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

• Published in: Pain (Amsterdam) Vol. 153; no. 1; pp. 86 - 94
• Main Authors: Marshall, Timothy M., Herman, David S., Largent-Milnes, Tally M., Badghisi, Hamid, Zuber, Konstantina, Holt, Shannon C., Lai, Josephine, Porreca, Frank, Vanderah, Todd W.
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 2012
• Subjects: Cholecystokinin; Descending facilitation; Microdialysis; Nerve injury; PGE 2; Rostral ventromedial medulla; Serotonin; Tactile hypersensitivity; Microdialysis; Serotonin; PGE 2; Nerve injury; Rostral ventromedial medulla; Cholecystokinin; Descending facilitation; Tactile hypersensitivity
• ISSN: 0304-3959; 1872-6623
• DOI: 10.1016/j.pain.2011.09.021

Nerve injury significantly increases endogenous cholecystokinin (CCK) in the rostral ventromedial medulla (RVM), and CCK drives descending facilitatory pathways from the RVM in naïve animals to increase spinal prostaglandin-E2 and serotonin (5-hydoxytryptophan/5-hydroxyindoleacetic acid). 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.