This is a new R01 application, submitted in response to RFA-DA-09-017, to study the neurobiology of pain, the neuropharmacology of analgesia, and the interactions between analgesic and abuse-related effects of opioids and other drugs in rats. Pain is a significant public health problem, and opioid analgesics constitute a principal class of drugs used to treat pain. However, the use of existing opioids is limited by side effects that include high abuse liability, and efforts to develop strong analgesics with reduced abuse liability have met with limited success. We and others have argued that improved progress in pain management and analgesic drug development may benefit from research on the neurobiology and neuropharmacology of the affective components of pain. This application is founded on the premises that (1) a cardinal and clinically significant sign of pain is depression of both behavior and mood, and (2) a key goal in pain treatment is a restoration of pain-depressed behaviors and an improvement in pain-depressed mood (i.e. affective analgesia). In this application, we propose to model pain-induced behavioral depression and affective analgesia using an assay of intracranial self-stimulation (ICSS) in rats. This procedure has been widely used to study modulation of motivated behavior and affect by drugs and other manipulations, and we submit that ICSS will also be useful as a tool for research on the neurobiology and treatment of affective components of pain. In support of this claim, we provide preliminary data to show that ICSS in rats is depressed by a commonly used noxious stimulus (IP injection of dilute acid), and that pain-induced depression of ICSS is blocked by the analgesic opioid morphine but exacerbated by the prodepressant kappa opioid agonist U69,593.
Four specific aims are proposed to extend these initial findings.
Specific Aim 1 will use systemically administered pharmacologic tools in a systematic evaluation of the role of opioid and monoamine neurotransmitter systems in pain- depressed ICSS and affective analgesia. We hypothesize a key role for opioid and monoaminergic systems in expression of pain-induced depression and affective analgesia.
Specific Aim 2 will evaluate effects of previous exposure to morphine alone, noxious stimuli alone, or noxious stimuli+opioid (i.e. analgesia) on opioid-induced facilitation of ICSS. We hypothesize that prior exposure to opioid analgesia will be less likely than prior exposure to opioid alone to enhance subsequent opioid facilitation of ICSS.
Specific Aim 3 will examine effects of chronic inflammatory and neuropathic pain manipulations on ICSS. We hypothesize that chronic pain will depress ICSS, and that morphine will produce greater facilitation of ICSS from a chronic-pain baseline of depressed ICSS than from non-pain or post-pain ICSS baselines.
Specific Aim 4 will test the hypothesis that pain-related depression of ICSS correlates with activation of the prodepressant CREB- Dynorphin pathway in nucleus accumbens. We predict that pain will stimulate CREB phosphorylation and dynorphin synthesis in nucleus accumbens, and that these pain effects will be blocked by affective analgesics.

Public Health Relevance

Both pain and drug abuse are significant public health problems, and mechanisms underlying pain and drug abuse may overlap and interact. This application is founded on the hypothesis that a focus on affective components of pain might provide an especially useful framework of behavioral data to guide complementary research on interactions between pain and drug abuse mechanisms. Studies are proposed to (1) examine behavioral interactions between pain and analgesic drugs in a behavioral assay commonly used to model motivation and affect in rats, and (2) assess neurochemical correlates of these interactions in the brain's principal reward pathway.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-H (50))
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Porter, Linda L
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Virginia Commonwealth University
Schools of Medicine
United States
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Negus, S Stevens (2018) Addressing the Opioid Crisis: The Importance of Choosing Translational Endpoints in Analgesic Drug Discovery. Trends Pharmacol Sci 39:327-330
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
Negus, S Stevens; Freeman, Kevin B (2018) Abuse Potential of Biased Mu Opioid Receptor Agonists. Trends Pharmacol Sci 39:916-919
Lazenka, Matthew L; Moerke, Megan J; Townsend, E Andrew et al. (2018) Dissociable effects of the kappa opioid receptor agonist nalfurafine on pain/itch-stimulated and pain/itch-depressed behaviors in male rats. Psychopharmacology (Berl) 235:203-213
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
Lazenka, Matthew F; Negus, S Stevens (2017) Oral modafinil facilitates intracranial self-stimulation in rats: comparison with methylphenidate. Behav Pharmacol 28:318-322
Lazenka, Matthew F; Freitas, Kelen C; Henck, Sydney et al. (2017) Relief of Pain-Depressed Behavior in Rats by Activation of D1-Like Dopamine Receptors. J Pharmacol Exp Ther 362:14-23
Schwienteck, Kathryn L; Li, Guanguan; Poe, Michael M et al. (2017) Abuse-related effects of subtype-selective GABAAreceptor positive allosteric modulators in an assay of intracranial self-stimulation in rats. Psychopharmacology (Berl) 234:2091-2101
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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