Although much progress has been made to treat pain, morphine and related opioids are still the most effective analgesics. However, their use is limited by concerns about abuse and the development of dependence during chronic administration. The utility and safety of morphine- like opioids may be improved by combining them with other drugs that increase analgesia through different (non-opioid) mechanisms. For example, combinations of opioids and drugs acting on serotonin (5-HT) systems (for example, SSRIs [fluoxetine]) are commonly used to treat pain. Also, combinations of opioids and 9-tetrahydrocannabinol (THC), which are used recreationally, might have advantages to treat pain. However, it is not clear if these drugs increase only the analgesic effects of opioids, or also their abuse- and dependence-related effects. Studies described in this revised application continue a history under this grant of examining opioids alone and with other drugs. In addition, they build on exciting preliminary findings that THC and drugs acting on 5-HT systems markedly increase the analgesic effects of morphine, but attenuate its discriminative stimulus effects. Drug discrimination and antinociception procedures will be used to characterize behavioral effects of morphine in combination with THC and other cannabinoid receptor agonists (Aim I) and in combination with drugs acting on 5-HT systems (Aim II). Receptor selective agonists and antagonists will help to examine which receptors mediate these interactions, and chronic dosing studies will investigate how these interactions are affected by chronic treatment. Studies under Aim III examine how THC and fluoxetine modify the reinforcing effects of heroin and the development of dependence on morphine. Collectively, these experiments examine interactions between morphine and cannabinoid or 5-HT drugs to determine whether their combination increases pain relief without increasing, and possibly decreasing, abuse and dependence.
Opioids are not effective for treating pain in many patients and their clinical use is limited by concerns about abuse and dependence. This grant examines interactions between morphine and serotonergic (e.g., fluoxetine) or cannabinoid (e.g., THC) drugs to determine whether the combination enhances their ability to alleviate pain without increasing, and possibly decreasing, their abuse and dependence.
|Maguire, David R; France, Charles P (2016) Effects of daily delta-9-tetrahydrocannabinol treatment on heroin self-administration in rhesus monkeys. Behav Pharmacol 27:249-57|
|Gerak, L R; France, C P (2016) Combined Treatment with Morphine and Î”9-Tetrahydrocannabinol in Rhesus Monkeys: Antinociceptive Tolerance and Withdrawal. J Pharmacol Exp Ther 357:357-66|
|Maguire, David R; Gerak, Lisa R; France, Charles P (2016) Effect of daily morphine administration and its discontinuation on delay discounting of food in rhesus monkeys. Behav Pharmacol 27:155-64|
|Maguire, David R; Gerak, Lisa R; France, Charles P (2016) Delay discounting of the Î¼-opioid receptor agonist remifentanil in rhesus monkeys. Behav Pharmacol 27:148-54|
|Maguire, David R; France, Charles P (2016) Interactions between cannabinoid receptor agonists and mu opioid receptor agonists in rhesus monkeys discriminating fentanyl. Eur J Pharmacol 784:199-206|
|Koek, Wouter; Gerak, Lisa R; France, Charles P (2015) Effects of amphetamine, morphine, and CP 55,â€‰940 on Go/No-Go task performance in rhesus monkeys. Behav Pharmacol 26:481-4|
|Gerak, L R; Zanettini, C; Koek, W et al. (2015) Cross-tolerance to cannabinoids in morphine-tolerant rhesus monkeys. Psychopharmacology (Berl) 232:3637-47|
|Maguire, David R; France, Charles P (2014) Impact of efficacy at the Î¼-opioid receptor on antinociceptive effects of combinations of Î¼-opioid receptor agonists and cannabinoid receptor agonists. J Pharmacol Exp Ther 351:383-9|
|Maguire, David R; Yang, Wenjuan; France, Charles P (2013) Interactions between Î¼-opioid receptor agonists and cannabinoid receptor agonists in rhesus monkeys: antinociception, drug discrimination, and drug self-administration. J Pharmacol Exp Ther 345:354-62|
|Li, Jun-Xu; Shah, Aparna P; Patel, Sunny K et al. (2013) Modification of the behavioral effects of morphine in rats by serotonin 5-HTâ‚A and 5-HTâ‚‚A receptor agonists: antinociception, drug discrimination, and locomotor activity. Psychopharmacology (Berl) 225:791-801|
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