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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Oshinsky, Michael L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Virginia Commonwealth University
Schools of Medicine
United States
Zip Code
Bagdas, Deniz; Muldoon, Pretal P; AlSharari, Shakir et al. (2016) Expression and pharmacological modulation of visceral pain-induced conditioned place aversion in mice. Neuropharmacology 102:236-43
Freitas, Kelen; Carroll, F Ivy; Negus, S Stevens (2016) Comparison of effects produced by nicotine and the α4β2-selective agonist 5-I-A-85380 on intracranial self-stimulation in rats. Exp Clin Psychopharmacol 24:65-75
Leitl, Michael D; Negus, S Stevens (2016) Pharmacological modulation of neuropathic pain-related depression of behavior: effects of morphine, ketoprofen, bupropion and [INCREMENT]9-tetrahydrocannabinol on formalin-induced depression of intracranial self-stimulation in rats. Behav Pharmacol 27:364-76
Zhen, Juan; Antonio, Tamara; Jacob, Joanna C et al. (2016) Efficacy of Hybrid Tetrahydrobenzo[d]thiazole Based Aryl Piperazines D-264 and D-301 at D₂ and D₃ Receptors. Neurochem Res 41:328-39
Lazenka, Matthew F; Legakis, Luke P; Negus, S Stevens (2016) Opposing effects of dopamine D1- and D2-like agonists on intracranial self-stimulation in male rats. Exp Clin Psychopharmacol 24:193-205
Miller, Laurence L; Leitl, Michael D; Banks, Matthew L et al. (2015) Effects of the triple monoamine uptake inhibitor amitifadine on pain-related depression of behavior and mesolimbic dopamine release in rats. Pain 156:175-84
Altarifi, Ahmad A; Yuan, Yunyun; Zhang, Yan et al. (2015) Effects of the novel, selective and low-efficacy mu opioid receptor ligand NAQ on intracranial self-stimulation in rats. Psychopharmacology (Berl) 232:815-24
Altarifi, Ahmad A; Rice, Kenner C; Negus, S Stevens (2015) Effects of μ-opioid receptor agonists in assays of acute pain-stimulated and pain-depressed behavior in male rats: role of μ-agonist efficacy and noxious stimulus intensity. J Pharmacol Exp Ther 352:208-17
Lazenka, Matthew F; Tomarchio, Aaron J; Lichtman, Aron H et al. (2015) Role of Dopamine Type 1 Receptors and Dopamine- and cAMP-Regulated Phosphoprotein Mr 32 kDa in Δ9-Tetrahydrocannabinol-Mediated Induction of ΔFosB in the Mouse Forebrain. J Pharmacol Exp Ther 354:316-27
Altarifi, Ahmad A; Negus, S Stevens (2015) Differential tolerance to morphine antinociception in assays of pain-stimulated vs. pain-depressed behavior in rats. Eur J Pharmacol 748:76-82

Showing the most recent 10 out of 29 publications