Citation

Chronic pain is a highly prevalent symptom in Multiple Sclerosis (MS) and affects approximately half of patients at some stage of the disease. MS affects women more frequently than men and neuropathic pain is also reported as more severe, and frequent, in females with the disease. The underlying causes of neuropathic pain remain to be elucidated and it is unclear why females are more greatly affected. The animal model experimental autoimmune encephalomyelitis (EAE) is used to study the pathophysiology of MS and MS-related pain. Studies have shown that pain behaviours and the disease course in mice with EAE may be improved with the administration of the antidepressant phenelzine (PLZ) which acts to elevate noradrenaline (NA), serotonin (5-HT), and gamma-aminobutyric acid (GABA) levels. Interestingly, studies have also demonstrated significant sex differences in the behavioural responses to PLZ and an acetylated derivative, N2-acetylphenelzine (N2-Ac-PLZ) (that elevates NA and 5-HT, but not GABA, levels) in the formalin pain assay. We have found that female mice do not respond to N2-Ac-PLZ in this particular pain model. As such, I sought to examine whether N2-Ac-PLZ beneficially improves pain behaviours and disease course within the sexes in mice with EAE. C57/BL6 mice of both sexes were treated with myelin oligodendrocytes glycoprotein 35-55 (MOG35-55) in Complete Freund’s Adjuvant (CFA) and pertussis toxin to induce EAE. The mice were monitored daily, and starting on day 7 post-induction, chronically treated with a vehicle or N2-Ac-PLZ every other day until day 34 post-induction. I used behavioural tasks to assess exploratory, anxiety-like, and mechanical hypersensitivity behaviours in the mice, as well as high performance liquid chromatography (HPLC) to assess spinal levels of NA, 5-HT, and GABA. In contrast to the formalin model, I find that N2-Ac-PLZ improved tactile hypersensitivity only in female mice with EAE. N2-Ac-PLZ treatment had no effect on the disease course of female or male mice with EAE. My examination of neurotransmitter levels within the spinal cord revealed that N2-Ac-PLZ treatment acted to increase levels of NA and 5-HT in both females and males, but with higher elevations observed in females. This study shows that treatment with N2-Ac-PLZ can attenuate tactile hypersensitivity in a disease-related chronic pain paradigm in a sex-specific manner. These data provide further evidence of sex differences in EAE, and insight into the causes of pain in the disease.