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.
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.
|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|
|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|
|Kwilasz, Andrew J; Abdullah, Rehab A; Poklis, Justin L et al. (2014) Effects of the fatty acid amide hydrolase inhibitor URB597 on pain-stimulated and pain-depressed behavior in rats. Behav Pharmacol 25:119-29|
|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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