Lack of Antinociceptive Cross-Tolerance With Co-Administration of Morphine and Fentanyl Into the Periaqueductal Gray of Male Sprague-Dawley Rats |
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| Institution: | 2. Department of Psychology, Washington State University, Pullman, Washington;3. Department of Neurological Surgery, Oregon Health & Science University, Portland, Oregon;2. School of Nursing, University of Pittsburgh, Pittsburgh, Pennsylvania;3. Schools of Medicine, University of California, San Francisco, California;4. Schools of Nursing, University of California, San Francisco, California;2. Department of Neurology and Jiuyuan Municipal Stroke Center, Shanghai Ninth People''s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;3. Clinical Research Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China;2. National Center for Complementary and Integrative Health, NIH, Bethesda, Maryland;3. Department of Physiological Nursing, University of California San Francisco, San Francisco, California;4. Department of Anesthesia and Perioperative Care, Division of Pain Medicine, University of California, San Francisco, San Francisco, California;5. Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington;6. Duke University Department of Anesthesiology, Division of Pain Medicine, Durham, North Carolina;2. Department of Orthopaedic and Trauma Surgery, Pain & Exercise Research Luebeck, University of Luebeck, Luebeck, Germany;3. Department of Pedagogy and Psychology, The Jerzy Kukuczka Academy of Physical Education, Katowice, Poland;4. Regional Specialised Hospital No. 4, Bytom, Poland;5. Department of Kinesiotherapy and Special Methods in Physiotherapy, The Jerzy Kukuczka Academy of Physical Education, Katowice, Poland;2. School of Psychology, University of Birmingham, United Kingdom;3. Hahn Institute for Magnetic Resonance Imaging, Essen, Germany;4. Highfield and Hybrid MR-Imaging, University Hospital Essen, Essen, Germany;5. University of Applied Sciences, Faculty of Electrical Engineering and Information Technology, Aachen, Germany;6. Wellcome Centre for Integrative Neuroimaging, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, United Kingdom |
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| Abstract: | Tolerance to the antinociceptive effect of mu-opioid receptor agonists, such as morphine and fentanyl, greatly limits their effectiveness for long-term use to treat pain. Clinical studies have shown that combination therapy and opioid rotation can be used to enhance opioid-induced antinociception once tolerance has developed. The mechanism and brain regions involved in these processes are unknown. The purpose of this study was to evaluate the contribution of the ventrolateral periaqueductal gray (vlPAG) to antinociceptive tolerance and cross-tolerance between administration and co-administration of morphine and fentanyl. Tolerance was induced by pretreating rats with morphine or fentanyl or low-dose combination of morphine and fentanyl into the vlPAG followed by an assessment of the cross-tolerance to the other opioid. In addition, tolerance to the combined treatment was assessed. Cross-tolerance did not develop between repeated vlPAG microinjections of morphine and fentanyl. Likewise, there was no evidence of cross-tolerance from morphine or fentanyl to the co-administration of morphine and fentanyl. Co-administration did not cause cross-tolerance to fentanyl. Cross-tolerance was only evident to morphine or morphine and fentanyl combined in rats pretreated with co-administration of low doses of morphine and fentanyl. This finding is consistent with the functionally selective signaling that has been reported for antinociception and tolerance after morphine and fentanyl binding to the mu-opioid receptor. This research supports the notion that combination therapy and opioid rotation may be useful clinical practices to decrease opioid tolerance and other side effects.PerspectiveThis preclinical study shows that there is a decrease in cross-tolerance between morphine and fentanyl within the periaqueductal gray, which is a key brain region in opioid antinociception and tolerance. |
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