Effects of co-administration of intrathecal nociceptin/orphanin FQ and opioid antagonists on formalin-induced pain in rats

Purpose: Nociceptin/orphanin FQ (N/OFQ) as an endogeneous hexadecapeptide is known to exert antinociceptive effects spinally. The aims of this study were to demonstrate the antinociceptive effects of i.t. N/OFQ and to investigate the possible interaction between N/OFQ and endogenous opioid systems using selective opioid receptor antagonists in rat formalin tests. Materials and Methods: I.t. N/ OFQ was injected in different doses (1-10 nmol) via a lumbar catheter prior to a 50 μL injection of 5% formalin into the right hindpaw of rats. Flinching responses were measured from 0-10 min (phase I, an initial acute state) and 11-60 min (phase II, a prolonged tonic state). To observe which opioid receptors are involved in the anti-nociceptive effect of i.t. N/OFQ in the rat-formalin tests, naltrindole (5-20 nmol), β-funaltrexamine (1-10 nmol), and norbinaltorphimine (10 nmol), selective δ-, μ- and κ-opioid receptor antagonists, respectively, were administered intra-thecally 5 min after i.t. N/OFQ. Results: I.t. N/OFQ attenuated the formalin-induced flinching responses in a dose-dependent manner in both phases I and II. I.t. administration of naltrindole and β-funaltrexamine dose-dependently reversed the N/OFQ-induced attenuation of flinching responses in both phases; however, norbinaltorphimine did not. Conclusion: I.t. N/OFQ exerted an antinociceptive effect in both phases of the rat-formalin test through the nociceptin opioid peptide receptor. In addition, the results suggested that δ- and μ-opioid receptors, but not κ-opioid receptors, are involved in the antinociceptive effects of N/OFQ in the spinal cord of rats.