Mechanisms and therapeutic implications of impaired sensory neuron opioid receptor expression, coupling and function in streptozotocin-induced diabetes

• Antragsteller: Professor Dr. Michael Schäfer
• Fachliche Zuordnung: Anästhesiologie
• Förderung: Förderung von 2008 bis 2012
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 108113013

Previously we have examined the differential molecular and cellular regulations of opioid responsiveness during states of human disease, e.g. inflammatory pain. Since painful diabetic neuropathy is a peripheral sensory neuron disease, is difficult to treat and is known to be less susceptible to opioid analgesics, we will investigate in this project the time course of reduced opioid responsiveness using in vitro and in vivo experiments and focus on the identification of some of the putative mechanisms. In a first approach (goal A) we test the hypothesis that rats with streptozotocin (STZ)-induced diabetes develop significant impairment of peripheral sensory neuron mu-opioid receptor coupling, signaling and efficacy. In our second approach (goal B) we test the hypotheses that during early stages sensory neuron mu-opioid receptors get phosphorylated by RAGE/PKC dependent mechanisms and during late stages the number and density of sensory neuron mu-opioid receptors is greatly reduced due to enhanced lysosomal targeting and subsequent degradation. Possible therapeutic strategies such as RAGE/PKC inhibition, growth factor (e.g. NGF) treatment and/or lysosomal/proteasomal inhibition will be assessed to rescue mu-opioid receptor expression, signaling and function. New insights may enable us to better understand why patients with painful diabetic neuropathy do more or less effectively respond to opioid treatment and to develop novel therapeutic strategies of improving opioid responsiveness under pathologic conditions.

• DFG-Verfahren: Sachbeihilfen
• Beteiligte Person: Professor Dr. Shaaban Mousa, Ph.D.