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Anesth Analg 2007; 105:1650-1656
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000287644.00420.49
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ANESTHETIC PHARMACOLOGY

Secondary Hyperalgesia in the Postoperative Pain Model Is Dependent on Spinal Calcium/Calmodulin-Dependent Protein Kinase II{alpha} Activation

Toni L. Jones, PhD, Adam C. Lustig, BS, and Linda S. Sorkin, PhD

From the Department of Anesthesiology, University of California San Diego, La Jolla, California.

Address correspondence to Toni L. Jones, PhD, University of California San Diego, Anesthesiology, 9500 Gilman Drive, LA Jolla, CA 92093-0818. Address e-mail to tljones{at}ucsd.edu.

BACKGROUND: Spinally administered non-N-methyl-d-aspartate (NMDA), but not NMDA, receptor antagonists block primary (1°) and secondary (2°) mechanical hyperalgesia and spontaneous pain after plantar incision. Hyperalgesia after thermal stimulation is also mediated by non-NMDA, but not NMDA, receptors. Although previous pain behavior studies in the thermal stimulus model demonstrated distinct protein kinase involvement downstream from spinal non-NMDA receptor activation, protein kinase signaling mechanisms have not been examined in the postoperative pain model. In the present study, we investigated whether spinal calcium/calmodulin-dependent protein kinase II{alpha} (CaMKII{alpha}) mediates 1° and/or 2° hyperalgesia and spontaneous pain behavior after plantar incision.

METHODS: Catheterized rats received a 1 cm incision in the hindpaw and were tested over 2 days for responses to mechanical stimulation adjacent to or 1 cm away from the incision site. Some rats received intrathecal (IT) pretreatment with a CaMKII{alpha} inhibitor (14, 34, or 104 nmol KN-93) or vehicle (5% dimethyl sulfoxide in sterile saline). Separate groups received IT 34 nmol or 104 nmol KN-93 and were tested for hindpaw weight bearing. Lumbar spinal cords were extracted 1 h after incision or sham treatment to measure phosphorylated CaMKII{alpha} and {alpha}-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid GLUR1-831 in Western immunoblots.

RESULTS: Incision increased spinal CaMKII{alpha} and GLUR1-831 phosphorylation. Although pretreatment with all doses of IT KN-93 reduced the development of 2° hyperalgesia, only 34 nmol KN-93 appeared to have an effect on 1° hyperalgesia. IT KN-93 did not affect nonevoked pain.

CONCLUSION: Spinal sensitization underlying incision-evoked hyperalgesia involves spinal CaMKII{alpha} activation and enhanced spinal {alpha}-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor (AMPA) function.






Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press
Copyright © 2007 by the International Anesthesia Research Society.