Introduction: Chronic pain is the most common non-motor symptom in Parkinson’s disease (PD) and is undertreated in half of PD pain cases (1). Subthalamic nucleus deep brain stimulation (STN DBS) relieves PD pain temporarily. To optimize STN DBS, we have combined it with duloxetine and shown increased mechanical thresholds indicative of antinociception in the hemiparkinsonian 6-hydroxydopamine (6OHDA) lesion rat model (2). In this study, we advance from investigating STN DBS-duloxetine’s effects on nociception to quantifying its effects on pain-related behavior in the place escape/avoidance paradigm (PEAP).
Methods: Male seven-week-old Sprague-Dawley parkinsonian rats were treated with STN DBS, duloxetine, or STN DBS-duloxetine. Rats underwent PEAP testing before and after treatment in a chamber consisting of a bright and dark side that were both easily accessible. When rats spent time in the dark side, they were poked with a suprathreshold (60.0 g) von Frey filament on their left/parkinsonian neuropathy-affected hind paw; in the bright side, rats were poked on their right/non-parkinsonian hind paw. Because rats inherently prefer dark environments, time spent in the bright side represented pain-related escape/avoidance behavior. Percent changes were calculated for bright side times before and after treatment, and data was analyzed using one-way ANOVA.
Results: Percent decrease in bright side time was significantly greater after STN DBS-duloxetine than after STN DBS (p=0.031) and duloxetine alone (p=0.036). STN DBS-duloxetine decreased bright side time by 32.82 ± 7.62% (n=4), while STN DBS (4.17 ± 11.55%, n=4) and duloxetine (1.22 ± 10.61%, n=5) caused minimal percent bright time changes. Therefore, STN DBS-duloxetine reduced pain-related behavior significantly more than STN DBS and duloxetine alone.
Conclusions: Our project presents STN DBS-duloxetine as a new treatment for PD pain. Because escape/avoidance behavior has been associated with the anterior cingulate cortex (ACC) (3), STN DBS-duloxetine’s mechanism may involve altering ACC neuronal activity in the descending inhibitory pain pathway.
Patient Care: Our research will improve patient care by helping to advance STN DBS-duloxetine into the clinic as a new therapy for PD pain. Past reflexive withdrawal behavioral tests have shown that STN DBS-duloxetine increases mechanical thresholds and reduces nociception significantly more than STN DBS alone does (2); this project will better assess STN DBS-duloxetine’s efficacy by investigating its effects on pain-related behavior. Namely, our research serves as the transition from studying STN DBS-duloxetine’s effects on nociception, the sensory detection of noxious stimuli; to pain, the multifaceted experience that involves higher cognitive processes and emotions. By elucidating how STN DBS-duloxetine alters pain, our research serves as a crucial step in STN DBS-duloxetine’s translation from the lab to patients in the clinic. STN DBS-duloxetine would also be a particularly well-suited treatment for PD pain patients because it utilizes two therapies that are already commonly used in this population – STN DBS is an FDA-approved treatment for PD’s motor symptoms, and duloxetine is an antihyperalgesic that significantly reduces pain in PD patients. By combining STN DBS with duloxetine, we can improve patient care by expanding the applications of STN DBS to also reducing PD pain, which affects 83% of PD patients and is undertreated in half of cases due to a current lack of effective therapies (1). Our research will also provide more insight into developing more PD pain treatments. The escape/avoidance behavior studied in this project has also been associated with neuronal activity in the anterior cingulate cortex (ACC) of the descending inhibitory pain pathway (3). The descending inhibitory pain pathway may therefore serve as a promising target for future new neuromodulation therapies to better treat PD pain.
Learning Objectives: 1) Understand that chronic pain is a prevalent PD non-motor symptom that needs new effective therapies.
2) Describe, in small groups, how to quantify pain-related behavior using the PEAP test.
3) Identify STN DBS-duloxetine as a potential new effective treatment for PD pain.
References: (1) Beiske AG, Loge JH, Ronningen A, Svensson E. Pain in Parkinson's disease: Prevalence and characteristics. Pain. 2009;141(1-2):173-7. doi: 10.1016/j.pain.2008.12.004. PubMed PMID: 19100686.
(2) Kaszuba BC, Walling I, Gee LE, Shin DS, Pilitsis JG. Effects of subthalamic deep brain stimulation with duloxetine on mechanical and thermal thresholds in 6OHDA lesioned rats. Brain Res. 2017;1655:233-41. doi: 10.1016/j.brainres.2016.10.025. PubMed PMID: 27984022.
(3) Uhelski ML, Morris-Bobzean SA, Dennis TS, Perrotti LI, Fuchs PN. Evaluating underlying neuronal activity associated with escape/avoidance behavior in response to noxious stimulation in adult rats. Brain Res. 2012;1433:56-61. doi: 10.1016/j.brainres.2011.11.016. PubMed PMID: 22137659.