Norepinephrine mediates the effects of restraint stress on Theiler's Murine Encephalomyelitis Virus

Abstract

Theiler's Murine Encephalomyelitis Virus (TMEV) is an important model of multiple sclerosis (MS) (Lipton, 1975). Theiler's virus induces a biphasic disease that, in the chronic phase, causes a remitting relapsing demyelination of the central nervous system (CNS) similar to that of MS. Chronic restraint stress in the acute/early phase profoundly affects vulnerability to TMEV. When an animal is subjected to a stressor, several biological pathways are activated. Previous studies conducted in our lab have investigated the role of the hypothalamic pituitary adrenal (HPA) axis and the glucocorticoid corticosterone. The sympathetic nervous system (SNS) is also activated by stress and initiates the release of the catecholamine norepinephrine (NE) from the adrenal medulla. Norepinephrine is believed to have immunosuppressive effects. Here, we attempt to determine if NE is mediating the deleterious effects restraint stress on TMEV. To examine this issue, seventy-one 24-day old male CBA mice were surgically implanted with either a pellet of the β₂-adrenergic antagonist nadolol, or a pellet containing only vehicle on three days prior to infection. The mice were then restrained for 12 hours overnight, and infected intracranially with 5 X10⁴ PFU of the BeAn strain of TMEV on day 0 post infection. For the following 4 weeks, restraint was administered 5 nights a week for 12 hours per session. The effects of stress on TMEV were measured daily using two scales, one to measure the relative sickness of the animal and the second to measure the degree of hind limb weakness and paralysis. The body weight of the animals was also recorded daily. This study confirms that norepinephrine is indeed a mediator of the stress response. Animals receiving the placebo had higher mortality, more severe clinical symptoms, and greater hind limb weakness and paralysis than animals receiving the norepinephrine antagonist nadolol.