Contents lists available at ScienceDirect Brain Research journal homepage: www.elsevier.com/locate/brainres Research report Effects of subthalamic deep brain stimulation with duloxetine on mechanical and thermal thresholds in 6OHDA lesioned rats Brian C. Kaszuba a , Ian Walling a , Lucy E. Gee a,b , Damian S. Shin a , Julie G. Pilitsis a,b, ⁎ a Department of Neuroscience & Experimental Therapeutics, Albany Medical College, Albany, NY, United States b Department of Neurosurgery, Albany Medical Center, Albany, NY, United States ARTICLE INFO Keywords: Subthalamic deep brain stimulation Parkinson's disease Mechanical allodynia Thermal hyperalgesia Hot plate test Von Frey test Randall-Selitto test Duloxetine ABSTRACT Chronic pain is the most common non-motor symptom of Parkinson's disease (PD) and is often overlooked. Unilateral 6-hydroxydopamine (6-OHDA) medial forebrain bundle lesioned rats used as models for PD exhibit decreased sensory thresholds in the left hindpaw. Subthalamic deep brain stimulation (STN DBS) increases mechanical thresholds and offers improvements with chronic pain in PD patients. However, individual responses to STN high frequency stimulation (HFS) in parkinsonian rats vary with 58% showing over 100% improvement, 25% showing 30–55% improvement, and 17% showing no improvement. Here we augment STN DBS by supplementing with a serotonin-norepinephrine reuptake inhibitor commonly prescribed for pain, duloxetine. Duloxetine was administered intraperitoneally (30 mg/kg) in 15 parkinsonian rats unilaterally implanted with STN stimulating electrodes in the lesioned right hemisphere. Sensory thresholds were tested using von Frey, Randall-Selitto and hot-plate tests with or without duloxetine, and stimulation to the STN at HFS (150 Hz), low frequency (LFS, 50 Hz), or off stimulation. With HFS or LFS alone (left paw; p=0.016; p=0.024, respectively), animals exhibited a higher mechanical thresholds stable in the three days of testing, but not with duloxetine alone (left paw; p=0.183). Interestingly, the combination of duloxetine and HFS produced significantly higher mechanical thresholds than duloxetine alone (left paw, p=0.002), HFS alone (left paw, p=0.028), or baseline levels (left paw; p < 0.001). These findings show that duloxetine paired with STN HFS increases mechanical thresholds in 6-OHDA-lesioned animals more than either treatment alone. It is possible that duloxetine augments STN DBS with a central and peripheral additive effect, though a synergistic mechanism has not been excluded. 1. Introduction Chronic pain is the most common non-motor symptom in Parkinson's disease (PD) (Beiske et al., 2009). Pain can be nociceptive or neuropathic (Truini et al., 2013). Nociceptive pain is most frequent (40–90%) and is typically musculoskeletal and visceral (Wasner and Deuschl, 2012). Significantly lower mechanical, thermal, and chemical thresholds compared to healthy controls have been shown in PD patients (Fil et al., 2013) and animal models of PD (Lin et al., 1981; Saade et al., 1997; Chudler and Lu, 2008; Marques et al., 2013; Zengin- Toktas et al., 2013; Park et al., 2015). Chronic pain is a significant problem leading to PD patients seeking various medical treatments and surgeries that may turn out to be ineffective and unnecessary. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been found to decrease pain in PD patients (Kim et al., 2008; Zahodne et al., 2009). Specifically, STN DBS has shown to improve pre-operative PD-related pain for up to eight years; however, 18 of 24 (75%) patients developed new pain symptoms over this time period (Jung et al., 2015). We have previously demonstrated both 150 and 50 Hz STN DBS improve mechanical thresholds in 6-hydroxydopamine (6OHDA) le- sioned rats (Gee et al., 2015). The response showed overall improve- ment, with 7 of 12 animals improving over 100% at 150 Hz, 7 of 12 improving over 100% on 50 Hz, and 5 of the 12 animals improving over 100% on both settings compared to baseline Von Frey (VF) mechanical thresholds. Four animals were non-responders, without increased thresholds on either setting, showing that individual rats may respond differently and that there is potential for improving DBS therapy (Gee et al., 2015). Current findings have not fully demonstrated the mechanism of action and ability to consistently provide benefit. In order to augment the effect of DBS on mechanical and thermal thresholds, this study evaluates the effects of administering STN DBS in combination with duloxetine, a non-narcotic pain medication commonly used in clinical settings. Duloxetine is a serotonin norepi- nephrine reuptake inhibitor (SNRI) commonly administered for anti- http://dx.doi.org/10.1016/j.brainres.2016.10.025 Received 29 April 2016; Received in revised form 24 October 2016; Accepted 27 October 2016 ⁎ Correspondence to: AMC Neurosurgery Group, 47 New Scotland Ave, MC 10. Physicians Pavilion, 1st Floor, Albany, NY 12208, United States. E-mail address: jpilitsis@yahoo.com (J.G. Pilitsis). Brain Research 1655 (2017) 233–241 Available online 29 October 2016 0006-8993/ © 2016 Elsevier B.V. All rights reserved. MARK