Korean J Pain.  2013 Jan;26(1):14-20. 10.3344/kjp.2013.26.1.14.

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

• Cho SY
• Park AR
• Yoon MH
• Lee HG
• Kim WM
• Choi JI

• KMID: 1779018
• DOI: http://doi.org/10.3344/kjp.2013.26.1.14

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 ED50 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 ED50, or ED50 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 microg in phase 1 (39.8% of control) and 10 microg 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.

Keyword

antinociception; formalin; interaction; morphine; nefopam

MeSH Terms

Analgesia
Animals
Catheters
Formaldehyde
Humans
Male
Morphine
Nefopam
Pain Measurement
Rats
Rats, Sprague-Dawley
Spinal Cord
Formaldehyde
Morphine
Nefopam

Figure

• 

  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 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 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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