Journal
BRITISH JOURNAL OF ANAESTHESIA
Volume 120, Issue 4, Pages 827-835Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.bja.2017.11.103
Keywords
cyclooxygenase-2; fentanyl; opioid-induced hyperalgesia; prostaglandin E2; surgery
Categories
Funding
- National Natural Foundation of China [81571071]
- Guangdong Province Natural Foundation [2014A030313203]
- National Institutes of Health [R01NS094664, R01NS094224, R01DA033390, U01HL117684]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS094224, R01NS094664, R01NS072206] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA033390] Funding Source: NIH RePORTER
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Background: Accumulated evidence suggests that spinal cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) may be implicated in the development of opioid-induced hyperalgesia. Methods: Rats received subcutaneous fentanyl injections at different doses ( 20-80 mg kg(-1)), four separate times at 15-min intervals. Some rats only received fentanyl (60 mg kg(-1) x 4 doses) with or without surgical incision. Fentanyl-induced hyperalgesia was evaluated via a tail-pressure or paw-withdrawal test. The concentrations of spinal COX-2, EP-1 receptor (EP-1R) mRNA, and PGE2 were measured. The effects of the COX-2 inhibitor, parecoxib (intraperitoneal 10 mg kg(-1)), or the EP-1R antagonist, SC51089 (intraperitoneal 100 mg kg(-1)), on hyperalgesia and spinal PGE2 were examined. Results: Acute repeated injections of fentanyl dose-dependently induced mechanical hyperalgesia, which reached a peak at the 1st day and persisted for 1-4 days postinjection. This hyperalgesia could be partly or totally prevented by the pretreatment of either parecoxib or SC51089. Consistently, the levels of spinal COX-2 mRNA and PGE2 were also dosedependently increased, reaching a peak at the first day and persisting for 2 days postinjection. Pretreatment with parecoxib could block the increase in spinal PGE2 and had no effects on spinal COX-2 and EP-1R mRNA. Fentanyl injection enhanced incision-induced mechanical and thermal hyperalgesia. Conclusions: Acute repeated fentanyl administration dose-dependently produced mechanical hyperalgesia and augmented surgery induced postoperative hyperalgesia. This behavioural change was paralleled with an increase in spinal COX-2 mRNA and PGE2 after fentanyl administration. Inhibition of COX-2 or blockade of EP-1R can partly or totally prevent hyperalgesia.
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