Substance P is contained within a subpopulation of nociceptive primary sensory neurons that project to the superficial dorsal horn of the spinal cord. Stimulation of the peripheral processes of primary afferent fibres at intensities that activate A delta and C fibres elicits a pronounced release of substance P from the cat spinal cord in vivo. Experiments with the neurotoxins capsaicin and 5,6-dihydroxytryptamine have shown that substance P release from the spinal cord in vivo derives largely from afferent fibres. Intrathecal perfusion of the cat spinal cord with morphine abolishes the nerve-evoked release of substance P while capsaicin produces a dramatic increase in peptide release. Prolonged treatment of rats with capsaicin depletes substance P from the dorsal horn and results in reduced sensitivity to noxious peripheral stimuli. The duration of the somatic action potential recorded from cultured sensory neurons is known to be decreased by enkephalin and is prolonged by capsaicin. The acute effects of both morphine and capsaicin on substance P may be mediated by an interaction with voltage-sensitive ion channels on the sensory neuron. These observations suggest that nociceptive input to the dorsal horn can be regulated by drugs that interact directly with substance P-containing sensory terminals.