Substance P is involved in terminating the hypothalamo- pituitary-adrenal axis response to acute stress through centrally located neurokinin-1 receptors.

The neurokinin substance P (SP) has been previously shown to inhibit basal hypothalamo-pituitary-adrenal (HPA) axis activity. This study was designed to investigate the effects of central injection of the specific neurokinin-1 receptor antagonist RP67580 on the HPA axis response to acute restraint stress. In non-restrained rats injected with RP67580, plasma ACTH and corticosterone levels were elevated at 30 and 60 min compared to rats injected with vehicle, but there were no differences between vehicle and RP67580 groups at 4h. In restrained rats injected with vehicle, plasma ACTH and corticosterone levels were significantly elevated at 30 min and 60 min following initiation of the stress but had returned to basal levels at 4h. In restrained rats injected icv with RP67580, plasma corticosterone and ACTH levels were significantly elevated at 30 min and 60 min, with no significant differences compared to the restraint stressed vehicle-injected group. However, in the RP67580-injected group, corticosterone and ACTH levels remained significantly elevated at 4h following onset of restraint compared to those in the restraint stressed vehicle-injected group. Corticotrophin-releasing factor mRNA levels in the parvocellular subdivision of the paraventricular nucleus of the hypothalamus and POMC mRNA levels in the anterior pituitary were significantly increased in the stressed group 4h following injection with RP67580 compared to the stressed group injected with vehicle alone. These data show that endogenous SP does not inhibit the initial magnitude of the HPA axis response to restraint stress, but does act through neurokinin-1 receptors at a central level to reduce the duration of the response to stress. This suggests that SP may be an important central agent controlling the transition between acute and chronic stress.