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.
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.
|Li, Jun-Xu (2015) Pain and depression comorbidity: a preclinical perspective. Behav Brain Res 276:92-8|
|Qiu, Yanyan; Thorn, David A; Zhang, Yanan et al. (2014) Behavioral effects of the imidazoline I(2) receptor ligand BU99006 in rats. Behav Pharmacol 25:130-6|
|Ding, Yuanyuan; Qiu, Yanyan; Jing, Li et al. (2014) Behavioral effects of the cannabinoid CB1 receptor allosteric modulator ORG27569 in rats. Pharmacol Res Perspect 2:e00069|
|Li, Yu-Ling; Liu, Qing; Gong, Qi et al. (2014) Brucine suppresses ethanol intake and preference in alcohol-preferring Fawn-Hooded rats. Acta Pharmacol Sin 35:853-61|
|Thorn, David A; Jing, Li; Qiu, Yanyan et al. (2014) Effects of the trace amine-associated receptor 1 agonist RO5263397 on abuse-related effects of cocaine in rats. Neuropsychopharmacology 39:2309-16|
|Kong, Wei-Lin; Min, Jia-Wei; Liu, Yuan-Lin et al. (2014) Role of TRPV1 in susceptibility to PTZ-induced seizure following repeated hyperthermia challenges in neonatal mice. Epilepsy Behav 31:276-80|
|Li, Jun-Xu; Thorn, David A; Qiu, Yanyan et al. (2014) Antihyperalgesic effects of imidazoline I(2) receptor ligands in rat models of inflammatory and neuropathic pain. Br J Pharmacol 171:1580-90|
|Li, Jun-Xu (2014) Trace amines and cocaine abuse. ACS Chem Neurosci 5:497-8|
|Thorn, David A; Zhang, Chaogui; Zhang, Yanan et al. (2014) The trace amine associated receptor 1 agonist RO5263397 attenuates the induction of cocaine behavioral sensitization in rats. Neurosci Lett 566:67-71|
|Qiu, Yanyan; He, Xiao-Hua; Zhang, Yanan et al. (2014) Discriminative stimulus effects of the novel imidazoline I? receptor ligand CR4056 in rats. Sci Rep 4:6605|
Showing the most recent 10 out of 15 publications