significa ntly attenuated only the HR (-54%; P < .01) but not the MAP response t o formalin. The NK1 receptor antagonist, RP 67580, injected i.c.v. at doses of 100, 500 and 2500 pmol significantly reduced both, the MAP an d HR responses to formalin by maximally 63% (P < .01) and 52% (P < .01 ), respectively. In a separate set of experiments, we compared the eff ect of the individual and simultaneous blockade of central NK1 and NK2 receptors on the cardiovascular and behavioral responses to formalin stress. Pretreatment with RP 67580 (100 pmol, i.c.v.) attenuated the M AP (-30%; P < .05), HR (-40%; P < .01) and HG (P < .05) responses to f ormalin. The NK1 receptor antagonist, SR 48968 (650 pmol, i.c.v.), aff ected neither the cardiovascular nor the behavioral responses. I.c.v. pretreatment with both tachykinin receptor antagonists (RP 67580: 100 pmol; SR 48968: 650 pmol) reduced the MAP, HR and HG responses to form alin to the same extent as RP 67580 alone. Pretreatment with the inact ive enantiomers, RP 68651 (100 pmol, i.c.v.) and SR 48965 (650 pmol, i .c.v.) did not alter the cardiovascular and behavioral responses to fo rmalin. Our results demonstrate that centrally administered NK1 recept or antagonists inhibit the cardiovascular and behavioral reactions in response to a noxious stimulus. They provide first pharmacological evi dence that endogenous SP acts as mediator of stress responses in the b rain.