Pain is a frequent and disabling consequence of metastatic cancer in humans. The cause of this pain is unknown but likely to involve mediator-dependent signaling by tumor cells to nociceptors. The potent vasoactive peptide, endothelin-1 (ET-1), is secreted in high concentrations by metastatic cancer cells and produces pain in animals and in humans. This proposal seeks as its broad long-term objective to understand how tumor mediators cause pain associated with cancer. We have shown that ET-1: 1) induces acute pain behavior and nociceptor excitation via endothelin-A receptors (ETA), 2) mediates mechanical and thermal hyperalgesia in rodent models of skin injury and inflammation, 3) evokes increased Cain2+ , and opening of tetrodotoxin-resistant (TTX-R) Na+ channels in isolated sensory neurons, via ETA, 3) triggers an analgesic cascade in skin, via ETB receptors, that is mediated by locally-released beta-endorphin acting on opioid receptors coupled to G protein inwardly-rectifying K+ channels (GIRKs). The goals of the proposed studies are to combine results from in vitro neurophysiology and pharmacology with neurobehavior to:
Specific Aim : 1: Establish that ET-1 initiates impulses in peripheral nociceptors, and identify the changes in ionic (Na+ and K+) currents that underlie this impulse initiation.
Specific Aim 2 : Establish that ET-1 sensitizes peripheral nociceptors both to the injection of depolarizing current and to the depolarizing actions of both capsaicin and ATP.
Specific Aim 3 : Determine the ionic basis for inhibitory effects of beta-endorphin on ET-1-induced changes in nociceptor excitability. The findings from these experiments will define the ionic mechanisms whereby ET-1 signals to nociceptors to cause acute and persistent pain, and the ionic mechanisms that underlie inhibitory effects of ETB driven, beta endorphin-mediated inhibition of ET-1-triggered pain. This information should help to identify: 1) new and useful directions for research into mechanisms underlying pain produced by metastatic cancer, and 2) novel targets for drug development aimed at treating this pain.
Showing the most recent 10 out of 36 publications
