Antinociceptive effects of nefopam activating descending serotonergic modulation via 5‐HT2 receptors in the nucleus raphe magnus

Abstract Background Nefopam is a centrally acting antinociceptive drug; however, the underlying mechanisms are not fully understood. This study investigated the supraspinal mechanisms of nefopam. Methods The effects of intraperitoneally administered nefopam were assessed in rats using the formalin test, and the mechanisms were investigated by intrathecal or intra‐nucleus raphe magnus (NRM) pre‐treatment with the serotonin (5‐HT) receptor antagonist or 5‐HT2 receptor antagonist. The change in extracellular 5‐HT levels was measured by spinal cord microdialysis. Results Intraperitoneally administered nefopam showed antinociceptive effects in the rat formalin test, which were reversed by intrathecal pre‐treatment with 5‐HT receptor antagonist dihydroergocristine. Microdialysis study revealed that systemic nefopam significantly increased 5‐HT level in the spinal dorsal horn. Pretreatment of cinanserin, a 5‐HT2 receptor antagonist, into the NRM blocked the antinociceptive effects of intraperitoneally delivered nefopam. Direct injection of nefopam into the NRM mimicked the effects of systemic nefopam, and this effect was reversed by intra‐NRM cinanserin pre‐treatment. The increase in spinal level of 5‐HT by systemic nefopam was attenuated by intra‐NRM cinanserin pre‐treatment. Conclusion The antinociceptive effects of systemically administered nefopam are mediated by 5‐HT2 receptors in the NRM, which recruit the descending serotonergic fibres to increase the release of 5‐HT into the spinal dorsal horn. Significance This study revealed supraspinal mechanisms of nefopam‐produced analgesia mediated by 5‐HT2 receptors in the NRM recruiting the descending serotonergic fibres to increase the release of 5‐HT into the spinal dorsal horn. These observations support a potential role for nefopam in multimodal analgesia based on its distinct mechanisms of action that are not shared by the other analgesics.