Development of inflammation-induced hyperalgesia and allodynia is associated with the upregulation of extrasynaptic AMPA receptors in tonically firing lamina II dorsal horn neurons

Olga Kopach,Nana Voitenko,Viacheslav Viatchenko-Karpinski,Pavel Belan

doi:10.3389/fphys.2012.00391

Abstract

Persistent peripheral inflammation changes AMPA receptor (AMPAR) trafficking in dorsal horn neurons by promoting internalization of GluR2-containing, Ca2+-impermeable AMPARs from the synapses and by increasing insertion of GluR1-containing, Ca2+-permeable AMPARs in extrasynaptic plasma membrane. These changes contribute to the maintenance of persistent inflammatory pain. However, much less is known about AMPAR trafficking during development of persistent inflammatory pain and direct studies of extrasynaptic AMPARs functioning during this period are still lacking. Using Complete Freund's adjuvant (CFA)-induced model of long-lasting peripheral inflammation, we showed that remarkable hyperalgesia and allodynia developes in 1–3 h after intraplantar CFA injection. By utilizing patch-clamp recording combined with Ca2+ imaging, we found a significant upregulation of extrasynaptic AMPARs in substantia gelatinosa (SG) neurons of the rat spinal cord 2–3 h after CFA injection. This upregulation was manifested as a robust increase in the amplitude of AMPAR-mediated currents 2–3 h post-CFA. These changes were observed specifically in SG neurons characterized by intrinsic tonic firing properties, but not in those that exhibited strong adaptation. Our results indicate that CFA-induced inflammation increases functional expression of extrasynaptic AMPARs in tonically firing SG neurons during development of pain hypersensitivity and that this increase may contribute to the development of peripheral persistent pain.

Highlights

Persistent or chronic pain is a public health problem worldwide and may result from infection, inflammation, peripheral injury to tissue or nerve
We show that development of inflammation-induced hyperalgesia and allodynia is associated with the upregulation of extrasynaptic AMPA receptors (AMPARs) in specific subtype of lamina II dorsal horn neuron
In this work, we have demonstrated that extrasynaptic amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are significantly upregulated in tonically firing dorsal horn substantia gelatinosa (SG) neurons during the development of persistent inflammatory pain

Summary

Introduction

Persistent or chronic pain is a public health problem worldwide and may result from infection, inflammation, peripheral injury to tissue or nerve. Cumulative evidence demonstrates that altered AMPAR trafficking in dorsal horn neurons is required for the persistent inflammatory pain maintenance. Extrasynaptic AMPARs are localized within spines, dendrites, and somata (Malinow and Malenka, 2002; Bredt and Nicoll, 2003). They are mobile and rapidly move between the plasma membrane and intracellular compartments by exocytosis and endocytosis, and can migrate laterally to and from synaptic sites adjusting synaptic strength (Borgdorff and Choquet, 2002; Choquet and Triller, 2003; Adesnik et al, 2005; Cognet et al, 2006). During neuropathological conditions, when a primary afferent input is strong, glutamate spillover is excessive (Allan and Rothwell, 2001) and results in increased excitotoxic vulnerability and neurons injury (Kullmann, 2000; Allan and Rothwell, 2001; Weng et al, 2006)

Methods

Results

Conclusion