We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Peripheral calcium-permeable AMPA receptors regulate chronic inflammatory pain in mice.
- Authors
Gangadharan, Vijayan; Rui Wang; Ulzhäfer, Bettina; Ceng Luo; Bardoni, Rita; Bali, Kiran Kumar; Agarwal, Nitin; Tegeder, Irmgard; Hildebrandt, Ulirich; Nagy, Gergely G.; Todd, Andrew J.; Ghirri, Alessia; Häussler, Annette; Sprengel, Rolf; Seeburg, Peter H.; MacDermott, Amy B.; Lewin, Gary R.; Kuner, Rohini; Wang, Rui; Ulzhöfer, Bettina
- Abstract
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type (AMPA-type) glutamate receptors (AMPARs) play an important role in plasticity at central synapses. Although there is anatomical evidence for AMPAR expression in the peripheral nervous system, the functional role of such receptors in vivo is not clear. To address this issue, we generated mice specifically lacking either of the key AMPAR subunits, GluA1 or GluA2, in peripheral, pain-sensing neurons (nociceptors), while preserving expression of these subunits in the central nervous system. Nociceptor-specific deletion of GluA1 led to disruption of calcium permeability and reduced capsaicin-evoked activation of nociceptors. Deletion of GluA1, but not GluA2, led to reduced mechanical hypersensitivity and sensitization in models of chronic inflammatory pain and arthritis. Further analysis revealed that GluA1-containing AMPARs regulated the responses of nociceptors to painful stimuli in inflamed tissues and controlled the excitatory drive from the periphery into the spinal cord. Consequently, peripherally applied AMPAR antagonists alleviated inflammatory pain by specifically blocking calcium-permeable AMPARs, without affecting physiological pain or eliciting central side effects. These findings indicate an important pathophysiological role for calcium-permeable AMPARs in nociceptors and may have therapeutic implications for the treatment chronic inflammatory pain states.
- Subjects
NEURAL receptors; PERIPHERAL nervous system; INFLAMMATION; NEURAL circuitry; GLUTAMIC acid; NEUROSCIENCES; LABORATORY mice; CALCIUM metabolism; NOCICEPTORS; ANIMAL experimentation; ARTHRITIS; BENZODIAZEPINES; CELL receptors; COMPARATIVE studies; SENSORY ganglia; RESEARCH methodology; MEDICAL cooperation; MICE; NEURAL transmission; PAIN; PERMEABILITY; RESEARCH; RESEARCH funding; TRANQUILIZING drugs; EVALUATION research; NEURAL pathways; ARTHRITIS Impact Measurement Scales; PHARMACODYNAMICS; PHYSIOLOGY; CELL physiology
- Publication
Journal of Clinical Investigation, 2011, Vol 121, Issue 4, p1608
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI44911