title: Role of prefrontal cortical calcium-independent phospholipase A2in antinociceptive effect of the norepinephrine reuptake inhibitor antidepresssant maprotiline.
abstract: 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 iPLA2mRNA 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 iPLA2antisense oligonucleotide injection to the prefrontal cortex, indicating a role of this enzyme in antinociception. In contrast, injection of iPLA2antisense 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 iPLA2antisense 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 iPLA2and its enzymatic products in the antinociceptive effect of maprotiline.
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Singapore.
authors: Wee-Siong
authors: WS
authors: Chew
authors: Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Singapore; Neurobiology and Ageing Research Programme, National University of Singapore, Singapore 119260, Singapore.
authors: Suku-Maran
authors: SM
authors: Shalini
authors: Neurobiology and Ageing Research Programme, National University of Singapore, Singapore 119260, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Singapore.
authors: Federico
authors: F
authors: Torta
authors: Neurobiology and Ageing Research Programme, National University of Singapore, Singapore 119260, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Singapore; Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 119260, Singapore.
authors: Markus R
authors: MR
authors: Wenk
authors: College of Dental Medicine, Columbia University, USA.
authors: Christian
authors: C
authors: Stohler
authors: Division of Oral and Maxillofacial Surgery, Faculty of Dentistry, National University of Singapore, Singapore 119260, Singapore.
authors: Jin-Fei
authors: JF
authors: Yeo
authors: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Singapore.
authors: Deron R
authors: DR
authors: Herr
authors: Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Singapore; Neurobiology and Ageing Research Programme, National University of Singapore, Singapore 119260, Singapore. Electronic address: wei_yi_ong@nuhs.edu.sg.
authors: Wei-Yi
authors: WY
authors: Ong
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D002351:Carrageenan; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000378:metabolism; D015118:Eicosapentaenoic Acid / Q000378:metabolism; D005157:Facial Pain / Q000188:drug therapy* / Q000276:immunology; D054522:Group VI Phospholipases A2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008376:Maprotiline / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D013003:Somatosensory Cortex / Q000187:drug effects / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000700:Analgesics; D018687:Antidepressive Agents, Second-Generation; D012333:RNA, Messenger; D004281:Docosahexaenoic Acids; D008376:Maprotiline; D002351:Carrageenan; D015118:Eicosapentaenoic Acid; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse
keywords: antinociception; lipid mediators; noradrenaline; pain; prefrontal cortex