Newly Published
Pain Medicine  |   August 2017
Src Kinase Inhibition Attenuates Morphine Tolerance without Affecting Reinforcement or Psychomotor Stimulation
Author Notes
  • From the Institute of Academic Anaesthesia, Division of Neuroscience, School of Medicine, Ninewells Hospital, University of Dundee, Dundee, United Kingdom (F.A.B., D.T.B.-H., C.S., L.W., T.G.H.); and Shirley and Stefan Hatos Center for Neuropharmacology, University of California, Los Angeles, California (W.W.).
  • Submitted for publication February 19, 2017. Accepted for publication July 14, 2017.
    Submitted for publication February 19, 2017. Accepted for publication July 14, 2017.×
  • Acknowledgments: The authors thank Lianne Strachan, Ph.D. (University of Dundee Behavioural Neuroscience Core Facility, Dundee, United Kingdom), for assistance with behavioral assays; Robert Lefkowitz, M.D. (Department of Medicine, Duke University, Durham, North Carolina), for β-arr2–/– mice; and Brigitte Kieffer, Ph.D. (Department of Psychiatry, McGill University, Montreal, Quebec, Canada), for µ–/– mice.
    Acknowledgments: The authors thank Lianne Strachan, Ph.D. (University of Dundee Behavioural Neuroscience Core Facility, Dundee, United Kingdom), for assistance with behavioral assays; Robert Lefkowitz, M.D. (Department of Medicine, Duke University, Durham, North Carolina), for β-arr2–/– mice; and Brigitte Kieffer, Ph.D. (Department of Psychiatry, McGill University, Montreal, Quebec, Canada), for µ–/– mice.×
  • Research Support: Supported by National Institute of Academic Anaesthesia/British Journal of Anaesthesia (London, United Kingdom) grant No. WKRO-2014-0052 (to Dr. Hales), Tenovus Scotland (Glasgow, Scotland) grant No. T15/54 (to Drs. Hales and Bull), and Wellcome Trust (London, United Kingdom) Ph.D. Fellowship grant No. 100674/Z/12/A (to Dr. Bull).
    Research Support: Supported by National Institute of Academic Anaesthesia/British Journal of Anaesthesia (London, United Kingdom) grant No. WKRO-2014-0052 (to Dr. Hales), Tenovus Scotland (Glasgow, Scotland) grant No. T15/54 (to Drs. Hales and Bull), and Wellcome Trust (London, United Kingdom) Ph.D. Fellowship grant No. 100674/Z/12/A (to Dr. Bull).×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Hales: Institute of Academic Anaesthesia, Division of Neuroscience, School of Medicine, Ninewells Hospital, University of Dundee, Dundee, DD1 9SY, United Kingdom. t.g.hales@dundee.ac.uk. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Pain Medicine / Pharmacology
Pain Medicine   |   August 2017
Src Kinase Inhibition Attenuates Morphine Tolerance without Affecting Reinforcement or Psychomotor Stimulation
Anesthesiology Newly Published on August 24, 2017. doi:10.1097/ALN.0000000000001834
Anesthesiology Newly Published on August 24, 2017. doi:10.1097/ALN.0000000000001834
Abstract

Background: Prolonged opioid administration leads to tolerance characterized by reduced analgesic potency. Pain management is additionally compromised by the hedonic effects of opioids, the cause of their misuse. The multifunctional protein β-arrestin2 regulates the hedonic effects of morphine and participates in tolerance. These actions might reflect µ opioid receptor up-regulation through reduced endocytosis. β-Arrestin2 also recruits kinases to µ receptors. We explored the role of Src kinase in morphine analgesic tolerance, locomotor stimulation, and reinforcement in C57BL/6 mice.

Methods: Analgesic (tail withdrawal latency; percentage of maximum possible effect, n = 8 to 16), locomotor (distance traveled, n = 7 to 8), and reinforcing (conditioned place preference, n = 7 to 8) effects of morphine were compared in wild-type, µ+/–, µ–/–, and β-arrestin2–/– mice. The influence of c-Src inhibitors dasatinib (n = 8) and PP2 (n = 12) was examined.

Results: Analgesia in morphine-treated wild-type mice exhibited tolerance, declining by day 10 to a median of 62% maximum possible effect (interquartile range, 29 to 92%). Tolerance was absent from mice receiving dasatinib. Tolerance was enhanced in µ+/– mice (34% maximum possible effect; interquartile range, 5 to 52% on day 5); dasatinib attenuated tolerance (100% maximum possible effect; interquartile range, 68 to 100%), as did PP2 (91% maximum possible effect; interquartile range, 78 to 100%). By contrast, c-Src inhibition affected neither morphine-evoked locomotor stimulation nor reinforcement. Remarkably, dasatinib not only attenuated tolerance but also reversed established tolerance in µ+/– mice.

Conclusions: The ability of c-Src inhibitors to inhibit tolerance, thereby restoring analgesia, without altering the hedonic effect of morphine, makes c-Src inhibitors promising candidates as adjuncts to opioid analgesics.