Interactions between kappa and mu opioid receptor agonists: effects of the ratio of drugs in mixtures
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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.
KeywordsOpioids Drug mixtures Drug interactions Antinociception Rats
The authors thank Lisa Gerak, David Maguire, and Gregory Collins for their helpful comments on the manuscript.
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.
- Binder W, Carmody J, Walker J (1999) Effect of gender on anti-inflammatory and analgesic actions of two k-opioids. J Pharmacol Exp Ther 292:303–309Google Scholar
- Elhabazi K, Ayachi S, Ilien B, Simonin F (2014) Assessment of morphine-induced hyperalgesia and analgesic tolerance in mice using thermal and mechanical nociceptive modalities. J Vis Exp 89:e5164Google Scholar
- Gunther T, Dasgupta P, Mann A, Miess E, Kliewer A, Fritzwanker S, Steinborn R, Schulz S (2017) Targeting multiple opioid receptors—improved analgesics with reduced side effects? Br J Pharmacol. https://doi.org/10.1111/bph.13809
- Maguire DR, France CP (2016) Additive antinociceptive effects of mixtures of the k-opioid receptor agonist spiradoline and the cannabinoid receptor agonist CP55940 in rats. Behav Pharmacol 27:69–72Google Scholar
- McPherson J, Rivero G, Baptist M, Llorente J, Al-Sabah S, Krasel C, Dewey WL, Bailey CP, Rosethorne EM, Charlton SJ, Henderson G, Kelly E (2010) Mu-opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization. Mol Pharmacol 78:756–766CrossRefPubMedPubMedCentralGoogle Scholar
- Towsend EA, Naylor JE, Negus SS, Edwards SR, Qureshi HN, McLendon HW, McCurdy CR, Kapanda CN, do Carmo JM, da Silva FS, Hall JE, Sufka KJ, Freeman KB (2017) Effects of nalfurafine on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone: modeling an abuse-deterrent opioid analgesic in rats. Psychopharmacology (Berl). https://doi.org/10.1007/s00213-017-4652-3
- Ward SJ, Takemori AE (1982) Relative involvement of mu, kappa, and delta receptor mechanisms in opiate-mediated antinociception in mice. J Pharmacol Exp Ther 224:525–530Google Scholar