Effects of Direct- and Indirect-acting Serotonin Receptor Agonists on the Antinociceptive and Discriminative Stimulus Effects of Morphine in Rhesus Monkeys

Overview

Journal Neuropsychopharmacology

Date 2011 Jan 7

PMID 21209613

Citations 11

Authors

Jun-Xu Li

Wouter Koek

Kenner C Rice

Charles P France

Affiliations

Soon will be listed here.

Abstract

Serotonergic (5-HT) systems modulate pain, and drugs acting on 5-HT systems are used with opioids to treat pain. This study examined the effects of 5-HT receptor agonists on the antinociceptive and discriminative stimulus effects of morphine in monkeys. Morphine increased tail-withdrawal latency in a dose-related manner; 5-HT receptor agonists alone increased tail-withdrawal latency at 50 °C but not 55 °C water. The antinociceptive effects of morphine occurred with smaller doses when monkeys received an indirect-acting (fenfluramine) or direct acting (8-OH-DPAT, F13714, buspirone, quipazine, DOM, and 2C-T-7) agonist. The role of 5-HT receptor subtypes in these interactions was confirmed with selective 5-HT(1A) (WAY100635) and 5-HT(2A) (MDL100907) receptor antagonists. None of the 5-HT drugs had morphine-like discriminative stimulus effects; however, fenfluramine and 5-HT(2A) receptor agonists attenuated the discriminative stimulus effects of morphine and this attenuation was prevented by MDL100907. The 5-HT(1A) receptor agonists did not alter the discriminative stimulus effects of morphine. Thus, 5-HT receptor agonists increase the potency of morphine in an assay of antinociception, even under conditions where 5-HT agonists are themselves without effect (ie, 55 °C water), without increasing (and in some cases decreasing) the potency of morphine in a drug discrimination assay. Whereas 5-HT(2A) receptor agonists increase the potency of morphine for antinociception at doses that have no effect on the rate of operant responding, 5-HT(1A) receptor agonists increase the potency of morphine only at doses that eliminate operant responding. These data suggest that drugs acting selectively on 5-HT receptor subtypes could help to improve the use of opioids for treating pain.

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References

Li J, Koek W, Rice K, France C . 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. 2010; 333(1):244-52. PMC: 2846017. DOI: 10.1124/jpet.109.163451. View

Higgins G, Wang Y, Sellers E . Preliminary findings with the indirect 5-HT agonist dexfenfluramine on heroin discrimination and self-administration in rats. Pharmacol Biochem Behav. 1993; 45(4):963-6. DOI: 10.1016/0091-3057(93)90148-m. View

Larson A, TAKEMORI A . Effect of fluoxetine hydrochloride (Lilly 110140), a specific inhibitor of serotonin uptake, on morphine analgesia and the development of tolerance. Life Sci. 1977; 21(12):1807-11. DOI: 10.1016/0024-3205(77)90162-x. View

Banks M, Rice K, Negus S . Antinociceptive interactions between Mu-opioid receptor agonists and the serotonin uptake inhibitor clomipramine in rhesus monkeys: role of Mu agonist efficacy. J Pharmacol Exp Ther. 2010; 335(2):497-505. PMC: 2967402. DOI: 10.1124/jpet.110.169276. View

Manchikanti L . National drug control policy and prescription drug abuse: facts and fallacies. Pain Physician. 2007; 10(3):399-424. View

Coda B, Hill H, Schaffer R, Luger T, Jacobson R, Chapman R . Enhancement of morphine analgesia by fenfluramine in subjects receiving tailored opioid infusions. Pain. 1993; 52(1):85-91. DOI: 10.1016/0304-3959(93)90118-9. View

CRISP T, Stafinsky J, Spanos L, Uram M, Perni V, Donepudi H . Analgesic effects of serotonin and receptor-selective serotonin agonists in the rat spinal cord. Gen Pharmacol. 1991; 22(2):247-51. DOI: 10.1016/0306-3623(91)90441-8. View

Ullrich T, Rice K . A practical synthesis of the serotonin 5-HT2A receptor antagonist MDL 100907, its enantiomer and their 3-phenolic derivatives as precursors for [11C]labeled PET ligands. Bioorg Med Chem. 2000; 8(10):2427-32. DOI: 10.1016/s0968-0896(00)00175-9. View

Li J, McMahon L, Gerak L, Becker G, France C . Interactions between Delta(9)-tetrahydrocannabinol and mu opioid receptor agonists in rhesus monkeys: discrimination and antinociception. Psychopharmacology (Berl). 2008; 199(2):199-208. PMC: 3480084. DOI: 10.1007/s00213-008-1157-0. View

10.

Miranda H, Puig M, Dursteler C, Prieto J, Pinardi G . Dexketoprofen-induced antinociception in animal models of acute pain: synergy with morphine and paracetamol. Neuropharmacology. 2006; 52(2):291-6. DOI: 10.1016/j.neuropharm.2006.07.025. View

11.

Xu W, Qiu X, Han J . Serotonin receptor subtypes in spinal antinociception in the rat. J Pharmacol Exp Ther. 1994; 269(3):1182-9. View

12.

Malmberg A, Yaksh T . Pharmacology of the spinal action of ketorolac, morphine, ST-91, U50488H, and L-PIA on the formalin test and an isobolographic analysis of the NSAID interaction. Anesthesiology. 1993; 79(2):270-81. DOI: 10.1097/00000542-199308000-00012. View

13.

Millan M, Colpaert F . 5-hydroxytryptamine (HT)1A receptors and the tail-flick response. II. High efficacy 5-HT1A agonists attenuate morphine-induced antinociception in mice in a competitive-like manner. J Pharmacol Exp Ther. 1991; 256(3):983-92. View

14.

Hynes M, Lochner M, Bemis K, Hymson D . Fluoxetine, a selective inhibitor of serotonin uptake, potentiates morphine analgesia without altering its discriminative stimulus properties or affinity for opioid receptors. Life Sci. 1985; 36(24):2317-23. DOI: 10.1016/0024-3205(85)90321-2. View

15.

Li J, Becker G, Traynor J, Gong Z, France C . Thienorphine: receptor binding and behavioral effects in rhesus monkeys. J Pharmacol Exp Ther. 2007; 321(1):227-36. DOI: 10.1124/jpet.106.113290. View

16.

Schuster C, Johanson C . Relationship between the discriminative stimulus properties and subjective effects of drugs. Psychopharmacol Ser. 1988; 4:161-75. DOI: 10.1007/978-3-642-73223-2_13. View

17.

McCreary A, Filip M, Cunningham K . Discriminative stimulus properties of (+/-)-fenfluramine: the role of 5-HT2 receptor subtypes. Behav Neurosci. 2003; 117(2):212-21. DOI: 10.1037/0735-7044.117.2.212. View

18.

Gatch M, Negus S, Mello N . Antinociceptive effects of monoamine reuptake inhibitors administered alone or in combination with mu opioid agonists in rhesus monkeys. Psychopharmacology (Berl). 1998; 135(1):99-106. DOI: 10.1007/s002130050490. View

19.

Koek W, Vacher B, Cosi C, Assie M, Patoiseau J, Pauwels P . 5-HT1A receptor activation and antidepressant-like effects: F 13714 has high efficacy and marked antidepressant potential. Eur J Pharmacol. 2001; 420(2-3):103-12. DOI: 10.1016/s0014-2999(01)01011-1. View

20.

Fasmer O, Berge O, Post C, Hole K . Effects of the putative 5-HT1A receptor agonist 8-OH-2-(di-n-propylamino)tetralin on nociceptive sensitivity in mice. Pharmacol Biochem Behav. 1986; 25(4):883-8. DOI: 10.1016/0091-3057(86)90402-8. View