Antinociceptive Effects of the Antidepressant Phenelzine are Mediated by Context-Dependent Inhibition of Neuronal Responses in the Dorsal Horn. (15th July 2018)

• Record Type: Journal Article
• Authors: Potter, Liam E.; Doolen, Suzanne; Mifflin, Katherine; Tenorio, Gustavo; Baker, Glen; Taylor, Bradley K.; Kerr, Bradley J.
• Is Part Of: Neuroscience. Volume 383(2018)
• Page Start: 205
• Page End: 215
• Publication Date: 2018-07-15
• Subjects: 5-HT 5-hydroxytryptamine (serotonin) -- 5-HT1AR 5-HT1A receptor -- aCFS artificial cerebrospinal fluid -- ANOVA analysis of variance -- CNS central nervous system -- DA dopamine -- EAE experimental autoimmune encephalomyelitis -- GABA gamma-aminobutyric acid -- GABA-T GABA-transaminase -- I.P. intraperitoneal -- IDA idazoxan -- IHC immunohistochemistry -- MAO monoamine oxidase -- MAOI monoamine oxidase inhibitor -- MOG myelin oligodendrocyte glycoprotein -- MS multiple sclerosis -- NA noradrenaline -- PB phosphate buffer -- PBS phosphate-buffered saline -- PEH phenylethylidenehydrazine -- PFA paraformaldehyde -- PLZ phenelzine -- RmANOVA repeated-measures ANOVA -- ROI region of interest -- ROS reactive oxygen species -- RT room temperature -- S.C. subcutaneous -- S1 primary somatosensory cortex -- SC spinal cord -- SCDH dorsal horn of the spinal cord -- SNRI selective norepinephrine reuptake inhibitor -- SSRI selective serotonin reuptake inhibitor -- TCA tricyclic antidepressant -- VEH vehicle -- VF/VFH von Frey (hair) -- WAY WAY-100, 635; MAOI -- pain -- phenelzine -- formalin -- calcium imaging -- dorsal horn; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2018.04.047
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: PLZ inhibits second phase formalin nocifensive behaviors. PLZ inhibits Glu-evoked Ca 2+ responses. PLZ exerts its effects through a 5-HT/5HT1AR pathway. Abstract: The putative strong anti-nociceptive properties of the antidepressant phenelzine (PLZ) have not been widely explored as a treatment for pain. Antinociceptive effects of PLZ were identified in the formalin model of tonic pain (Mifflin et al., 2016) and in allodynia associated with experimental autoimmune encephalomyelitis, (EAE) a mouse model of multiple sclerosis (Potter et al., 2016). Here, we further clarify the specific types of stimuli and contexts in which PLZ modulates nociceptive sensitivity. Our findings indicate that PLZ selectively inhibits ongoing inflammatory pain while sparing transient reflexive and acute nociception. We also investigated the cellular mechanisms of action of PLZ in the dorsal horn, and as expected of a monoamine-oxidase inhibitor, PLZ increased serotonin (5HT) immunoreactivity. We next used two approaches to test the hypothesis that PLZ inhibits the activation of spinal nociresponsive neurons. First, we evaluated the formalin-evoked protein expression of the immediate early gene, c- fos . PLZ reduced Fos expression in the superficial dorsal horn. Second, we evaluated the effects of PLZ on intracellular calcium responses to superfusion of glutamate (0.3–1.0 mM) in an ex vivo lumbar spinal cord slice preparation. Superfusion with PLZ (100–300 μM) reduced 1 mM glutamate-evoked calcium responses. This was blocked by pretreatment with the 5HT1A-receptor antagonist WAY-100, 635, but not the alpha-2 adrenergic antagonist idazoxan. We conclude that PLZ exerts antinociceptive effects through a 5-HT/5HT1AR-dependent inhibition of neuronal responses within nociceptive circuits of the dorsal horn.