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, 26 (1), 14-20

Antinociceptive Effect of Intrathecal Nefopam and Interaction With Morphine in Formalin-Induced Pain of Rats

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Antinociceptive Effect of Intrathecal Nefopam and Interaction With Morphine in Formalin-Induced Pain of Rats

Soo Young Cho et al. Korean J Pain.

Abstract

Background: Nefopam, a non-opiate analgesic, has been regarded as a substance that reduces the requirement for morphine, but conflicting results have also been reported. The inhibition of monoamine reuptake is a mechanism of action for the analgesia of nefopam. The spinal cord is an important site for the action of monoamines however, the antinociceptive effect of intrathecal nefopam was not clear. This study was performed to examine the antinociceptive effect of intrathecal (i.t.) nefopam and the pattern of pharmacologic interaction with i.t. morphine in the formalin test.

Methods: Male Sprague-Dawley rats were implanted with an i.t. catheter, and were randomly treated with a vehicle, nefopam, or morphine. Formalin was injected into the hind-paw 10 min. after an i.t. injection of the above experiment drugs. After obtaining antinociceptive ED(50) of nefopam and morphine, the mixture of nefopam and morphine was tested for the antinociceptive effect in the formalin test at a dose of 1/8, 1/4, 1/2 of ED(50), or ED(50) of each drug followed by an isobolographic analysis.

Results: Intrathecal nefopam significantly reduced the flinching responses in both phases of the formalin test in a dose-dependent manner. Its effect, however, peaked at a dose of 30 µg in phase 1 (39.8% of control) and 10 µg during phase 2 (37.6% of control). The isobolograhic analysis indicated an additive interaction of nefopam and morphine during phase 2, and a synergy effect in antinociception during phase 1.

Conclusions: This study demonstrated that i.t. nefopam produces an antinociceptive effect in formalin induced pain behavior during both phases of the formalin test, while interacting differently with i.t. morphine, synergistically during phase 1, and additively during phase 2.

Keywords: antinociception; formalin; interaction; morphine; nefopam.

Figures

Fig. 1
Fig. 1
Formalin induced flinching responses are attenuated dose-dependently by intrathecal injection of morphine in a dose-dependent manner. Time course after formalin injection (top panel), and dose response curve (middle and bottom) are shown. Each line represents the mean ± SEM of 6-8 rats/group. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control.
Fig. 2
Fig. 2
Time course after formalin injection (top panel), and dose response curve (middle and bottom) are shown. Intrathecal nefopam significantly reduced the flinching responses in a dose dependent manner during both phases with peak effect at 30 µg. Formalin induced flinching responses are attenuated dose-dependently by intrathecal injection of morphine in a dose-dependent manner. Each line represents the mean ± SEM of 6-8 rats/group. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control.
Fig. 3
Fig. 3
Isobologram for the combined intrathecal administration of nefopam and nefopam during phase 1 (top panel) and phase 2 (bottom). ED50 with SEM of nefopam and morphine are plotted on x and y axes. The line connecting ED50 of nefopam and morphine on x and y axes is the theoretical additive line. The point (A) is the theoretical ED50 with SEM of drug combination, and point (B) represents the experimental ED50 with SEM. ***P < 0.001 vs. theoretical ED50.

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