Activation of descending pain-facilitatory pathways from the rostral ventromedial medulla by cholecystokinin elicits release of prostaglandin-E 2 in the spinal cord

Timothy M. Marshall, David S. Herman, Tally M. Largent-Milnes, Hamid Badghisi, Konstantina Zuber, Shannon C. Holt, Josephine Lai, Frank Porreca, Todd W. Vanderah

Research output: Contribution to journalArticle

30 Scopus citations

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 CCK 2 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 L 5/L 6 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-E 2) PGE 2 measured in cerebrospinal fluid from the lumbar spinal cord. The peak increase in spinal PGE 2 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-HT 3 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 PGE 2 and 5-HT in the spinal cord.

Original languageEnglish (US)
Pages (from-to)86-94
Number of pages9
JournalPain
Volume153
Issue number1
DOIs
StatePublished - Jan 2012

Keywords

  • Cholecystokinin
  • Descending facilitation
  • Microdialysis
  • Nerve injury
  • PGE
  • Rostral ventromedial medulla
  • Serotonin
  • Tactile hypersensitivity

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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