LH-RH analogue acts as substance P antagonist by inhibiting spinal cord vasomotor responses

Intrathecal injections of the luteinizing hormone-releasing hormone (LH-RH) analogue, [D-pGlu1-D-Phe2-D-Trp3,6]-LH-RH caused dose-dependent decreases in mean arterial blood pressure in anesthetized rats similar to those seen with [D-Pro4-D-Trp7,9]-substance P4-11. Similarly, intrathecal injections of either peptide reversed the pressor response elicited by application of kainic acid on the ventral surface of the medulla oblongata. Both analogues also had similar IC50 values (approximately 10(-5) M) for the inhibition of specific [3H]substance P binding in tissue-sections of the intermediolateral cell column. However, the LH-RH analogue failed to block substance P (SP)-induced contractions of the isolated guinea pig ileum and did not affect tail-flick withdrawal time in a thermal nociceptive test, whereas the SP analogue acted as an antagonist in both of these bioassays. These results suggest that [D-pGlu1-D-Phe2-D-Trp3,6]-LH-RH may act as an antagonist which can inhibit the sympathetic vasomotor outflow and potentially be a substance P-physalaemin (SP-P) receptor antagonist in the central nervous system but without effect on peripheral SP-P receptors.