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.
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.
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|Legakis, Luke P; Bigbee, John W; Negus, S Stevens (2018) Lack of paclitaxel effects on intracranial self-stimulation in male and female rats: comparison to mechanical sensitivity. Behav Pharmacol 29:290-298|
|Negus, S Stevens; Moerke, Megan J (2018) Determinants of opioid abuse potential: Insights using intracranial self-stimulation. Peptides 112:23-31|
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|Legakis, L P; Negus, S S (2018) Repeated Morphine Produces Sensitization to Reward and Tolerance to Antiallodynia in Male and Female Rats with Chemotherapy-Induced Neuropathy. J Pharmacol Exp Ther 365:9-19|
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|Altarifi, Ahmad A; David, Bethany; Muchhala, Karan H et al. (2017) Effects of acute and repeated treatment with the biased mu opioid receptor agonist TRV130 (oliceridine) on measures of antinociception, gastrointestinal function, and abuse liability in rodents. J Psychopharmacol 31:730-739|
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