The peptide neurotransmitter substance P modulates sensitivity to pain by activating the neurokinin-1 (NK-1) receptor, which is expressed by discrete populations of neurons throughout the central nervous system(1-4). Substance P is synthesized by small-diameter sensory 'pain' fibres(5), and release of the peptide into the dorsal horn of the spinal cord following intense peripheral stimulation(6) promotes central hyperexcitability and increased sensitivity to pain(7-10). However, despite the availability of specific NK-1 antagonists(4), the function of substance P in the perception of pain remains unclear Here we investigate the effect of disrupting the gene encoding the NK-1 receptor in mice, We found that the mutant mice were healthy and fertile, but the characteristic amplification ('wind up') and intensity coding of nociceptive reflexes was absent, Although substance P did not mediate the signalling of acute pain or hyperalgesia, it was essential for the full development of stress-induced analgesia and for an aggressive response to territorial challenge, demonstrating that the peptide plays an unexpected role in the adaptive response to stress.