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

作者：Marshall Timothy M; Herman David S; Largent Milnes Tally M; Badghisi Hamid; Zuber Konstantina; Holt Shannon C; Lai Josephine; Porreca Frank; Vanderah Todd W^*

来源：Pain, 2012, 153(1): 86-94.

DOI：10.1016/j.pain.2011.09.021

• Rostral ventromedial medulla
• Descending facilitation
• Cholecystokinin
• Serotonin
• PGE(2)
• Microdialysis
• Tactile hypersensitivity
• Nerve injury

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 L-5/L-6 spinal nerves (SNL). Microinjection of CCK into the RVM of naive 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-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 PGE(2) and 5-HT in the spinal cord.

• 出版日期2012-1