An important approach to the understanding of anesthesia and analgesia is to characterize the physiological mediators involved and to decipher the mechanisms used by these mediators in the transmission of nociceptive information. The studies proposed here target the actions of a particular family of neuropeptides and neuropeptide receptors in nociception. Substance P, one of the best characterized of the neuropeptides, has been shown by a number of methods to be intimately involved in the transmission of nociceptive information. This peptide is a member of a peptide family known as the tachykinins, and until a few years ago it was believed to be the only tachykinin peptide in mammals. The discovery by ourselves and others that other tachykinins and tachykinin receptors exist in the mammalian CNS, notably in the dorsal root ganglia/dorsal spinal cord system (a crucial site for nociceptive sensory transmission) has led to the recognition that substance P is not the only tachykinin implicated in this process. There is good reason to believe that other tachykinins and tachykinin receptors are also involved, and that previous work which considered only substance P is at best incomplete. In particular, very little is known about the molecular nature of tachykinin receptors and the biochemical mechanisms underlying the effects of the tachykinin peptides on target cells. The long-term goal of the proposed studies is to achieve a better understanding of how these receptors work at a molecular level, and thus of the fundamental neural mechanisms related to nociception. Such understanding could lead toward intelligent design of novel analgesic drugs and therapy, both providing relief from suffering and diminishing economic losses due to worker morbidity.
One specific aim of the proposed studies is to determine the primary structure of tachykinin receptors by methods of protein biochemistry and molecular biology, and to produce antibodies against them as aids toward localization and functional analysis of the receptors. Another is to examine in detail the biochemical mechanisms of signal transduction employed by these receptors following their activation by ligand. The studies proposed here will thus provide a better understanding of the structural organization of a class of receptors involved in nociception and the mechanisms by which they effect their actions.
