title: Manipulation of Neurotransmitter Levels Has Differential Effects on Formalin-Evoked Nociceptive Behavior in Male and Female Mice.
abstract: Changes in serotonin (5-hydroxytryptamine; 5-HT), noradrenaline (NA), and γ-aminobutyric acid (GABA) levels in the spinal cord are known to occur in response to nociceptive stimuli, yet little research has examined possible underlying sex differences in these changes and how they might affect nociception. We have used pharmacological approaches in a well established model of tonic nociception, the formalin test, to explore the effects of altering neurotransmitter levels on nociceptive responses in male and female C57BL/6 mice. The monoamine oxidase (MAO) inhibitor phenelzine (PLZ), its metabolite phenylethylidenehydrazine (PEH), and a derivative compound of PLZ, N(2)-acetylphenelzine (N(2)-AcPLZ), were used to increase endogenous levels of: GABA, 5-HT, and NA (PLZ); GABA alone (PEH); or 5-HT and NA only (N(2)-AcPLZ). Although both sexes had a reduction in second phase nociceptive behaviors with PEH pretreatment, the analgesic effect of PLZ was only observed in male mice. High performance liquid chromatography analysis revealed male mice had greater spinal cord increases in 5-HT and NA levels compared with female mice. Female mice, in contrast, had greater increases in GABA levels with pretreatments. With N(2)-AcPLZ pretreatment, only male mice had a reduction in second phase nociceptive behaviors despite similar increases in 5-HT and NA levels in both sexes. These findings suggest that male mice may utilize serotonergic and noradrenergic pathways more efficiently for the attenuation of nociceptive behavior and female mice are more dependent on alternate mechanisms. To our knowledge, these findings are the first on the antinociceptive properties of altering 5-HT, NA, and GABA levels with the MAO inhibitor PLZ and its derivatives in a model of tonic pain processing. They also reveal significant underlying sex differences associated with these treatments.
  
  
  CONCLUSIONS
  The present study found that nociception in male and female mice may be regulated by different neurotransmitter systems. These results indicate that different pharmacological approaches may be needed to treat pain in both sexes.
authors.affiliation: Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Mifflin
authors.affiliation: Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Curtis
authors.initials: C
authors.lastname: Benson
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Thorburn
authors.affiliation: Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada; Department of Psychiatry (NRU), University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Glen B
authors.initials: GB
authors.lastname: Baker
authors.affiliation: Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada; Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada; Department of Anesthesiology and Pain Medicine, University of Alberta, Edmonton, Alberta, Canada. Electronic address: bradley.kerr@ualberta.ca.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Kerr
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002369:Castration; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005404:Fixatives / Q000633:toxicity*; D005557:Formaldehyde / Q000633:toxicity*; D019329:Idazoxan / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D059225:Nociception / Q000187:drug effects; D059226:Nociceptive Pain / Q000139:chemically induced* / Q000378:metabolism*; D010624:Phenelzine / Q000031:analogs & derivatives / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D012727:Sex Characteristics
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D001713:Biphenyl Compounds; D005404:Fixatives; D008996:Monoamine Oxidase Inhibitors; D018377:Neurotransmitter Agents; D010879:Piperazines; D011725:Pyridines; C515421:SB-699551-A; D012702:Serotonin Antagonists; D005557:Formaldehyde; C043198:N-acetylphenelzine; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D010624:Phenelzine; D019329:Idazoxan
keywords: Pain; formalin; noradrenalin; serotonin; γ-aminobutyric acid