, Volume 235, Issue 8, pp 2245–2256 | Cite as

Interactions between kappa and mu opioid receptor agonists: effects of the ratio of drugs in mixtures

  • Vanessa Minervini
  • Hannah Y. Lu
  • Jahnavi Padarti
  • Daniela C. Osteicoechea
  • Charles P. FranceEmail author
Original Investigation



Pain is the leading reason for seeking health care, and mu opioid receptor agonists continue to be prescribed despite well-documented adverse effects. Kappa opioid receptor agonists have antinociceptive effects with little to no abuse liability and might be useful for treating pain in mixtures. Kappa:mu opioid mixtures might be useful if therapeutic effects of each drug can be selectively increased while reducing or avoiding the adverse effects that occur with larger doses of each drug alone.


This study characterized the effects of the kappa opioid receptor agonist spiradoline alone (0.32–56 mg/kg) and in 1:10, 1:3, 1:1, and 3:1 mixtures with the mu opioid receptor agonists morphine (1.0–32 mg/kg) and etorphine (1–10 μg/kg) on warm water tail-withdrawal latency, body temperature, responding for food, and fecal output in male Sprague-Dawley rats (n = 24).


Antinociceptive effects were greater than additive for 1:10 and 1:3 spiradoline:morphine mixtures and for 1:10, 1:3, and 1:1 spiradoline:etorphine mixtures. The potency of spiradoline to produce hypothermia was greater with 1:3 and 3:1 spiradoline:etorphine mixtures but not with 1:10 or 1:1 mixtures or with any spiradoline:morphine mixture. The effects of 1:3 spiradoline:morphine on responding for food were additive, whereas 1:1 and 3:1 were greater than additive. Spiradoline did not significantly alter morphine-induced decreases in fecal output.


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.


Opioids Drug mixtures Drug interactions Antinociception Rats 



The authors thank Lisa Gerak, David Maguire, and Gregory Collins for their helpful comments on the manuscript.

Funding information

This work was supported by the National Institutes of Health (NIH) National Institute on Drug Abuse [Grants K05DA017918, T32DA031115, F32DA043348] and the Welch Foundation [Grant AQ-0039].

Compliance with ethical standards

The experimental protocol was approved by the Institutional Animal Care and Use Committee at the University of Texas Health Science Center at San Antonio and in accordance with guidelines set forth by the Guide for the Care and Use of Laboratory Animals (2011).

Conflict of interest

The authors declare that they have no conflict of interest.


The content expressed here is solely the responsibly of the authors and does not necessarily represent the views of the NIH.

Supplementary material

213_2018_4920_MOESM1_ESM.pdf (241 kb)
Online Resource 1 (PDF 241 kb)
213_2018_4920_MOESM2_ESM.pdf (269 kb)
Online Resource 2 (PDF 269 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity of Texas Health Science CenterSan AntonioUSA
  2. 2.Addiction Research, Treatment and Training (ARTT) Center of ExcellenceUniversity of Texas Health Science CenterSan AntonioUSA
  3. 3.Department of PsychiatryUniversity of Texas Health Science CenterSan AntonioUSA

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