Peripheral inflammation induces tumor necrosis factor dependent AMPA receptor trafficking and Akt phosphorylation in spinal cord in addition to pain behavior

Choi, Jeong Il; Svensson, Camilla I.; Koehrn, Fred J.; Bhuskute, Aditi; Sorkin, Linda S.

doi:10.1016/j.pain.2010.02.008

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Volume 149, Issue 2 , Pages 243-253, May 2010

Peripheral inflammation induces tumor necrosis factor dependent AMPA receptor trafficking and Akt phosphorylation in spinal cord in addition to pain behavior☆

Jeong Il Choi
- Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA
- Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School and Hospital, Gwangju, Republic of Korea
- Corresponding authors. Address: 9500 Gilman Drive, La Jolla, CA 92093-0818, USA. Tel.: +1 619 543 3498; fax: +1 619 543 6070 (L.S. Sorkin).
Camilla I. Svensson
- Department of Pharmacology, Karolinska Institute, Stockholm, Sweden
- Corresponding authors. Address: 9500 Gilman Drive, La Jolla, CA 92093-0818, USA. Tel.: +1 619 543 3498; fax: +1 619 543 6070 (L.S. Sorkin).
Fred J. Koehrn
- Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA
Aditi Bhuskute
- College of Medicine, University of Arizona, Tucson, AZ, USA
Linda S. Sorkin
- Department of Anesthesiology, University of California, San Diego, La Jolla, CA 92093, USA
- Corresponding authors. Address: 9500 Gilman Drive, La Jolla, CA 92093-0818, USA. Tel.: +1 619 543 3498; fax: +1 619 543 6070 (L.S. Sorkin).

Received 18 August 2009; received in revised form 20 November 2009; accepted 4 February 2010. published online 04 March 2010.

Abstract

In the present study, intraplantar carrageenan induced increased mechanical allodynia, phosphorylation of PKB/Akt and GluR1 ser 845 (PKA site) as well as GluR1, but not GluR2 movement into neuronal membranes. This change in membrane GluR1/GluR2 ratio is indicative of Ca²⁺ permeable AMPA receptor insertion. Pain behavior was reduced and biochemical changes blocked by spinal pretreatment, but not post-treatment, with a tumor necrosis factor (TNF) antagonist, Etanercept (100μg). Pain behavior was also reduced by spinal inhibition of phosphatidylinositol 3-kinase (PI-3K) (wortmannin; 1 and 5μg) and LY294002; 50 and 100μg) and Akt (Akt inhibitor IV; 3μg). Phosphorylated Akt was found exclusively in neurons in grey matter and in oligodendrocytes in white matter. Interestingly, this increase was seen first in superficial dorsal horn and α-motor neurons (peak 45min) and later (peak 2h post-injection) in deep dorsal horn neurons. Akt and GluR1 phosphorylation, AMPA receptor trafficking and mechanical allodynia were all TNF dependent. Whether phosphorylation of Akt and of GluR1 are in series or in parallel or upstream of pain behavior remains to be determined. Certainly, TNF-mediated GluR1 trafficking appears to play a major role in inflammatory pain and TNF-mediated effects such as these could represent a path by which glia contribute to neuronal sensitization (spinal LTP) and pathological pain.