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Anesthesiology. 2011 Dec;115(6):1281-90. doi: 10.1097/ALN.0b013e31823499cc.

Shifts in cell-type expression accompany a diminishing role of spinal p38-mapkinase activation over time during prolonged postoperative pain.

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  • 1Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115-6110, USA.



Surgery often causes prolonged postoperative pain, the mechanisms of which are unknown. The authors investigated the role of p38, a pain-associated mitogen-activated protein kinase, in induction and maintenance of such pain.


Male rats were subjected to the skin-muscle incision retraction procedure at the saphenous region; the procedure causes ~4 weeks of secondary tactile hyperalgesia in the ipsilateral plantar region, indicating central sensitization. The spinal cord was sectioned from L3 and L4 + L5 vertebral segments and stained for activated p38 (P-p38) at postoperative day 3 (POD 3), just as secondary hyperalgesia develops; at PODs 10-12, the time of maximum hyperalgesia; and at POD 35, after the resolution of hyperalgesia. Some sections were costained for microglia, astrocytes, and neurons. Intrathecal injections of a P-p38 inhibitor were performed at POD 2 or POD 9, and subsequent changes in pain were monitored.


Skin-muscle incision retraction increased the numbers of dorsal horn P-p38 positive cells in L3 by ~3-fold and in L4 + L5 by ~7-fold from POD 3 to PODs 11-12. This increase was accompanied by a shift from microglia to neurons, resulting in a ~20-fold increase in P-p38-positive neurons in L4-L5 over this time. No P-p38 was detected in astrocytes. A P-p38 inhibitor given at POD 2 prevented development of secondary hypersensitivity, but when given at POD 9 the same dose gave weak relief of pain for less than 3 h.


Spinal P-p38 mitogen-activated protein kinase, activated after incision retraction, is important for the induction of prolonged pain, but despite increased pain near the time of maximum pain, its functional importance for the maintenance of pain is not great.

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