Introduction: Chronic pain is the most-reported non-motor symptom of Parkinson’s Disease (PD) patients. Both clinical and preclinical trials have shown mechanical and thermal thresholds to be reduced with PD. The mechanisms of pain in PD are not fully understood, and patients seek relief through a range of therapies, including subthalamic deep brain stimulation (STN DBS) and pharmaceuticals such as gabapentin, NSAIDs, or duloxetine. We hypothesize that combing STN DBS with administration of duloxetine in a unilateral 6-hydroxydopamine (6OHDA) lesion model will improve thresholds.
Methods: Male Sprague-Dawley rats underwent craniotomy for simultaneous right 6OHDA medial forebrain bundle lesion and right STN electrode implantation. Parkinsonian phenotype was determined using 80% limb use asymmetry via a limb asymmetry test (LAT). Mechanical and thermal threshold testing was performed using vonFrey filaments (VF) and randall-selitto (RS) and hot plate (HPT), respectively. Animals underwent nine days of testing, alternating VF and RS with HPT. Testing was performed each day with animals receiving no stimulation, 150Hz stimulation, and 50Hz stimulation in a randomized order. After behavioral testing, rats were perfused with paraformaldehyde and the brains extracted for electrode placement verification and immunohistochemical evaluation of unilateral dopamine depletion.
Results: Significant improvement in time on the hot plate occurred between baseline and on-Duloxetine testing (p=0.0257). STN DBS alone showed significant improvement in VF thresholds at 150Hz stimulation on all testing days (pDay1=0.0265, pDay2=0.0002, pDay3=0.0220). STN DBS with Duloxetine presented significant improvement in mechanical thresholds versus both duloxetine (p=0.0069) and STN DBS (p=0.0189) by themselves; VF thresholds nearly doubled from STN DBS alone.
Conclusions: Duloxetine and 150Hz STN DBS combined produced larger increases in VF threshold tests than either intervention alone. Duloxetine and STN DBS have a potentially additive effect in modulating mechanical sensitivity in 6OHDA-lesioned rats.
Patient Care: This study could potentially lead to the development of improved treatments of pain in Parkinson's Disease via combining pharmaceuticals with deep brain stimulation therapies to obtain results neither could separately. This could allow for lower doses of drug or reduced current levels in stimulation, lessening the likelihood of side-effects.
Learning Objectives: By the conclusion of this session, participants should be able to:
1) Appreciate that mechanical and thermal thresholds can be modulated by STN DBS and/or duloxetine in 6-OHDA lesioned rats.
2) Describe the maximal benefit that can be achieved in 6-OHDA lesioned rats using combination therapies.
References:  Gee L.E., Chen N., Ramirez-Zamora A., Shin D.S., Pilitsis J.G. (2015) The effects of subthalamic deep brain stimulation on mechanical and thermal thresholds in 6OHDA lesioned rats. Euro J Neurosci., 1460-9568.
 Djaldetti R, Yust-Katz S, Kolianov V, Melamed E, Dabby R (2007) The effect of duloxetine on primary pain symptoms in Parkinson disease. Clin Neuropharmacol. 30(4):201-5.
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