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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Siemian, Justin N; LaMacchia, Zach M; Spreuer, Vilma et al. (2018) The imidazoline I2 receptor agonist 2-BFI attenuates hypersensitivity and spinal neuroinflammation in a rat model of neuropathic pain. Biochem Pharmacol 153:260-268
Siemian, Justin N; Wang, Kaixuan; Zhang, Yanan et al. (2018) Mechanisms of imidazoline I2 receptor agonist-induced antinociception in rats: involvement of monoaminergic neurotransmission. Br J Pharmacol 175:1519-1534
Xue, Zhaoxia; Siemian, Justin N; Johnson, Bernard N et al. (2018) Methamphetamine-induced impulsivity during chronic methamphetamine treatment in rats: Effects of the TAAR 1 agonist RO5263397. Neuropharmacology 129:36-46
Xue, Zhaoxia; Siemian, Justin N; Zhu, Qing et al. (2018) Further pharmacological comparison of D-methamphetamine and L-methamphetamine in rats: abuse-related behavioral and physiological indices. Behav Pharmacol :
Liu, Jian-Feng; Seaman Jr, Robert; Siemian, Justin N et al. (2018) Role of trace amine-associated receptor 1 in nicotine's behavioral and neurochemical effects. Neuropsychopharmacology 43:2435-2444
Bernosky-Smith, Kimberly A; Qiu, Yan-Yan; Feja, Malte et al. (2018) Ventral tegmental area D2 receptor knockdown enhances choice impulsivity in a delay-discounting task in rats. Behav Brain Res 341:129-134
Siemian, Justin N; Shang, Li; Seaman Jr, Robert W et al. (2018) Effects of imidazoline I2 receptor agonists on reserpine-induced hyperalgesia and depressive-like behavior in rats. Behav Pharmacol :
Siemian, Justin N; Jia, Shushan; Liu, Jian-Feng et al. (2018) Neuroanatomical characterization of imidazoline I2 receptor agonist-induced antinociception. Eur J Neurosci 47:1087-1095
Siemian, Justin N; Xue, Zhaoxia; Blough, Bruce E et al. (2017) Comparison of some behavioral effects of d- and l-methamphetamine in adult male rats. Psychopharmacology (Berl) 234:2167-2176
Thorn, David A; Zhang, Yanan; Li, Jun-Xu (2017) Tolerance and cross-tolerance to the antinociceptive effects of oxycodone and the imidazoline I2 receptor agonist phenyzoline in adult male rats. Psychopharmacology (Berl) 234:1871-1880

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