Skip to main content

Advertisement

SpringerLink
Log in

Cross-tolerance to cannabinoids in morphine-tolerant rhesus monkeys

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Opioids remain the drugs of choice for treating moderate to severe pain, although adverse effects limit their use. Therapeutic utility might be improved by combining opioids with other drugs to enhance analgesic effects, but only if adverse effects are not similarly changed.

Objective

Cannabinoids have been shown to enhance the antinociceptive potency of opioids without increasing other effects; this study examined whether the effectiveness of cannabinoids is altered in morphine-dependent monkeys.

Methods

Four monkeys received up to 10 mg/kg morphine twice daily. Changes in the antinociceptive effects of opioid receptor agonists (morphine, U50,488) and cannabinoid receptor agonists (WIN 55,212, CP 55,940, and Δ9-tetrahydrocannabinol [THC]) were determined by measuring the latency for monkeys to remove their tails from 40, 50, 54, and 58 °C water.

Results

Before treatment, all drugs increased tail withdrawal latency from warm (54 °C) water. Chronic morphine treatment decreased the potency of each drug; the magnitude of rightward shift in dose-effect curves was greatest for morphine, WIN 55,212 and CP 55,940 with at least sixfold shifts for each drug during treatment. Discontinuation of morphine treatment resulted in signs that are indicative of withdrawal, including increased heart rate, decreased daytime activity, and tongue movement.

Conclusion

Tolerance developed to the antinociceptive effects of morphine and cross-tolerance developed to cannabinoids under conditions that produced modest physical dependence. Compared with the doses examined in this study, much smaller doses of opioids have antinociceptive effects when given with cannabinoids; it is possible that tolerance will not develop to chronic treatment with opioid/cannabinoid mixtures.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL (2011) Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther 90:844–851

    Article  CAS  PubMed  Google Scholar 

  • Basilico L, Parolaro D, Colleoni M, Costa B, Giagnoni G (1999) Cross-tolerance and convergent dependence between morphine and cannabimimetic agent WIN 55,212-2 in guinea-pig ileum myenteric plexus. Eur J Pharmacol 376:265–271

    Article  CAS  PubMed  Google Scholar 

  • Becker GL, Gerak LR, Koek W, France CP (2008) Antagonist-precipitated and discontinuation-induced withdrawal in morphine-dependent rhesus monkeys. Psychopharmacology 201:373–382

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cichewicz DL (2004) Synergistic interactions between cannabinoid and opioid analgesics. Life Sci 74:1317–1324

    Article  CAS  PubMed  Google Scholar 

  • Cichewicz DL, Welch SP (2003) Modulation of oral morphine antinociceptive tolerance and naloxone-precipitated withdrawal signs by oral Δ9-tetrahydrocannabinol. J Pharmacol Exp Ther 305:812–817

    Article  CAS  PubMed  Google Scholar 

  • Cox ML, Haller VL, Welch SP (2007) Synergy between Δ9-tetrahydrocannabinol and morphine in the arthritic rat. Eur J Pharmacol 567:125–130

    Article  CAS  PubMed  Google Scholar 

  • Fischer BD, Ward SJ, Henry FE, Dykstra LA (2010) Attenuation of morphine antinociceptive tolerance by a CB1 receptor agonist and an NMDA receptor antagonist: interactive effects. Neuropharmacology 58:554–550

    Article  Google Scholar 

  • Gold LH, Balster RL, Barrett RL, Britt DT, Martin BR (1992) A comparison of the discriminative stimulus properties of Δ9-tetrahydrocannabinol and CP 55,940 in rats and rhesus monkeys. J Pharmacol Exp Ther 262:479–486

    CAS  PubMed  Google Scholar 

  • Gossop M, Bradley B (1984) Insomnia among addicts during supervised withdrawal from opiates: a comparison of oral methadone and electrostimulation. Drug Alcohol Depend 13:191–198

    Article  CAS  PubMed  Google Scholar 

  • Institute of Medicine (2011) Relieving pain in America: a blueprint for transforming prevention, care, education, and research. The National Academies Press, Washington, DC

    Google Scholar 

  • Kao C-W, Wu S-C, Lin K-C, Chen C-L, Huang C-J, Cheng K-W, Jawan B, Wang C-H (2012) Pain management of living liver donors with morphine with or without ketorolac. Transplant Proc 44:360–362

    Article  CAS  PubMed  Google Scholar 

  • Katz JL (1986) Effects of clonidine and morphine on opioid withdrawal in rhesus monkeys. Psychopharmacology 88:392–397

    Article  CAS  PubMed  Google Scholar 

  • Kleber HD, Gold MS, Riordan CE (1980) The use of clonidine in detoxification from opiates. Bull Narc 32:1–9

    CAS  PubMed  Google Scholar 

  • Kolesnikov YA, Wilson RS, Pasternak GW (2003) The synergistic analgesic interactions between hydrocodone and ibuprofen. Anesth Analg 97:1721–1723

    Article  CAS  PubMed  Google Scholar 

  • Li JX, Becker GL, Traynor JR, Gong ZH, France CP (2007) Thienorphine: receptor binding and behavioral effects in rhesus monkeys. J Pharmacol Exp Ther 321:227–236

    Article  CAS  PubMed  Google Scholar 

  • Li JX, McMahon LR, Gerak LR, Becker GL, France CP (2008) Interactions between Δ9-tetrahydrocannabinol and μ opioid receptor agonists in rhesus monkeys: discrimination and antinociception. Psychopharmacology 199:199–208

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Li JX, Koek W, France CP (2012) Interactions between Δ9-tetrahydrocannabinol and heroin: self administration in rhesus monkeys. Behav Pharmacol 23:754–761

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Light AB, Torrance EG (1929) The effects of abrupt withdrawal followed by re-administration of morphine in human addicts, with special reference to composition of the blood, the circulation and the metabolism. Arch Intern Med 44:3–16

    Google Scholar 

  • Maguire DR, France CP (2014) Impact of efficacy at the μ-opioid receptor on antinociceptive effects of combinations of μ-opioid receptor agonists and cannabinoid receptor agonists. J Pharmacol Exp Ther 351:383–389

    Article  PubMed  Google Scholar 

  • Maguire DR, Yang W, France CP (2013) Interactions between μ-opioid receptor agonists and cannabinoid receptor agonists in rhesus monkeys: antinociception, drug discrimination, and drug self-administration. J Pharmacol Exp Ther 345:354–362

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Maguma H, Taylor DA (2011) The effect of chronic opioid vs. cannabinoid exposure on the expression of tolerance to morphine- or WIN-55,212-2-induced analgesia and hypothermia in the guinea pig. Eur J Pharmacol 660:334–340

    Article  CAS  PubMed  Google Scholar 

  • Massi P, Vaccani A, Romorini S, Parolaro D (2001) Comparative characterization in the rat of the interaction between cannabinoids and opiates for their immunosuppressive and analgesic effects. J Neuroimmunol 117:116–124

    Article  CAS  PubMed  Google Scholar 

  • Naef M, Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Zbinden A, Brenneisen R (2003) The analgesic effects of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain 105:79–88

    Article  CAS  PubMed  Google Scholar 

  • Narang S, Gibson D, Wasan AD, Ross EL, Michna E, Nedeljkovic SS, Jamison RN (2008) Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain 9:254–264

    Article  CAS  PubMed  Google Scholar 

  • Pertwee RG (2009) Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br J Pharmacol 156:397–411

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pertwee RG (2012) Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci 367:3353–3363

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Raffa RB (2001) Pharmacology of oral combination analgesics: rational therapy for pain. J Clin Pharm Ther 26:257–264

    Article  CAS  PubMed  Google Scholar 

  • Raffa RB, Pergolizzi JV, Segarnick DJ, Tallarida RJ (2010) Oxycodone combinations for pain relief. Drugs Today (Barc) 46:379–398

    Article  CAS  Google Scholar 

  • Rahn EJ, Hohmann AG (2009) Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics 6:713–737

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rodriguez JS, McMahon LR (2014) JWH-018 in rhesus monkeys: differential antagonism of discriminative stimulus, rate-decreasing, and hypothermic effects. Eur J Pharmacol 740:151–159

    Article  CAS  PubMed  Google Scholar 

  • Sell SL, McMahon LR, Koek W, France CP (2005) Monoaminergic drugs and directly observable signs of LAAM-withdrawal in rhesus monkeys. Behav Pharmacol 16:53–58

    Article  CAS  PubMed  Google Scholar 

  • Smith FL, Cichewicz D, Martin ZL, Welch SP (1998) The enhancement of morphine antinociception by Δ9-tetrahydrocannabinol. Pharmacol Biochem Behav 60:559–566

    Article  CAS  PubMed  Google Scholar 

  • Smith FL, Selley DE, Sim-Selley LJ, Welch SP (2007) Low dose combination of morphine and Δ9-tetrahydrocannabinol circumvents antinociceptive tolerance and apparent desensitization of receptors. Eur J Pharmacol 571:129–137

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Vivian JA, Kishioka S, Butelman ER, Broadbear J, Lee KO, Woods JH (1998) Analgesic, respiratory and heart rate effects of cannabinoid and opioid agonists in rhesus monkeys: antagonist effects of SR 141716A. J Pharmacol Exp Ther 286:697–703

    CAS  PubMed  Google Scholar 

  • Wang T, Collet JP, Shapiro S, Ware MA (2008) Adverse effects of medical cannabinoids: a systematic review. CMAJ 178:1669–1678

    Article  PubMed Central  PubMed  Google Scholar 

  • Welch SP, Stevens DL (1992) antinociceptive activity of intrathecally administered cannabinoids alone, and in combination with morphine, in mice. J Pharmacol Exp Ther 262:10–18

    CAS  PubMed  Google Scholar 

  • Welch SP, Thomas C, Patrick GS (1995) Modulation of cannabinoid-induced antinociception following intracerebroventricular versus intrathecal administration to mice: possible mechanism for interactions with morphine. J Pharmacol Exp Ther 272:310–321

    CAS  PubMed  Google Scholar 

  • Yesilyurt O, Dogrul A (2004) Lack of cross-tolerance to the antinociceptive effects of systemic and topical cannabinoids in morphine-tolerant mice. Neurosci Lett 371:122–127

    Article  CAS  PubMed  Google Scholar 

  • Zilm DH, Sellers EM (1978) The quantitative assessment of physical dependence on opiates. Drug Alcohol Depend 3:419–428

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank Marlisa Burton, Christopher Cruz, Marissa McCarthy, Carlos Moreno, Chris Robinson, and Crystal Taylor for their expert technical assistance.

Conflict of interest

This project was supported by USPHS Grants DA05018 and DA17918 from the National Institute on Drug Abuse. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 7764, San Antonio, TX, 78229-3900, USA

    L. R. Gerak, C. Zanettini, W. Koek & C. P. France

  2. Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    W. Koek & C. P. France

Authors
  1. L. R. Gerak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Zanettini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W. Koek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. P. France
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. P. France.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gerak, L.R., Zanettini, C., Koek, W. et al. Cross-tolerance to cannabinoids in morphine-tolerant rhesus monkeys. Psychopharmacology 232, 3637–3647 (2015). https://doi.org/10.1007/s00213-015-4023-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-015-4023-x

Keywords

Search

Navigation