Role of prefrontal cortical calcium-independent phospholipase A2 in antinociceptive effect of the norepinephrine reuptake inhibitor antidepresssant maprotiline

Neuroscience. 2017 Jan 6:340:91-100. doi: 10.1016/j.neuroscience.2016.10.037. Epub 2016 Oct 24.


The prefrontal cortex is essential for executive functions such as decision-making and planning. There is also accumulating evidence that it is important for the modulation of pain. In this study, we investigated a possible role of prefrontal cortical calcium-independent phospholipase A2 (iPLA2) in antinociception induced by the norepinephrine reuptake inhibitor (NRI) and tetracyclic (tricyclic) antidepressant, maprotiline. Intraperitoneal injections of maprotiline increased iPLA2 mRNA and protein expression in the prefrontal cortex. This treatment also reduced grooming responses to von-Frey hair stimulation of the face after facial carrageenan injection, indicating decreased sensitivity to pain. The antinociceptive effect of maprotiline was abrogated by iPLA2 antisense oligonucleotide injection to the prefrontal cortex, indicating a role of this enzyme in antinociception. In contrast, injection of iPLA2 antisense oligonucleotide to the somatosensory cortex did not reduce the antinociceptive effect of maprotiline. Lipidomic analysis of the prefrontal cortex showed decrease in phosphatidylcholine species, but increase in lysophosphatidylcholine species, indicating increased PLA2 activity, and release of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) after maprotiline treatment. Differences in sphingomyelin/ceramide were also detected. These changes were not observed in maprotiline-treated mice that received iPLA2 antisense oligonucleotide to the prefrontal cortex. Metabolites of DHA and EPA may help to strengthen a known supraspinal antinociceptive pathway from the prefrontal cortex to the periaqueductal gray. Together, results indicate a role of prefrontal cortical iPLA2 and its enzymatic products in the antinociceptive effect of maprotiline.

Keywords: antinociception; lipid mediators; noradrenaline; pain; prefrontal cortex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic Uptake Inhibitors / pharmacology
  • Analgesics / pharmacology*
  • Animals
  • Antidepressive Agents, Second-Generation / pharmacology
  • Carrageenan
  • Disease Models, Animal
  • Docosahexaenoic Acids / metabolism
  • Eicosapentaenoic Acid / metabolism
  • Facial Pain / drug therapy*
  • Facial Pain / immunology
  • Group VI Phospholipases A2 / antagonists & inhibitors
  • Group VI Phospholipases A2 / genetics
  • Group VI Phospholipases A2 / metabolism*
  • Male
  • Maprotiline / pharmacology*
  • Mice, Inbred C57BL
  • Pain Threshold / drug effects
  • Pain Threshold / physiology
  • Prefrontal Cortex / drug effects*
  • Prefrontal Cortex / immunology
  • RNA, Messenger / metabolism
  • Somatosensory Cortex / drug effects
  • Somatosensory Cortex / metabolism


  • Adrenergic Uptake Inhibitors
  • Analgesics
  • Antidepressive Agents, Second-Generation
  • RNA, Messenger
  • Docosahexaenoic Acids
  • Maprotiline
  • Carrageenan
  • Eicosapentaenoic Acid
  • Group VI Phospholipases A2
  • Pla2g6 protein, mouse