The NK1 receptor is essential for the full expression of noxious inhibitory controls in the mouse

Behavioral analysis of the NK1 receptor gene knock-out (NK1(-/-)) mouse ind icated that substance P was closely involved in orchestrating the physiolog ical and behavioral response of the animal to major environmental stressors . In particular, endogenous pain control mechanisms, such as stress-induced analgesia were substantially impaired in mutant mice, suggesting a reducti on in descending inhibitory controls to the spinal cord from the brainstem. To directly test the integrity of descending controls in NK1(-/-) mice, we have analyzed c-Fos expression in laminae I-II of the lumbar and cervical cord and in the rostral ventromedial medulla in an experimental paradigm kn own to require recruitment of descending inhibitory controls. Anesthetized mice were stimulated with water at 50 degreesC either on their forepaw, hin dpaw, or on both the hindpaw plus forepaw concurrently. Wild-type mice, nai ve or treated with an NK1 antagonist (RP67580) or its inactive isomer (RP68 651), were compared with NK1(-/-) mice. C-Fos expression at the lumbar lami nae I-II level was significantly reduced, whereas it was significantly grea ter in the raphe magnus and pallidus nuclei in the double stimulation situa tion in wild-type compared with NK1(-/-) mice. Blocking the NK1 receptor ph armacologically reproduced, in an enantiomere-selective manner, the data fr om NK1(-/-) mice, with no evidence for recruitment of descending inhibition at the lumbar cord level after forepaw stimulation. The present study demo nstrates that the NK1 receptor is essential for the full development of nox iously evoked descending inhibition.