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 (2014) Impact of efficacy at the ?-opioid receptor on antinociceptive effects of combinations of ?-opioid receptor agonists and cannabinoid receptor agonists. J Pharmacol Exp Ther 351:383-9|
|Li, Jun-Xu; Shah, Aparna P; Patel, Sunny K et al. (2013) Modification of the behavioral effects of morphine in rats by serotonin 5-HT?A and 5-HT?A receptor agonists: antinociception, drug discrimination, and locomotor activity. Psychopharmacology (Berl) 225:791-801|
|Maguire, David R; Yang, Wenjuan; France, Charles P (2013) Interactions between *-opioid receptor agonists and cannabinoid receptor agonists in rhesus monkeys: antinociception, drug discrimination, and drug self-administration. J Pharmacol Exp Ther 345:354-62|
|Maguire, David R; Li, Jun-Xu; Koek, Wouter et al. (2013) Effects of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) and quipazine on heroin self-administration in rhesus monkeys. Psychopharmacology (Berl) 225:173-85|
|Maguire, David R; Gerak, Lisa R; France, Charles P (2013) Delay discounting of food and remifentanil in rhesus monkeys. Psychopharmacology (Berl) 229:323-30|
|Matsumoto, Rae R; Li, Su-Min; Katz, Jonathan L et al. (2011) Effects of the selective sigma receptor ligand, 1-(2-phenethyl)piperidine oxalate (AC927), on the behavioral and toxic effects of cocaine. Drug Alcohol Depend 118:40-7|
|Li, Jun-Xu; Koek, Wouter; Rice, Kenner C et al. (2011) Effects of direct- and indirect-acting serotonin receptor agonists on the antinociceptive and discriminative stimulus effects of morphine in rhesus monkeys. Neuropsychopharmacology 36:940-9|
|Panos, John J; Baker, Lisa E (2010) An in vivo microdialysis assessment of concurrent MDMA and cocaine administration in Sprague-Dawley rats. Psychopharmacology (Berl) 209:95-102|
|Li, Jun-Xu; Koek, Wouter; Rice, Kenner C et al. (2010) Differential effects of serotonin 5-HT1A receptor agonists on the discriminative stimulus effects of the 5-HT2A receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane in rats and rhesus monkeys. J Pharmacol Exp Ther 333:244-52|
|Gerak, Lisa R; Galici, Ruggero; France, Charles P (2009) Self administration of heroin and cocaine in morphine-dependent and morphine-withdrawn rhesus monkeys. Psychopharmacology (Berl) 204:403-11|
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