Korean J Pain.  2016 Jul;29(3):164-171. 10.3344/kjp.2016.29.3.164.

The Role of Spinal Dopaminergic Transmission in the Analgesic Effect of Nefopam on Rat Inflammatory Pain

• Kim DY
• Chae JW
• Lim CH
• Heo BH
• Park KS
• Lee HG
• Choi JI
• Yoon MH
• Kim WM

• KMID: 2327637
• DOI: http://doi.org/10.3344/kjp.2016.29.3.164

Abstract

BACKGROUND
Nefopam has been known as an inhibitor of the reuptake of monoamines, and the noradrenergic and/or serotonergic system has been focused on as a mechanism of its analgesic action. Here we investigated the role of the spinal dopaminergic neurotransmission in the antinociceptive effect of nefopam administered intravenously or intrathecally.
METHODS
The effects of intravenously and intrathecally administered nefopam were examined using the rat formalin test. Then we performed a microdialysis study to confirm the change of extracellular dopamine concentration in the spinal dorsal horn by nefopam. To determine whether the changes of dopamine level are associated with the nefopam analgesia, its mechanism was investigated pharmacologically via pretreatment with sulpiride, a dopaminergic D2 receptor antagonist.
RESULTS
When nefopam was administered intravenously the flinching responses in phase I of the formalin test were decreased, but not those in phase II of the formalin test were decreased. Intrathecally injected nefopam reduced the flinching responses in both phases of the formalin test in a dose dependent manner. Microdialysis study revealed a significant increase of the level of dopamine in the spinal cord by intrathecally administered nefopam (about 3.8 fold the baseline value) but not by that administered intravenously. The analgesic effects of intrathecally injected nefopam were not affected by pretreatment with sulpiride, and neither were those of the intravenous nefopam.
CONCLUSIONS
Both the intravenously and intrathecally administered nefopam effectively relieved inflammatory pain in rats. Nefopam may act as an inhibitor of dopamine reuptake when delivered into the spinal cord. However, the analgesic mechanism of nefopam may not involve the dopaminergic transmission at the spinal level.

Keyword

Analgesia; Dopamine; Microdialysis; Nefopam; Spinal cord; Sulpiride

MeSH Terms

Analgesia
Animals
Dopamine
Microdialysis
Nefopam*
Pain Measurement
Rats*
Spinal Cord
Spinal Cord Dorsal Horn
Sulpiride
Synaptic Transmission
Dopamine
Nefopam
Sulpiride

Figure

• 

  Fig. 1 Time-response (A) and dose-response data (B) of intravenously administered nefopam on flinching behavior during the formalin test. Each drug was administered 10 min before the formalin test. Data are presented as the number of flinching or the percentage of control. Intravenously administered nefopam reduced the flinching responses in phase I at a dose of 3 mg/kg. Each line or bar represents mean ± SEM of 5 rats. *P < 0.05 compared to control.

• 

  Fig. 2 Time-response (A) and dose-response data (B) of intrathecally administered nefopam on flinching behavior during the formalin test. Each drug was administered 10 min before the formalin test. Data are presented as the number of flinching or the percentage of control. Intrathecally administered nefopam reduced the flinching responses in both phases of formalin test in a dose dependent manner. Each line or bar represents mean ± SEM of 5 rats. *P < 0.05 †P < 0.001 compared to control.

• 

  Fig. 3 Microdialysis study measuring extracellular dopamine level at the spinal dorsal horn after intravenous (3 mg/kg) or intrathecal (30 µg) delivery of nefopam. Data are presented over time as a percent change from the baseline (n = 5 in each group). *P < 0.05 compared to baseline (BL) value.

• 

  Fig. 4 The effects of intravenous pretreatment with intravenous sulpiride (3 mg/kg) on the analgesic effect of intravenous (3 mg/kg) nefopam (A), or those with intrathecal sulpiride (100 µg) on intrathecal (30 µg) nefopam (B). The antinociception produced by nefopam was not attenuated by sulpiride. Each line or bar represents mean ± SEM of 5 rats.

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