Peripheral calcium-permeable AMPA receptors regulate chronic inflammatory pain in mice
Vijayan Gangadharan, Rui Wang, Bettina Ulzhöfer, Ceng Luo, Rita Bardoni, Kiran Kumar Bali, Nitin Agarwal, Irmgard Tegeder, Ullrich Hildebrandt, Gergely G. Nagy, Andrew J. Todd, Alessia Ghirri, Annette Häussler, Rolf Sprengel, Peter H. Seeburg, Amy B. MacDermott, Gary R. Lewin, Rohini Kuner
Vijayan Gangadharan, Rui Wang, Bettina Ulzhöfer, Ceng Luo, Rita Bardoni, Kiran Kumar Bali, Nitin Agarwal, Irmgard Tegeder, Ullrich Hildebrandt, Gergely G. Nagy, Andrew J. Todd, Alessia Ghirri, Annette Häussler, Rolf Sprengel, Peter H. Seeburg, Amy B. MacDermott, Gary R. Lewin, Rohini Kuner
View: Text | PDF
Research Article Neuroscience

Peripheral calcium-permeable AMPA receptors regulate chronic inflammatory pain in mice

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.

Authors

Vijayan Gangadharan, Rui Wang, Bettina Ulzhöfer, Ceng Luo, Rita Bardoni, Kiran Kumar Bali, Nitin Agarwal, Irmgard Tegeder, Ullrich Hildebrandt, Gergely G. Nagy, Andrew J. Todd, Alessia Ghirri, Annette Häussler, Rolf Sprengel, Peter H. Seeburg, Amy B. MacDermott, Gary R. Lewin, Rohini Kuner

×

Figure 2

Patch clamp analysis of AMPA-induced modulation of synaptic transmission between primary afferents and spinal dorsal horn neurons in SNS-GluA1–/– and SNS-GluA2–/– mice and their control littermates, GluA1fl/fl and GluA2fl/fl mice.

Options: View larger image (or click on image) Download as PowerPoint
Patch clamp analysis of AMPA-induced modulation of synaptic transmission...
(A) Glutamatergic EPSCs recorded from a lamina II neuron obtained from a wild-type mouse. Application of AMPA (250 nM) caused a depression of EPSC, an increase of amplitude variability, and the appearance of some failures, which were reversed upon washing AMPA out. (B–D) Plot data showing the ratio of CV-2 as a function of relative EPSC amplitude. Each symbol represents 1 neuron. (B) Graph representing CV changes in control experiments (low extracellular calcium and change of holding potential) mimicking presynaptic and postsynaptic modulations, respectively. 1/CV2treatment/1/CV2control represents the ratio between 1/coefficient of variation squared, obtained during treatment (either 1mM extracellular calcium or holding potential = –55 mV), and 1/coefficient of variation squared, measured in control (i.e., 2 mM extracellular calcium or holding potential = –85 mV). Itreatment/Icontrol represents the ratio between mean EPSC amplitude, measured during treatment (see above), and mean EPSC amplitude measured in control. (C and D) Effects of AMPA on EPSC amplitudes and CV values in wild-type, GluA1fl/fl, and SNS-GluA1–/– mutant mice. A subpopulation of neurons from SNS-GluA1–/– mice exhibited a pure postsynaptic modulation, since the CV remained constant in AMPA. 1/CV2AMPA/1/CV2control represents the ratio between 1/coefficient of variation squared, obtained during application of AMPA250 nM and 1/coefficient of variation squared, measured in control. IAMPA/Icontrol represents the ratio between mean EPSC amplitude, measured during AMPA application, and mean EPSC amplitude measured in control. (E) The ratio of CV in AMPA to CV in control is significantly lower in SNS-GluA1–/– mice, as compared with that in GluA1fl/fl mice (*P < 0.05, t test).