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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. Substance P is synthesized by small-diameter sensory 'pain' fibres, and release of the peptide into the dorsal horn of the spinal cord following intense peripheral stimulation promotes central hyperexcitability and increased sensitivity to pain. However, despite the availability of specific NK-1 antagonists, 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.

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1 Non-steroidal anti-in¯ammatory drugs (NSAIDs) are e ective anti-in¯ammatory and analgesic drugs although they also induce unwanted side e ects due to the inhibition of the physiological e ects regulated by prostaglandins. This has led to the search for new compounds with fewer side e ects, such as the nitro-NSAIDs (NO-NSAIDs). Paracetamol is an analgesic drug devoid of some of the side e ect of the NSAIDs but without anti-in¯ammatory activity. NCX-701 is a nitric oxide releasing version of paracetamol with anti-in¯ammatory and analgesic properties. 2 We have tested, in the single motor unit technique, the antinociceptive actions of intravenous cumulative doses of NCX-701 vs paracetamol, studying their antinociceptive e ects in responses to noxious mechanical and electrical stimulation (wind-up). 3 Paracetamol did not induce any signi®cant e ect at the doses tested (maximum of 480 mmol kg 71 , 72.5 mg kg 71 ). NCX-701 however was very e ective in reducing responses to noxious mechanical stimulation (32+10% of control response) and wind-up (ED 50 of 147+1 mmol kg 71 , 41.5+0.3 mg kg 71 ). The inhibition was not reversed by 1 mg kg 71 of the opioid antagonist naloxone. In control experiments performed with either the vehicle or the NO donor NOC-18, no signi®cant changes were observed in the nociceptive responses studied. 4 We conclude that NCX-701 is a very e ective non-opioid antinociceptive agent in normal animals and its action is located mainly at central areas. The antinociceptive e ect was not due solely to the release of NO.