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Institute of Pharmacology

Mechanisms of plasticity at synapses between nociceptors and spinal neurons in inflammatory pain states

 

Plasticity of primary sensory neurons and of the synapses tey make with dorsal horn neurons is an important component of the cellular basis for the development and maintenance of chronic, pathogenic pain. Here, glutamate serves as the primary nociceptive neurotransmitter and activates several ionotropic and metabotropic receptors.

 

In several past projects, we have extensively characterized the role of spinal and thalamic NMDA receptors in cutaneous and visceral nociception in rat models using behavioural, pharmacological and electrophysiological methods. Recently, we have characterized the role of calcium-permeable AMPA receptors in nociception and chronic inflammatory pain using transgenic mouse models. Our results show that AMPA receptors are not mere mediators of fast excitatory neurotransmission in acute pain as previously thought, but are critically required for activity-induced potentiation in pathological states (Hartmann et al., Neuron 2004). Furthermore, we have recently reported that synaptic proteins of the Homer1 family, which interconnect metabotropic glutamate receptors (mGluR1/5) with intracellular calcium stores, are important modulators of inflammatory pain. We found that persistend nociceptive activity leads to the induction of the splice product Homer1a, which disrupts the mGluR1/5 signaling complex, and thereby plays a protective role against chronic pain (Tappe et al., Nature Medicine 2006).

 

A major interest in the lab is to study the functional significance of protein-protein interactions at synapses in the modulation of pain and other neurological functions. For example, we have addressed the heteromerization of GABAB receptor subunits (Kuner et al., Science 1999), identified and characterized novel protein-interactions of nitric oxide synthase (Dreyer et al. 2003, 2004), studied the role of interactions between Homer proteins and mGluR1/5 in the context of striatal function (Tappe et al., PNAS 2006) and addressed the role of proteins interacting with cannabinoid receptors in analgesic tolerance to cannabinoids (Tappe et al., J. Neuroscience 2007).

 

Expression of AAV-viruses expressing desired proteins, shRNAs or EGFP into the superficial laminae of L3-L5 spinal dorsal horn segments in mice in vivo

 

 

 

 

Several current projects are directed at elucidating novel mediators of synaptic plasticity at synapses between primary afferents and spinal neurons. In addition to transgenic approaches, the RNAi methodology and adeno-associated viruses (AAV) are our key tools for inducing molecular perturbations in the spinal cord. We use several models of inflammatory pain, including arthritis, to study alterations in pain behaviour in vivo. Furthermore, patch-clamp recordings and calcium imaging on spinal cord slices are employed for addressing potentiation of synaptic transmission. This work is partly supported by the Landesstiftung RNAi Program of Baden-Württemberg.

 

Group members involved: Anke Tappe-Theodor, Bettina Hartmann, Ceng Luo, Vijayan Gangadharan, Kiran Kumar Bali, Tamara Djuric, Hans-Joseph Wrede