Chronic pain is a global health care challenge and is poorly controlled by existing therapeutic strategies. This medical reality urges the development of safer and more effective analgesics. One approach is to identify novel analgesic targets. Our recent studies have suggested imidazoline I2 receptors as a novel drug target for acute nociception, although its role in chronic pain is less clear. As the etiology of many chronic pain conditions is multifaceted, combination therapy may be particularly effective against chronic pain by integrating multiple analgesic mechanisms of action. Although opioids are the most effective analgesics, their use is limited by concerns about abuse and the development of tolerance and dependence during chronic administration. Thus, combining opioids with other analgesics such as I2 receptor agonists may achieve better analgesic effects while decreasing some adverse effects of opioids. Building on exciting preliminary findings, studies described in this application will examine the antinociceptive and unwanted (tolerance and abuse liability) effects of I2 receptor agonists and test the feasibility of combining morphine and I2 receptor agonists against chronic pain. Mechanical and thermal hyperalgesia measures will be used to characterize the antinociceptive effects of I2 receptor agonists and morphine, alone or in combination, in models of complete Freund's adjuvant-induced inflammatory pain and chronic constriction injury-induced neuropathic pain (Aim I). Repeated treatment with I2 receptor agonists alone or combined with morphine will be performed to investigate the development of antinociceptive tolerance using the same procedures (Aim II). An intravenous self-administration procedure will be used to assess the reinforcing effects of I2 receptor agonists alone and how I2 receptor agonists modify the reinforcing effects of morphine (Aim III). Collectively, these experiments address two related and highly significant questions: (1) Do I2 receptor agonists represent a novel class of effective and safe analgesics for chronic pain and (2) Does the combination of I2 receptor agonists with morphine increase pain relief without increasing, or possibly decreasing, the abuse liability and development of tolerance.

Public Health Relevance

Chronic pain affects millions of people and existing analgesics are only effective in a fraction of the pain patients. This grant evaluates the effectiveness of imidazoline I2 receptors agonists and examines the feasibility of combining I2 receptor agonists and morphine for pain relief. The proposed research will validate I2 receptors as a novel drug target for the development of effective and safe analgesics against chronic pain.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Rapaka, Rao
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State University of New York at Buffalo
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United States
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Thorn, David A; Li, Jiuzhou; Qiu, Yanyan et al. (2016) Agmatine attenuates the discriminative stimulus and hyperthermic effects of methamphetamine in male rats. Behav Pharmacol 27:542-8
Siemian, Justin N; Li, Jiuzhou; Zhang, Yanan et al. (2016) Interactions between imidazoline I2 receptor ligands and acetaminophen in adult male rats: antinociception and schedule-controlled responding. Psychopharmacology (Berl) 233:873-82
Thorn, David A; Qiu, Yanyan; Jia, Shushan et al. (2016) Antinociceptive effects of imidazoline I2 receptor agonists in the formalin test in rats. Behav Pharmacol 27:377-83
Liu, Jian-Feng; Thorn, David A; Zhang, Yanan et al. (2016) Effects of Trace Amine-associated Receptor 1 Agonists on the Expression, Reconsolidation, and Extinction of Cocaine Reward Memory. Int J Neuropsychopharmacol 19:
Grandy, David K; Miller, Gregory M; Li, Jun-Xu (2016) ""TAARgeting Addiction""--The Alamo Bears Witness to Another Revolution: An Overview of the Plenary Symposium of the 2015 Behavior, Biology and Chemistry Conference. Drug Alcohol Depend 159:9-16
Thorn, David A; Zhang, Yanan; Li, Jun-Xu (2016) Effects of the imidazoline I2 receptor agonist 2-BFI on the development of tolerance to and behavioural/physical dependence on morphine in rats. Br J Pharmacol 173:1363-72
Siemian, Justin N; Obeng, Samuel; Zhang, Yan et al. (2016) Antinociceptive Interactions between the Imidazoline I2 Receptor Agonist 2-BFI and Opioids in Rats: Role of Efficacy at the μ-Opioid Receptor. J Pharmacol Exp Ther 357:509-19
Li, Jun-Xu (2016) Buprenorphine analogue BU08028 is one step closer to the Holy Grail of opioid research. Proc Natl Acad Sci U S A 113:10225-7
Qiu, Yanyan; Zhang, Yanan; Li, Jun-Xu (2015) Discriminative stimulus effects of the imidazoline I2 receptor ligands BU224 and phenyzoline in rats. Eur J Pharmacol 749:133-41
Jing, Li; Li, Jun-Xu (2015) Trace amine-associated receptor 1: A promising target for the treatment of psychostimulant addiction. Eur J Pharmacol 761:345-52

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