Yonsei Med J.  2013 May;54(3):763-771. 10.3349/ymj.2013.54.3.763.

Effects of Co-Administration of Intrathecal Nociceptin/Orphanin FQ and Opioid Antagonists on Formalin-Induced Pain in Rats

• Lee H

• KMID: 1727895
• DOI: http://doi.org/10.3349/ymj.2013.54.3.763

Abstract

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 microL 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), beta-funaltrexamine (1-10 nmol), and norbinaltorphimine (10 nmol), selective delta-, micro- and kappa-opioid receptor antagonists, respectively, were administered intrathecally 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 beta-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 delta- and micro-opioid receptors, but not kappa-opioid receptors, are involved in the antinociceptive effects of N/OFQ in the spinal cord of rats.

Keyword

Antinociception; formalin test; nociceptin/orphanin FQ; opioid receptor

MeSH Terms

Analgesics/administration & dosage/*pharmacology
Animals
Formaldehyde/toxicity
Injections, Spinal
Male
Naltrexone/administration & dosage/analogs & derivatives/pharmacology
Narcotic Antagonists/administration & dosage/*pharmacology
Opioid Peptides/administration & dosage/*pharmacology
Pain Measurement
Rats
Rats, Sprague-Dawley
Receptors, Opioid/*agonists/drug effects
Analgesics
Narcotic Antagonists
Opioid Peptides
Receptors, Opioid
Formaldehyde
Naltrexone

Figure

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  Fig. 1 Time-effect curves of intrathecal nociceptin/orphanin FQ (N/OFQ) for flinching responses in the formalin test. X-axis: time (min) after formalin injection. Y-axis: number of flinches for each 5-min session. Different doses of NC and saline (as a vehicle) were administered 10 min before formalin injection. I.t. administration of N/OFQ dose-dependently attenuated formalin-induced flinching responses (p<0.05). Each value represents mean±SD (n=8). Symbols represent different dosing conditions for each panel. ED50 values (Cl95 values) of N/OFQ were 5.3 (4.2-6.4) nmol in dose-response curves and 4.3 (3.2-5.4) nmol and 6.6 (4.8-8.3) nmol for phase I and phase II, respectively. SD, standard deviation.

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  Fig. 2 The cumulative flinching scores of the rat formalin test after intrathecal administration of nociceptin/orphanin FQ (N/OFQ). X-axis: various doses of N/OFQ (1, 5, 10 nmol in 10 µL) and vehicle (0.9% sterile saline, 10 µL). The drugs and tested vehicle were administered 10 min before formalin injection. Y-axis: percentage of control for total flinches during phase I (1-10 min, top panel) and phase II (11-60 min, right panel) after formalin injection. Each values represents mean±SD (n=8). †p<0.01, ‡p<0.001 versus control. SD, standard deviation.

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  Fig. 3 The cumulative flinching scores of rat formalin test after intrathecal administration of nociceptin/orphanin FQ (N/OFQ) and (Nphe1)NC(1-13)-NH2. X-axis: bars represent the different dose conditions of each phase. (Nphe1)NC(1-13)-NH2 or 10 mL of 0.9% sterile saline (control) was administered 5 min after i.t. injection of N/OFQ (10 nmol). Y-axis: percentage of control for total flinches during phase I (1-10 min, top panel) and phase II (11-60 min, bottom panel) after formalin injection. Each values represents mean±SD (n=8). †p<0.01, ‡p<0.001 versus control. SD, standard deviation.

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  Fig. 4 Time-effect curves of intrathecal nociceptin/orphanin FQ (N/OFQ) and co-administered naltrindole (NTI) for flinching responses in the formalin test. X-axis: time (min) after formalin injection. Y-axis: number of flinches for each 5-min session. Each value represents mean±SD (n=8). Symbols represent the different dose conditions for each panel. Ten nmol of N/OFQ was administered intrathecally, followed 5 min later by 5, 10, or 20 nmol of NTI and vehicle (0.9% sterile saline), before formalin injection. I.t. co-administration of NTI dose-dependently reversed N/OFQ-induced flinching attenuations in the formalin test (p<0.05). SD, standard deviation.

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  Fig. 5 The cumulative flinching scores after intrathecal administration of nociceptin/orphanin FQ (N/OFQ) and naltrindole (NTI) in the formalin test. X-axis: doses of NTI (0, 5, 10, or 20 nmol). Ten nmol of N/OFQ was administered intrathecally, followed 5 min later with NTI. Y-axis: percentage of control for total flinches during phase I (1-10 min, top panel) and phase II (11-60 min, bottom panel) after formalin injection. Each value represents mean±SD (n=8). *p<0.05, ‡p<0.001 versus vehicle pre-treated group (N/OFQ+NTI0). SD, standard deviation.

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  Fig. 6 Time-effect curves of intrathecal nociceptin/orphanin FQ (N/OFQ) and co-administered β-funaltrexamine (FNX) for flinching responses in the formalin test. X-axis: time (min) after formalin injection. Y-axis: number of flinches for each 5-min session. Each value represents mean±SD (n=8). Symbols represent the different dose conditions for each panel. Ten nmol of N/OFQ was administered intrathecally, followed 5 min later by 1, 5, or 10 nmol of FNX and vehicle (0.9% sterile saline), before the formalin injection. I.t. co-administration of FNX dose-dependently reversed N/OFQ-induced flinching attenuations in the formalin test (p<0.05). SD, standard deviation.

• 

  Fig. 7 The cumulative flinching scores of the rat formalin test after intrathecal administration of nociceptin/orphanin FQ (N/OFQ) and β-funaltrexamine (FNX). X-axis: doses of FNX (0, 1, 5, or 10 nmol). Ten nmol of N/OFQ was administered intrathecally, followed 5 min later with FNX. Y-axis: percentage of control for total flinches during phase I (1-10 min, top panel) and phase II (11-60 min, bottom panel) after formalin injection. Each value represents mean±SD (n=8). †p<0.01, ‡p<0.001 versus vehicle pre-treated group (N/OFQ+FNX0). SD, standard deviation.

• 

  Fig. 8 The cumulative flinching scores of rat formalin test after intrathecal-administered nociceptin/orphanin FQ (N/OFQ) and norbinaltorphimine (nor-BNI). X-axis: doses of nor-BNI (0 or 10 nmol). Ten nmol of N/OFQ was administered intrathecally, followed 5 min later with nor-BNI. Y-axis: percentage of control for total flinches during phase I (1-10 min, top panel) and phase II (11-60 min, bottom panel) after formalin injection. Each value represents mean±SD (n=8). ‡p<0.001 versus vehicle pre-treated group (N/OFQ+nor-BNI0). SD, standard deviation.

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