Spinal noradrenergic modulation and the role of the alpha-2 receptor in the antinociceptive effect of intrathecal nefopam in the formalin test

Abstract

Background: Nefopam has shown an analgesic effect on acute pain including postoperative pain. The reuptake of monoamines including serotonin and noradrenaline has been proposed as the mechanism of the analgesic action of nefopam, but it remains unclear. Although alpha-adrenergic agents are being widely used in the perioperative period, the role of noradrenergic modulation in the analgesic effect of nefopam has not been fully addressed.

Methods: Changes in the antinociceptive effect of intrathecal (i.t.) nefopam against formalin-elicited flinching responses were explored in Sprague-Dawley rats pretreated with i.t. 6-hydroxydopamine (6-OHDA), which depletes spinal noradrenaline. In addition, antagonism to the effect of nefopam by prazosin and yohimbine was evaluated to further elucidate the antinociceptive mechanism of i.t. nefopam.

Results: Pretreatment with i.t. 6-OHDA alone did not alter the flinching responses in either phase of the formalin test, while it attenuated the antinociceptive effect of i.t. nefopam significantly during phase 1, but not phase 2. The antagonist of the alpha-2 receptor, but not the alpha-1 receptor, reduced partially, but significantly, the antinociceptive effect of i.t. nefopam during phase 1, but not during phase 2.

Conclusions: This study demonstrates that spinal noradrenergic modulation plays an important role in the antinociceptive effect of i.t. nefopam against formalin-elicited acute initial pain, but not facilitated pain, and this action involves the spinal alpha-2 but not the alpha-1 receptor.

Keywords: alpha-2 receptor; formalin; nefopam; noradrenergic system; spinal cord.

Fig. 1

Effects of intrathecal 6-OHDA treatment on flinching behavior and antinociception produced by intrathecal nefopam in the formalin test. Treatment with intrathecal 6-OHDA, 3 days prior to the formalin test, does not alter the flinching responses in either phase. However, 6-OHDA treatment attenuates the antinociceptive effect of i.t. nefopam significantly during phase 1, but not phase 2. ^*P < 0.01 when compared to control, ^†Indicates P < 0.01.

Fig. 2

Effects of antagonism of the alpha-2 adrenoreceptor on the antinociceptive effect of i.t. nefopam. Yohimbine, an antagonist of the alpha-2 receptor, but not the alpha-1 receptor, reduces partially, but significantly, the antinociceptive effect of i.t. nefopam during phase 1. During phase 2, the flinching responses of nefopam-treated animals are not different from those of the yohimbine plus nefopam-treated group. ^*Indicates P < 0.05, ^†P < 0.01.