The objectives of this proposal are: (1) to examine novel brain regions in which deep brain stimulation (DBS) reverses mechanical allodynia in rats following spinal nerve ligation (SNL), and (2) to determine the brain regions in whic DBS produces rewarding and/or reinforcing effects in SNL rats using conditioned place preference or operant conditioning paradigms. In the search for novel targets for treatment of neuropathic pain, preclinical investigation using reflexive withdrawal from mechanical or thermal stimuli has produced few new therapies that have succeeded in the clinic. A variety of other behavioral endpoints have been proposed for investigation in laboratory animals with neuropathic pain, such as conditioned place preference and operant reinforcement with analgesics. The growing problem of prescription opioid abuse underscores the need to examine non-pharmacological strategies for treatment of neuropathic pain in addition to pharmacological approaches. Clinically, pain at rest has proven difficult to treat compared to elicited pain from external stimuli. Behaviors that are altered in rats following nerve injury othr than reflexive withdrawal from external stimuli include decreased exploratory behavior, increased anxiety-like behavior, conditioned place preference with analgesics, and analgesic self-administration. The proposed research will examine the effects of DBS on both elicited and non-elicited behaviors in rats with SNL using classical and novel behavioral endpoints. DBS has proven to be effective for treatment of neuropathic pain in humans to an extent, however improvement of this treatment modality has been hampered in part by the lack of preclinical studies in appropriate animal models that explore novel brain sites for potential clinical application. Preclinical studies of DBS have largely used acute pain models in rodents, however DBS is ineffective against acute pain states in humans. Therefore translation of the preclinical studies using DBS into the clinic has proven difficult. Preliminary data indicate that DBS maintains operant behavior in SNL rats only at stimulation parameters that reverse mechanical allodynia. The proposed studies will expand on these data and identify brain regions for which DBS reverses mechanical hypersensitivity in rats following nerve injury, and determine if DBS of these brain regions produces rewarding or reinforcing effects selectively in rats with neuropathic pain. Hopefully these studies will provide novel targets for clinical studies of DBS in patients with neuropathic pain, as well as provide a means for future studies that examine the mechanism of DBS-induced analgesia in laboratory animals.

Public Health Relevance

Chronic pain is a growing health problem that is costly both in loss of productivity and treatment expense. The use of large doses of opioids for chronic pain treatment is associated with an increase in prescription opioid abuse. Discovery of new therapies for chronic pain has been limited and there is a need for novel preclinical approaches. Non-pharmacological approaches that have been tried in the clinic include deep brain stimulation, however progress has been hampered by a lack of preclinical studies that identify novel target regions. This proposal seeks to identify novel brain sites in which deep brain stimulation reverses mechanical allodynia in rats with chronic pain and selectively produces reward or reinforcement in nerve-injured rats.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Chen, Daofen
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Wake Forest University Health Sciences
Schools of Medicine
United States
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Martin, Thomas J; Grigg, Amanda; Kim, Susy A et al. (2015) Assessment of attention threshold in rats by titration of visual cue duration during the five choice serial reaction time task. J Neurosci Methods 241:37-43
Ewan, Eric E; Martin, Thomas J (2013) Analgesics as reinforcers with chronic pain: Evidence from operant studies. Neurosci Lett 557 Pt A:60-4