The overall objective of this program project grant (PPG) application is to investigate the mechanisms and evaluate the clinical efficacy of peripheral opioid analgesia. This PPG application will test the overall hypothesis that opioids inhibit sensitized nociceptors via activation of opioid receptors expressed on peripheral nociceptive neurons to produce analgesia. All projects will evaluate nociceptors that respond to a combination of bradykinin/PGE2. These stimuli activate nociceptors involved with many pain conditions. All of the sub-projects, from cell culture to clinical trials, will evaluate this same class of nociceptors. In addition, all sub-projects utilize trigeminal sensory neurons with major hypotheses from all sub-projects evaluated in either primate trigeminal neuron cultures or in humans experiencing orofacial pain. This unifying scientific focus emphasizes the interrelatedness and tightly woven nature of the following sub-projects: Sub-Project 0001 (PI: W. Clarke): Determine signal transduction pathways in sensory neurons that: 1) induce functional competence in pre-existing """"""""silent"""""""" mu- (MOR), delta- (DOR) and kappa- (KOR) opioid receptors on sensory neurons; 2) mediate opioid ligand-dependent signaling by activation of MOR, DOR or KOR. Sub-Project 0002 (PI: S. Milam): Determine the effects of integrin-neuronal interactions on the expression, trafficking and function of the MOR, DOR and KOR on cultured sensory neurons. Sub-Project 0003 (PI: K. Hargreaves): Determine the effects of peripheral MOR, DOR and KOR selective agonists on nociceptor activation in biopsies taken from normal healthy patients versus patients with inflammatory pain, and characterize the peripheral analgesic effects of mu versus kappa opioid agonists. Collectively, these studies provide a comprehensive evaluation of the hypotheses that opioids inhibit sensitized nociceptors via activation of opioid receptors expressed on peripheral nociceptive neurons to produce analgesia. In addition, these sub-projects will characterize mechanisms regulating opioid receptor function in trigeminal sensory neurons.
