Access
To read this story in full you will need to login or make a payment (see right).
Letter
Nature Medicine 12, 677 - 681 (2006)
Published online: 21 May 2006 | doi:10.1038/nm1406
Synaptic scaffolding protein Homer1a protects against chronic inflammatory pain
Anke Tappe1, Matthias Klugmann2,5,6, Ceng Luo1,6, David Hirlinger1, Nitin Agarwal1, Justus Benrath3, Markus U Ehrengruber4,5, Matthew J During2,5 & Rohini Kuner1
Abstract
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.
To read this story in full you will need to login or make a payment (see right).
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and persistenceNature Medicine Article (01 Nov 2006)
Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptorsNature Neuroscience Article (01 Jul 2007)
Primary afferent tachykinins are required to experience moderate to intense painNature Letters to Editor (26 Mar 1998)
Peripheral group I metabotropic glutamate receptors modulate nociception in miceNature Neuroscience Article (01 Apr 2001)
See all 14 matches for Research