This is a competing renewal application to continue our preclinical research on expression, neurobiology and treatment of pain-related behavioral depression. Pain is a significant clinical challenge that is often associated with clinically relevnt depression of behavior and mood. Moreover, relief of pain-related depression is a common goal of treatment in both human and veterinary medicine. Our research is founded on the proposition that research on pain-related depression could provide new basic-science insights on mechanisms that mediate affective dimensions of pain and new strategies for pain treatment. Our data so far suggest a role for dysregulated mesocorticolimbic dopamine (DA) signaling in nucleus accumbens (NAc) and prefrontal cortex (PFC) as a mediator of pain-depressed behavior, and studies proposed in this application would pursue hypotheses related to this mechanism. Specifically, during the current project period, we developed and validated a new behavioral assay of acute and chronic pain-depressed behavior in rats. We then used this procedure to achieve the following research goals: (1) evaluation of >40 drugs from multiple drug classes to confirm that our procedure is both sensitive to known analgesics and selective for analgesics vs. non- analgesics;(2) correlation of pain-related depression of behavior and pain-related depression of DA release in NAc;and (3) discovery that pain states also increase PFC expression of brain-derived neurotrophic factor, a protein implicated in depression consequent to non-pain stressors. In this competing renewal application, we propose to extend on this work in a series of three specific aims.
Aim 1 will test the hypothesis that DA agonists wil compensate for pain effects and produce analgesia in behavioral assays of pain- depressed behavior. We propose to evaluate analgesic effects of D1, D2 and D3 DA receptor agonists in assays of acute and chronic pain-depressed behavior. Our hypothesis predicts that agonists at one or more DA receptor subtype will be effective. Effects of indirect DA agonists will also be examined for comparison.
Aim 2 will test the hypothesis that pain states modulate downstream mediators of DA signaling in NAc and PFC. We propose to assess pain effects on PFC DA release to complement our microdialysis studies in NAc. In addition, we propose to test consequences of pain-altered DA release by evaluating (a) density of the DA transporter and of D1, D2 and D3 receptors, and (b) expression of two complementary and physiologically relevant indicators of DA tone ( FosB and phosphorylation of protein kinase B). We predict compensatory changes in response to pain-related decreases in DA.
Aim 3 will test the hypothesis that pain states will also modulate signaling mediated by BDNF in NAc and PFC. Increased expression of BDNF within the mesocorticolimbic system has been implicated in the development of depressive behavior. We predict that pain states will augment BDNF signaling, and that direct overexpression or knockdown of BDNF signaling within this system with viral vectors will modulate expression of pain-depressed behavior.

Public Health Relevance

This is a competing renewal application to continue our preclinical research on expression, neurobiology and treatment of pain-related behavioral depression. Based on progress during the current funding period, we propose now to focus on the mesocorticolimbic dopamine system as a key mediator of acute and chronic pain- related depression. Behavioral, microdialysis, and neurochemical studies will assess both pain-related changes in the mescorticolimbic dopamine system and potential analgesic effects of treatments that target this system.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01NS070715-06
Application #
8786356
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Oshinsky, Michael L
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
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Leitl, Michael D; Potter, David N; Cheng, Kejun et al. (2014) Sustained pain-related depression of behavior: effects of intraplantar formalin and complete freund's adjuvant on intracranial self-stimulation (ICSS) and endogenous kappa opioid biomarkers in rats. Mol Pain 10:62
Leitl, Michael D; Onvani, Sara; Bowers, M Scott et al. (2014) Pain-related depression of the mesolimbic dopamine system in rats: expression, blockade by analgesics, and role of endogenous *-opioids. Neuropsychopharmacology 39:614-24
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Hillhouse, Todd M; Porter, Joseph H; Negus, S Stevens (2014) Reply to: Rapid antidepressant effects and abuse liability of ketamine. Psychopharmacology (Berl) 231:2043-4
Hillhouse, Todd M; Porter, Joseph H; Negus, S Stevens (2014) Comparison of antidepressant-like and abuse-related effects of phencyclidine in rats. Drug Dev Res 75:479-88
Hillhouse, Todd M; Porter, Joseph H; Negus, S Stevens (2014) Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 on intracranial self-stimulation in rats. Psychopharmacology (Berl) 231:2705-16
Negus, S Stevens; Miller, Laurence L (2014) Intracranial self-stimulation to evaluate abuse potential of drugs. Pharmacol Rev 66:869-917
Rosenberg, Marisa B; Carroll, F Ivy; Negus, S Stevens (2013) Effects of monoamine reuptake inhibitors in assays of acute pain-stimulated and pain-depressed behavior in rats. J Pain 14:246-59
Altarifi, Ahmad A; Rice, Kenner C; Negus, S Stevens (2013) Abuse-related effects of ýý-opioid analgesics in an assay of intracranial self-stimulation in rats: modulation by chronic morphine exposure. Behav Pharmacol 24:459-70

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