טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentWeissman-Fogel Irit
SubjectPain Perception and Vagal Function in an Animal Model of
Neuropathic Pain
DepartmentDepartment of Medicine
Supervisor Professor David Yarnitsky


Abstract

Background: There is an inter-personal variability in pain perception that becomes more powerful in neuropathy conditions. It is very difficult to predict who will develop pain based on our understanding of the etiology of the impairment, so it is essential to better understand the mechanisms responsible for the development of painful neuropathy. Recent evidence of an inhibitory influence of the vagus nerve on the central pain pathways may be relevant in cases of nervous system disorders, i.e polyneuropathy, where there might be a combination of sensory and vagal neuropathy. The purpose of this set of studies was to examine the relationship between the degree of induced change in vagal activity and the development of painful neuropathy in an animal model of polyneuropathy.

Methods: 141 rats were assigned to one of 5 experimental groups in order to create different degrees of vagal activity induced by: injection of Vincristine, a cytotoxic agent (30µg/kg/day- VCR 30 and 100µg/kg/day- VCR 100), sub-diaphragmatic vagotomy (SDV), sub-diaphragmatic vagotomy followed by Vincristine (30µg/kg/day) (SDV+VCR), and a no-treatment control (CTRL). Pain behavior using a wide range of behavioral tests were collected from rats in order to determine the degrees of hyperalgesia, allodynia and spontaneous pain. In addition, vagal activity measurements (employing a telemetry system) were collected from rats and was analyzed by using time and frequency analyses of R-R interval and SBP, with comparisons between experimental  groups (VCR 30 and VCR 100) and the CTRL group.

Results: Rats of the VCR+SDV group: (1) Tended to develop mechanical brush allodynia (2) Demonstrated greater incidence of  spontaneous pain behavior and (3) Increase in pain response to repeated non-painful mechanical stimuli - compared to VCR group (p=0.08; p=0.0036, p<0.01, respectively). This response developed in the first week of Vincristine in rats that underwent SDV+VCR (p<0.001) and only on the second week in rats injected with VCR alone (p<0.007). There was no difference in mechanical pain threshold and in heat pain response between these two groups. Time domain analysis of beat-to-beat heart rate variability, which measures the interval differences between successive R-R intervals, showed a decrease in the parameters representing a decrease in vagal activity in VCR 100 group.
Conclusions: Decrease in vagal activity (due to autonomic neuropathy in polyneuropathic disorders) contributes to the severity and the time-course of painful peripheral neuropathy, by heterosynaptic facilitation of central sensitization of second order neurons in the dorsal horn.