Opioid-induced Hyperalgesia in a Murine Model of Postoperative Pain: Role of Nitric Oxide Generated from the Inducible Nitric Oxide Synthase

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Opioid-induced delayed hyperalgesia and allodynia have been reported in human and animal models. The authors evaluated the influence of different opioids used during clinical anesthesia on nociceptive sensitivity and incisional pain in mice. The role of the inducible nitric oxide synthase on surgical pain and opioid-induced pronociception also was investigated.


CD1 mice were used to study the efficacy of opioids inducing pronociception and enhancing incisional pain. The implication of nitric oxide generated from the inducible nitric oxide synthase was investigated using knockout mice (C57/BL6) for its gene. Mice underwent right hind paw surgery under sevoflurane anesthesia combined with subcutaneous administration of saline or the opioids fentanyl (0.05 mg/kg), alfentanil (1 mg/kg), and remifentanil (0.04 mg/kg). Nociception was evaluated daily for 7 days using paw-pressure, plantar, and von Frey tests.


The antinociceptive effect of opioids was followed by long-lasting thermal hyperalgesia and mechanical allodynia (each lasting between 2 and 7 days), but not mechanical hyperalgesia. Intraoperative infusion of opioids significantly enhanced incisional pain in all tests. The most prominent effects were observed with remifentanil. The inducible nitric oxide synthase gene deletion attenuated both remifentanil- and incision-induced pronociceptive effects. In mutant mice for the inducible nitric oxide synthase gene, remifentanil was still efficient in enhancing incisional pain, but the global pronociceptive effect was attenuated significantly as compared with wild-type mice.


The authors’ study demonstrates that the intraoperative administration of fentanyl or remifentanil enhances the extent and duration of postoperative pain. The results suggest a role of the nitric oxide systems in the cause of acute postoperative pain and opioid-induced pronociception.

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