There is growing evidence suggesting that kappa-opioid receptors are present on the peripheral terminals of primary afferent neurons and that activation of these receptors is associated with profound analgesia in animal models of pain. Several kappa-opioid agonists which have limited access to the central nervous system have been described recently, but these compounds have not been investigated in great detail. Since there is considerable interest in the development of potential non-addictive analgesics, peripherally selective kappa-opioid agonists could be anti- nociceptive against pain states without many of he adverse side-effects currently associated with the mu-agonist opioid analgesics. This proposal seeks to identify the role that centrally- and peripherally-acting opioids play in modulating neuropeptide release in the CNS during the somatosensory states of pain and itch. Intra-cerebral microdialysis will be used to measure changes in the extracellular level of substance P (SP) released from periaqueductal gray (PAG) of freely moving rats after noxious cold stimulation and after an itch-inducing stimulus. Next, we will evaluate whether pre-treatment with selective opioid, including peripheral kappa-agonists, will attenuate SP release during the corresponding analgesia or pruritus assays. These studies will determine whether SP within the brain plays a neuromodulatory role in the transmission of nociceptive information from activated peripheral opioid receptors.