Overall, mixtures of kappa and mu opioids might have therapeutic potential for treating pain, particularly when the mixture has a greater ratio of mu to kappa agonist. If adverse effects of each constituent drug are reduced or avoided, then kappa:mu mixtures might be advantageous to mu opioids alone.

Intravenous (i.v.) drug self-administration remains the "gold standard" for assessing abuse potential of drugs. Failure of a drug to maintain self-administration might indicate merely the absence of positive reinforcing effects but might also indicate presence of aversive effects. Sensitivity to aversive effects is thought to affect the initiation and maintenance of drug use as well as relapse. Choice procedures are used to study positive reinforcing effects of drugs and to a much lesser extent to study punishing effects of drugs. Experiment 1 compared the mu opioid receptor agonist remifentanil (0.001-0.01 mg/kg/infusion), the kappa receptor agonist spiradoline (0.0056-0.056 mg/kg/infusion), and histamine (1.0 mg/kg/infusion) in rats choosing between a food pellet only and an intravenous (i.v.) infusion + a food pellet. To test whether a history with one punishing drug affects the punishing effects of a second drug, Experiment 2 compared sensitivity to spiradoline in rats with and without a history of histamine punishment. All rats predominantly chose a pellet alone when histamine + a pellet was the alternative, and they predominantly chose remifentanil + a pellet over a pellet alone. In Experiment 2, spiradoline was punishing in rats with a history of histamine punishment but not drug-naïve rats. This food choice procedure is sensitive to reinforcing and punishing effects of different drugs in the same subjects, suggesting that the procedure is well-suited for studying drug mixtures (e.g., mu and kappa agonists) and the impact of different physiological conditions (e.g., pain) on reinforcement and punishment.

Prescription opioids (mu receptor agonists) are commonly used to treat moderate to severe pain despite well‐documented adverse effects (e.g., constipation, abuse). Kappa opioid receptor agonists also have antinociceptive and adverse effects but might be useful for treating pain in drug mixtures. The use of smaller doses in mixtures might reduce or avoid adverse effects that occur with larger doses of either drug given alone. This study evaluated the kappa opioid receptor agonist spiradoline, the mu opioid receptor agonist morphine, and spiradoline:morphine mixtures (in 3:1, 1:1, 1:3, and 1:10 ratios) for their effects on antinociception and gastrointestinal (GI) motility to test the hypothesis that mixtures selectively enhance antinociceptive effects. Tail withdrawal latency from 50°C water was used to assay antinociception in one group of 8 male Sprague Dawley rats, and fecal output (count) was used to assay GI motility in another group of 8 male Sprague Dawley rats. Drugs were given i.p., with tests separated by at least 5 days. Spiradoline (3.2–32 mg/kg) and morphine (1.78–17.8 mg/kg) dose‐dependently increased tail withdrawal latency to a maximum of 20 sec; morphine (1–10 mg/kg) dose‐dependently decreased fecal count from 12 to less than 2 pellets. Spiradoline:morphine in 3:1 and 1:1 ratios had additive antinociceptive effects. The potency of morphine for antinociceptive effects was increased by spiradoline:morphine in 1:3 and 1:10 ratios (greater than predicted additivity). Conversely, in no instances was the potency of morphine increased for effects on GI motility. The potency of morphine to inhibit GI motility was either unchanged (e.g., 1:10) or decreased (e.g., 3:1) by spiradoline:morphine mixtures. Overall, spiradoline:morphine mixtures selectively reduce the dose of morphine needed to produce antinociceptive (therapeutic) effects. It remains to be determined whether spiradoline:morphine mixtures have other adverse effects (abuse, respiratory depression, and dysphoria) and whether interactions between spiradoline and morphine on these outcomes might be related to the ratio of each drug in mixtures.Support or Funding InformationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.