Cyclooxygenase-2 inhibition potentiates morphine antinociception at the spinal level in a postoperative pain model

Background and Objectives: After peripheral inflammatory stimuli, spinal cord cyclooyxgenase-2 (COX-2) mRNA and protein levels increase, whereas COX-1 is unchanged. In animal models of inflammatory pain, intrathecal COX-2 selective inhibitors suppress hyperalgesia. However, the role of spinal COX-2 inhibition in postoperative pain is not well elucidated. This study investigates whether a water-soluble COX-2 selective inhibitor, L-745, 337, can modify allodynic responses in a rat model of postoperative pain. Methods: Allodynia was induced in the left plantar hindpaw by surgical incision. Animals then received intrathecal (0-80 μg) or subcutaneous (0-30 mg/kg) L-745, 337 coadministered with intrathecal morphine (0-2 nmol). Reduction of mechanical allodynia (increased withdrawal threshold) was quantified with calibrated von Frey hairs. Results: L-745, 337 alone, whether intrathecal or systemic, had no effect on withdrawal threshold. When intrathecal L-745, 337 at doses of 40 to 80 μg was combined with a subthreshold dose (0.5 nmol) of morphine, withdrawal thresholds were increased in a dose-dependent manner. Adding 80 μg L-745, 337 to 1 nmol morphine produced an antiallodynic effect greater than that of morphine at twice the dose. Subcutaneous L-745, 337, up to 30 mg/kg combined with intrathecal morphine resulted in the same antiallodynic response as morphine alone. Conclusion: These results suggest a spinal interaction of COX-2 inhibition with opiate analgesia may allow a reduction of postoperative pain with lower doses of opiate.