Nature Medicine
- 12, 677 - 681 (2006)
Published online: 21 May 2006; | doi:10.1038/nm1406
Synaptic scaffolding protein Homer1a protects against chronic inflammatory painAnke Tappe1, Matthias Klugmann2, 5, 6, Ceng Luo1, 6, David Hirlinger1, Nitin Agarwal1, Justus Benrath3, Markus U Ehrengruber4, 5, Matthew J During2, 5 & Rohini Kuner11
Pharmacology Institute, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany. 2
Department of Molecular Medicine & Pathology, University of Auckland, 85 Park Road, Auckland, New Zealand. 3
Department of Anesthesiology and General Intensive Care, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. 4
Brain Research Institute, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. 5
Institute for Neurobiology, IZN, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany (M.K.). Kantonsschule Hohe Promenade, Promenadengasse 11, CH-8001 Zürich, Switzerland (M.U.E.). Department of Neurological Surgery, Weill Medical College of Cornell University, New York, New York 10021, USA (M.J.D.). 6
These authors contributed equally to this work.
Correspondence should be addressed to Rohini Kuner rohini.kuner@pharma.uni-heidelberg.de Glutamatergic signaling and intracellular calcium mobilization in the spinal cord are crucial for the development of nociceptive plasticity, which is associated with chronic pathological pain1,
2. Long-form Homer proteins anchor glutamatergic receptors to sources of calcium influx and release at synapses3,
4,
5, which is antagonized by the short, activity-dependent splice variant Homer1a. We show here that Homer1a operates in a negative feedback loop to regulate the excitability of the pain pathway in an activity-dependent manner. Homer1a is rapidly and selectively upregulated in spinal cord neurons after peripheral inflammation in an NMDA receptor–dependent manner. Homer1a strongly attenuates calcium mobilization as well as MAP kinase activation induced by glutamate receptors and reduces synaptic contacts on spinal cord neurons that process pain inputs. Preventing activity-induced upregulation of Homer1a using shRNAs in mice in vivo exacerbates inflammatory pain. Thus, activity-dependent uncoupling of glutamate receptors from intracellular signaling mediators is a novel, endogenous physiological mechanism for counteracting sensitization at the first, crucial synapse in the pain pathway. Furthermore, we observed that targeted gene transfer of Homer1a to specific spinal segments in vivo reduces inflammatory hyperalgesia. Thus, Homer1 function is crucially involved in pain plasticity and constitutes a promising therapeutic target for the treatment of chronic inflammatory pain.
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