P1: Involvement of P2 receptors in the modulation of nociceptive afferent stimuli

Dr. rer. nat. Thomas Riedel and Prof. Dr. med. Peter Illes (Rudolf-Boehm-Institute for Pharmacology and Toxicology, Universität Leipzig)

Pain is a multidimensional sensory process that, acutely, is physiologically adaptive in response to dangerous (e.g., sharp, hot, or chemical) stimuli in the environment. Persistent pain can range from increased sensitivity to mildly painful stimuli (hyperalgesia) or to otherwise innocuous stimuli (allodynia). Whereas, acute pain has an important signalling character, helping to avoid its source or to immobilize an injured extremity, chronic pain acquires the quality of a debilitating illness causing unnecessary suffering of the afflicted individuals.

ATP released in consequence of various noxious stimuli from peripheral tissues excites a range of P2X receptor-types situated at astrocytes, microglia or at the sensory nerve terminals themselves. Astrocytes and microglia release diverse endogenous compounds which sensitize the nociceptors to the stimulatory effect of pain mediators including ATP itself.

The present project aims at characterizing the binding domains of pain-relevant P2X2 and P2X2/3 receptors by alanin-scanning mutagenesis as well as to model the structure of the P2X3 receptor and the kinetics of agonist binding at this receptor. Further, it will clarify the role of an assumed cross-talk between astrocytes and layer II neurons of the spinal cord dorsal horn via the P2X7 receptor-mediated release of reactive oxygen radicals from astrocytes. We will investigate these questions both at intact astrocyte-neuron networks in spinal cord slices and at the level of the whole animal. A wide range of mutually complementary methods will be utilized throughout, such as electrophysiology, Ca²⁺ imaging, molecular biology, immunohistochemistry, computer simulation and behavioural pharmacology.

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