Modification of the behavioral effects of morphine in rats by serotonin (5-HT)1A and 5-HT2A receptor agonists: antinociception, drug discrimination, and locomotor activity

Abstract

Rationale Indirect-acting serotonin (5-HT) receptor agonists can enhance the antinociceptive effects of morphine; however, the specific 5-HT receptor subtype(s) mediating this enhancement is not established. Objective This study examined interactions between morphine and both 5-HT1A and 5-HT2A receptor agonists in rats using measures of antinociception (radiant heat tail flick and warm water tail withdrawal), drug discrimination (3.2 mg/kg morphine versus saline), and locomotion. Methods Male Sprague-Dawley rats (n=7–8 per group) were used to examine the effects of morphine alone and in combination with DOM (5-HT2A agonist) and 8-OH-DPAT (5-HT1A agonist). Results DOM did not modify antinociceptive or discriminative stimulus effects while modestly attenuating locomotor-stimulating effects of morphine; the effect of DOM (0.32 mg/kg) on morphine-induced locomotion was prevented by the 5-HT2A receptor selective antagonist MDL 100907. In contrast, 8-OH-DPAT (0.032–0.32 mg/kg) fully attenuated the antinociceptive effects (both procedures), did not modify the discriminative stimulus effects, and enhanced (0.32 mg/kg) the locomotor-stimulating effects of morphine. These effects of 8-OH-DPAT were prevented by the 5-HT1A receptor selective antagonist WAY100635. Conclusion Agonists acting at 5-HT1A or 5-HT2A receptors do not modify all effects of mu opioid receptor agonists in a similar manner. Moreover, interactions between 5-HT and opioid receptor agonists vary significantly between rats and nonhuman primates, underscoring the value of comparing drug interactions across a broad range of conditions and in multiple species.

The trace amine associated receptor 1 agonist RO5263397 attenuates the induction of cocaine behavioral sensitization in rats

“…When RO5263397 was studied in combination with cocaine, RO5263397 was injected immediately before the animals were put into the test chambers and a dose of cocaine (15 mg/kg) was administered 20 min (habituation period) later, which was followed by a 60 min test period. A separate experiment also examined the effect of RO5263397 on the dose-effect curve of cocaine by using a cumulative dosing procedure [9]. For this experiment, RO5263397 was administered immediately prior to the start of the test session and different doses of cocaine (cumulative doses of 3.2, 10, 32 mg/kg) were given at times 20 min, 40 min and 60 min.…”

“…The locomotor effects of each dose of cocaine were recorded for 20 min but for each dose the data from the first 5 min immediately after the drug injection were discarded because the rats always demonstrated a brief hyperactivity due to handling and injection. This procedure generates highly consistent and reliable dose response curves of drugs such as morphine, cocaine and methamphetamine [2, 9, 15]. …”

Associations of the 5‐hydroxytryptamine (serotonin) Receptor 1B gene (HTR1B) with alcohol, cocaine, and heroin abuse

“…Function of HTR3A was implicated in alcohol addiction (Shorter and Kosten 2011) and the association of the HTR1B gene variant was found with heroin dependence among Han Chinese (Gao and others 2011). Indirect-acting HTR receptor agonists can enhance the antinociceptive effects of morphine although the specific subtype(s) mediating this enhancement is not established (Li and others 2012). Many drugs target the serotonin system, including Vilazodone that was approved by the United States Food and Drug Administration (informally USFDA) in 2011 for depression (Bach and Arango 2012), Methoxectamine, a HTR2 agonist currently being explored as a fast-acting antidepressant, and Rotundine, currently used in China to treat cocaine addiction (Hagan and others 2012).…”

Generalization tests using different dosing routes from those of drug discrimination training in rats

“…In this study, the response rate in po morphine at 30 mg/kg tended to decrease. Morphine shows sufficient antinociceptive effects in a tail-flick test at 30 mg/kg by po (Okura et al, 2008), at 3 or 10 mg/kg by ip (Li et al, 2013;Unal et al, 2013) and by sc administration (He et al, 2009), suggesting that the plasma concentrations at these dose levels are comparable. However, ip morphine at 3 and 10 mg/kg decreases the response rates to approximately 80 and 50%, respectively, but not at 0.3 and 1 mg/kg (Morgan et al, 1999), and slight sedation is noted in some rats in our laboratory (data not shown).…”

“…The sc morphine generalized to the training dose of morphine at 3 mg/kg, and the po morphine generalized at 10-fold this dose level (30 mg/kg). In discrimination training, sc morphine at 3 mg/kg is a commonly used route and dose combination, as is ip administration at this dose (Nishida et al, 1989;Easterling and Holtzman, 1998;Li et al, 2013). This means that sc morphine at 3 mg/kg induces sufficient discrimination stimulus effects.…”