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Effects of nalfurafine on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone: modeling an abuse-deterrent opioid analgesic in rats

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Abstract

Rationale

Strategies to reduce the misuse of mu opioid agonists are critically needed. Previous work has shown that kappa opioid agonists can diminish the abuse-related effects and augment the antinociceptive effects of mu agonists. However, use of traditional kappa agonists is limited by their dysphoric side effects.

Objectives

The current study examined the effects of nalfurafine, a clinically available atypical kappa agonist, on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone in male rats.

Methods

To determine oxycodone/nalfurafine mixture proportions to be examined intravenously across procedures, a progressive ratio (PR) self-administration procedure compared the reinforcing effects of oxycodone (56 μg/kg/inj) available alone or as a mixture with co-administered nalfurafine (0.32, 1, or 3.2 μg/kg/inj), corresponding to oxycodone/nalfurafine proportions of 175:1, 56:1, and 18:1, respectively. Next, PR and thermal antinociception dose-effect functions were each determined for oxycodone, nalfurafine, and the same oxycodone/nalfurafine mixture proportions. Finally, the respiratory-depressant effects of equi-antinociceptive doses of oxycodone, nalfurafine, and the mixtures were compared.

Results

Nalfurafine decreased the reinforcing effects of oxycodone, and the 18:1 mixture did not function as a reinforcer. Oxycodone and nalfurafine each produced dose-dependent antinociception, and the mixtures produced additive antinociception. In addition, antinociceptive doses of the 56:1 and 18:1 mixtures did not produce respiratory depression.

Conclusions

These results suggest that nalfurafine may augment the thermal antinociceptive effects while reducing the reinforcing and respiratory-depressant effects of oxycodone.

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References

  • Barrett AC (2006) Low efficacy opioids: implications for sex differences in opioid antinociception. Exp Clin Psychopharmacol 14:1–11

    Article  CAS  PubMed  Google Scholar 

  • Bassi M, Nakamura NB, Furuya WI, Colombari DS, Menani JV, do Carmo JM, da Silva AA, Hall JE, Colombari E (2015) Activation of the brain melanocortin system is required for leptin-induced modulation of chemorespiratory function. Acta Physiol 213:893–901

    Article  CAS  Google Scholar 

  • Bolanos CA, Garmsen GM, Clair MA, McDougall SA (1996) Effects of the kappa-opioid receptor agonist U-50,488 on morphine-induced place preference conditioning in the developing rat. Eur J Pharmacol 317:1–8

    Article  CAS  PubMed  Google Scholar 

  • Bruijnzeel AW (2009) Kappa-opioid receptor signaling and brain reward function. Brain Res Rev 62:127–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Centers for disease control and prevention: National center for health statistics (2015) Number of age-adjusted rates of drug-poisoning deaths involving opioid analgesics and heroin: United States, 1999–2014. https://www.cdc.gov/nchs/data/health_policy/AADR_drug_poisoning_involving_OA_Heroin_US_2000-2014.pdf

  • Dogra S, Yadav PN (2015) Biased agonism at kappa opioid receptors: implication in pain and mood disorders. Eur J Pharmacol 763:184–190

    Article  CAS  PubMed  Google Scholar 

  • Duthie DJ, Nimmo WS (1987) Adverse effects of opioid analgesic drugs. Br J Anaesth 59:61–77

    Article  CAS  PubMed  Google Scholar 

  • Freeman KB, Naylor JE, Prisinzano TE, Woolverton WL (2014) Assessment of the kappa opioid agonist, salvinorin a, as a punisher of drug self-administration in monkeys. Psychopharmacology 231:2751–2758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frenk SM, Porter KS, Paulozzi LJ (2015) Centers for disease control and prevention: National center for health statistics (2015) Prescription Opioid Analgesic Use Among Adults: United States, 1999–2012. https://www.cdc.gov/nchs/products/databriefs/db189.htm

  • Funada M, Suzuki T, Narita M, Misawa M, Nagase H (1993) Blockade of morphine reward through the activation of kappa-opioid receptors in mice. Neuropharmacology 32:1315–1323

    Article  CAS  PubMed  Google Scholar 

  • Glick SD, Maisonneuve IM, Raucci AS (1995) Kappa opioid inhibition of morphine and cocaine self-administration in rats. Brain Res 681:147–152

    Article  CAS  PubMed  Google Scholar 

  • Hasabe K, Kawai K, Suzuki T, Kawamura K, Tanaka T, Narita M et al (2004) Possible pharmacotherapy of the opioid kappa receptor agonist for drug dependence. Ann N Y Acad Sci 1025:404–413

    Article  Google Scholar 

  • Honma K, Hiroshige T (1978) Simultaneous determination of circadian rhythms of locomotor activity and body temperature in the rat. Jpn J Physiol 28:159–169

    Article  CAS  PubMed  Google Scholar 

  • Huskinson SL, Naylor JE, Townsend EA, Rowlett JK, Blough BE, Freeman KB (2017) Self-administration and behavioral economics of second-generation synthetic cathinones in male rats. Psychopharmacology 234:589–598

    Article  CAS  PubMed  Google Scholar 

  • Inui S (2015) Nalfurafine hydrochloride to treat pruritus: a review. Clin Cosmet Investing Dermatol 8:249–255

    Article  CAS  Google Scholar 

  • Jones MR, Kaye AD, Kaye AJ, Urman RD (2016) The emerging therapeutic roles of kappa-opioid agonists. J Opioid Manag 12:101–107

    PubMed  Google Scholar 

  • Ko MC, Husbands SM (2009) Effects of atypical kappa-opioid receptor agonists on intrathecal morphine-induced itch and analgesia in primates. J Pharmacol Exp Ther 328:193–200

    Article  CAS  PubMed  Google Scholar 

  • Kumagai H, Ebata T, Takamori K, Muramatsu T, Nakamoto H, Suzuki H (2010) Effect of a novel kappa-receptor agonist, nalfurafine hydrochloride, on severe itch in 337 haemodialysis patients: a phase III, randomized, double-blind, placebo-controlled study. Nephrol Dial Transplant 25:1251–1257

    Article  CAS  PubMed  Google Scholar 

  • Kumagai H, Ebata T, Takamori K, Miyasato K, Muramatsu T, Nakamoto H et al (2012) Efficacy and safety of a novel ĸ-agonist for managing intractable pruritus in dialysis patients. Am J Nephrol 36:175–183

    Article  CAS  PubMed  Google Scholar 

  • Kuzmin AV, Semenova S, Gerrits MA, Zvartau EE, Van Ree JM (1997) Kappa-opioid receptor agonist U50,488H modulates cocaine and morphine self-administration in drug naïve rats and mice. Eur J Pharmacol 321:265–271

    Article  CAS  PubMed  Google Scholar 

  • Milan A (1973) Ventilation measured by body plethysmography in hibernating mammals and in poikitotherms. Respir Physiol 17:32–44

    Article  Google Scholar 

  • Millan MJ (1990) Kappa-opioid receptors and analgesia. Trends Pharmacol Sci 11:70–76

    Article  CAS  PubMed  Google Scholar 

  • Mori T, Nomura M, Nagase H, Narita M, Suzuki T (2002) Effects of a newly synthesized kappa opioid receptor agonist, TRK-820, on the discriminative stimulus and rewarding effects of cocaine in rats. Psychopharmacology 161:17–22

    Article  CAS  PubMed  Google Scholar 

  • National Research Council of the National Academies (2011). Guide for the Care and Use of Laboratory Animals. Eighth Edition. Washington, DC: The National Academies Press

  • Negus SS, Vanderah TW, Brandt MR, Bilsky EJ, Becerra L, Borsook D (2006) Preclinical assessment of candidate analgesic drugs: recent advancements and future challenges. J Pharmacol Exp Ther 319:507–514

    Article  CAS  PubMed  Google Scholar 

  • Negus SS, Schrode K, Stevenson GW (2008) Mu/kappa opioid interactions in rhesus monkeys: implications for analgesia and abuse liability. Exp Clin Psychopharmacol 16:386–399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • OxyContin® [package insert] (2016) Purdue Pharma LP. Stamford, CT, USA: December 2016

  • Schattaurer SS, Kuhar JR, Song A, Chavkin C (2017) Nalfurafine is a G-protein biased agonist having significantly greater bias at the human than rodent form of the kappa opioid receptor. Cell Signal 32:59–65

    Article  Google Scholar 

  • Shook JE, Watkins WD, Camporesi EM (1990) Differential roles of opioid receptors in respiration, respiratory disease, and opiate-induced respiratory depression. Am Rev Respir Dis 142:895–909

    Article  CAS  PubMed  Google Scholar 

  • Tallarida RJ (2000) Drug synergism and dose-effect data analysis. Chapman and Hall/CRC, Boca Raton

    Book  Google Scholar 

  • Tallarida RJ (2012) Revisiting the isobole and related quantitative methods for assessing drug synergism. J Pharmacol Exp Ther 342:2–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomsen M, Woldbye D, Wortwein G, Fink-Jensen A, Wess J, Caine SB (2005) Reduced cocaine self-administration in muscarinic M5 acetylcholine receptor-deficient mice. J Neurosci 25:8141–8149

    Article  CAS  PubMed  Google Scholar 

  • Townsend EA, Beloate LN, Huskinson SL, Roma PG, Freeman KB (2015) Corn oil, but not cocaine, is a more effective reinforcer in obese than in lean Zucker rats. Physiol Behav 143:136–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ueno Y, Mori A, Yanagita T (2013) One year long-term study on the abuse-liability of nalfurafine in hemodialysis patients. Int J Clin Pharmacol Ther 51:823–831

    Article  CAS  PubMed  Google Scholar 

  • United States food and drug administration center for drug evaluation and research (2015) Abuse-deterrent opioids evaluation and labeling guidance for industry. https://www.fda.gov/downloads/Drugs/Guidances/UCM334743.pdf

Download references

Acknowledgements

The authors would like to thank Hunter Bruce, Georganna Nutt, Yvonne Zuchowski, and Josh Woods for their expert technical assistance.

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Authors and Affiliations

  1. Graduate Program in Neuroscience, The University of Mississippi Medical Center, Jackson, MS, USA

    E. Andrew Townsend

  2. Department of Psychiatry and Human Behavior, The University of Mississippi Medical Center, Jackson, MS, USA

    E. Andrew Townsend & Kevin B. Freeman

  3. National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, USA

    Jennifer E. Naylor

  4. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA

    S. Stevens Negus

  5. Millsaps College, Jackson, MS, USA

    Shelley R. Edwards & Hina N. Qureshi

  6. School of Medicine, The University of Mississippi Medical Center, Jackson, MS, USA

    Hunter W. McLendon

  7. Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS, USA

    Christopher R. McCurdy & Coco N. Kapanda

  8. UF Translational Drug Development Core, Department of Medicinal Chemistry, School of Pharmacy, University of Florida, Gainesville, FL, USA

    Christopher R. McCurdy

  9. Deprtment of Physiology and Biophysics, The University of Mississippi Medical Center, Jackson, MS, USA

    Jussara M. do Carmo, Fernanda S. da Silva & John E. Hall

  10. Department of Psychology, University of Mississippi, University, MS, USA

    Kenneth J. Sufka

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  1. E. Andrew Townsend
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  2. Jennifer E. Naylor
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  3. S. Stevens Negus
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  6. Hunter W. McLendon
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  9. Jussara M. do Carmo
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  10. Fernanda S. da Silva
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  11. John E. Hall
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  12. Kenneth J. Sufka
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  13. Kevin B. Freeman
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Corresponding author

Correspondence to E. Andrew Townsend.

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Funding

The study was supported by R01-DA039167 to KBF from the National Institute on Drug Abuse.

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Townsend, E.A., Naylor, J.E., Negus, S.S. et al. Effects of nalfurafine on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone: modeling an abuse-deterrent opioid analgesic in rats. Psychopharmacology 234, 2597–2605 (2017). https://doi.org/10.1007/s00213-017-4652-3

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