Preoperative Inhibition Of Cyclooxygenase-1 In The Spinal

Preoperative Inhibition of Cyclooxygenase-1 in the Spinal Cord Reduces Postoperative Pain
Xiaoying Zhu,
MD,

Dawn R. Conklin,

BS,

and James C. Eisenach,

MD

Program of Neuroscience, Department of Anesthesiology and Center for the Study of Pharmacologic Plasticity in the Presence of Pain, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Intrathecaladministration of cyclooxygenase (COX)-1, but not COX-2, specific inhibitors given on postoperative day 1 has analgesic effects in an incisional model of postoperative pain. We investigated the effects of preoperative administration of intrathecal COX inhibitors in this model. Fifteen minutes before surgery, rats received intrathecally the COX-1 preferring inhibitor, ketorolac, the specific COX-1inhibitor, SC-560, the COX-2 inhibitor, NS-398, or vehicle. A 1-cm longitudinal incision was then made through skin, fascia, and muscles of the plantar aspect of a left paw in male rats. Withdrawal

threshold to von Frey filaments was measured at 2 h, 4 h, and at intervals up to 5 days later. Ketorolac and SC-560 increased withdrawal threshold to mechanical stimulation, but NS-398 had no significanteffect. These results suggest that COX-1 plays an important role in spinal cord pain processing and sensitization after surgery and that preoperative intrathecal administration of specific COX-1 inhibitors may be useful to treat postoperative pain. (Anesth Analg 2005;100:1390 –3)

P

rostaglandins (PGs) are important mediators of pain and inflammation (1). Cyclooxygenase (COX) is therate-limiting enzyme that catalyzes the conversion of arachidonic acid to PGs. Two isoforms of COX, COX-1 and COX-2, are expressed constitutively in the spinal cord (2– 4). Hindpaw injection of complete Freund’s adjuvant produces mechanical allodynia and thermal hyperalgesia in the hindpaws and joints, accompanied by a significant increase in COX-2 mRNA (5,6) and protein (6) in the lumbar spinal cord.However, COX-1 mRNA (5) and protein (7) remain unchanged by these manipulations. Intrathecal COX-2 inhibitors attenuate inflammationinduced mechanical allodynia and thermal hyperalgesia (6,8 –10), but a COX-1 inhibitor has no such effect (9). These studies demonstrate that COX-2 plays a prominent role in inflammatory pain. In contrast to these results with inflammation, in an incisional model ofpostoperative pain, COX-1 expression increases in glia in the ipsilateral lumbar spinal

dorsal horn. In addition, postoperative intrathecal administration of COX-1, but not COX-2, specific inhibitors exerts analgesic effects (4,11). Because intrathecal injections are usually administered before surgery and preoperative treatment with some drugs reduces postoperative pain (12,13), we investigatedwhether intrathecal preoperative treatment with COX-1 inhibitors attenuates postoperative pain in this paw incision model by examining the effects of intrathecal COX-1 and COX-2 inhibitors given 15 min before surgery on postoperative hypersensitivity to mechanical stimulation. Lack of selective COX-3 inhibitors precluded us from examining the role of this isoenzyme.

Methods
With approval by theAnimal Care and Use Committee in Wake Forest University, male Sprague-Dawley rats (220 –260 g) were used in this study. Rats were anesthetized with 2%–3% halothane and lumbar intrathecal catheters were implanted by a slightly modified procedure to that previously described (14). Briefly, an incision was made through the atlanto-occipital membrane and a 7.5- to 8.0-cm 32-gauge catheter was insertedinto the intrathecal space such that the caudal end of the catheter was near to the lumbar enlargement. One week later, after paw withdrawal threshold was measured and 15 min before paw incision surgery, rats were randomized to receive intrathecal ketorolac, 50 g, NS-398, 50 g, SC-560, 100 g, or either
©2005 by the International Anesthesia Research Society 0003-2999/05

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