Activation of descending pain-facilitatory pathways from the rostral ventromedial medulla by cholecystokinin elicits release of prostaglandin-E₂ in the spinal cord.

Abstract

Cholecystokinin (CCK) has been suggested to be both pro-nociceptive and "anti-opioid" by actions on pain-modulatory cells within the rostral ventromedial medulla (RVM). One consequence of activation of RVM CCK₂ receptors may be enhanced spinal nociceptive transmission; but how this might occur, especially in states of pathological pain, is unknown. Here, in vivo microdialysis was used to demonstrate that levels of RVM CCK increased by approximately 2-fold after ligation of L₅/L₆ spinal nerves (SNL). Microinjection of CCK into the RVM of naïve rats elicited hypersensitivity to tactile stimulation of the hindpaw. In addition, RVM CCK elicited a time-related increase in (prostaglandin-E₂) PGE₂ measured in cerebrospinal fluid from the lumbar spinal cord. The peak increase in spinal PGE₂ was approximately 5-fold and was observed at approximately 80 minutes post-RVM CCK, a time coincident with maximal RVM CCK-induced mechanical hypersensitivity. Spinal administration of naproxen, a nonselective COX-inhibitor, significantly attenuated RVM CCK-induced hindpaw tactile hypersensitivity. RVM-CCK also resulted in a 2-fold increase in spinal 5-hydroxyindoleacetic acid (5-HIAA), a 5-hydoxytryptophan (5-HT) metabolite, as compared with controls, and mechanical hypersensitivity that was attenuated by spinal application of ondansetron, a 5-HT₃ antagonist. The present studies suggest that chronic nerve injury can result in activation of descending facilitatory mechanisms that may promote hyperalgesia via ultimate release of PGE₂ and 5-HT in the spinal cord.

• Authors: Timothy M Marshall, David S Herman, Tally M Largent-Milnes, Hamid Badghisi, Konstantina Zuber, Shannon C Holt, Josephine Lai, Frank Porreca, Todd W Vanderah
• Journal: Pain (Pain) Vol. 153 Issue 1 Pg. 86-94 (Jan 2012) ISSN: 1872-6623 [Electronic] United States
• PMID: 22030324 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Chemical References

• Cholecystokinin
• Dinoprostone

Topics

• Animals
• Cholecystokinin (metabolism, pharmacology)
• Dinoprostone (metabolism)
• Hyperalgesia (chemically induced, metabolism)
• Male
• Medulla Oblongata (drug effects, metabolism)
• Pain (metabolism)
• Pain Measurement
• Rats
• Rats, Sprague-Dawley
• Spinal Cord (drug effects, metabolism)
• Spinal Nerves (injuries, metabolism)