Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8840681 | Neuroscience | 2018 | 37 Pages |
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 (0.3-1.0â¯mM) in an ex vivo lumbar spinal cord slice preparation. Superfusion with PLZ (100-300â¯Î¼M) reduced 1â¯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.
Keywords
EAEACFsRepeated-measures ANOVAGABA-transaminaseIdazoxanIDAMAOISNRI5-HT1ARs.c.GABA-TMAORMANOVAPFAi.p.TCAROI5-HTPBSMOG5-HT1A receptor5-hydroxytryptamine (serotonin)ROSexperimental autoimmune encephalomyelitisgamma-aminobutyric acidImmunohistochemistryIHCSelective norepinephrine reuptake inhibitorphosphate bufferanalysis of varianceANOVACalcium imagingintraperitonealTricyclic antidepressantPainCNSRoom temperatureDopaminesubcutaneousPEHcentral nervous systemdorsal horndorsal horn of the spinal cordSpinal cordFormalinPhenelzineprimary somatosensory cortexartificial cerebrospinal fluidPhosphate-buffered salineWAYregion of interestSelective serotonin reuptake inhibitormonoamine oxidase inhibitorSSRIMultiple sclerosismonoamine oxidasenoradrenalinevehVehicleparaformaldehydeGABAmyelin oligodendrocyte glycoproteinReactive oxygen species
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Authors
Liam E. Potter, Suzanne Doolen, Katherine Mifflin, Gustavo Tenorio, Glen Baker, Bradley K. Taylor, Bradley J. Kerr,