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Nat Med. 2017 Feb;23(2):164-173. doi: 10.1038/nm.4262. Epub 2017 Jan 16.

Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia.

Corder G1,2,3,4, Tawfik VL1,2,3,4, Wang D1,2,3,4, Sypek EI1,5, Low SA1,2,3,4, Dickinson JR1,6, Sotoudeh C1,2,3,4, Clark JD1,7, Barres BA4,8, Bohlen CJ4,8, Scherrer G1,2,3,4.

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Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, California, USA.
Department of Molecular and Cellular Physiology, Stanford University, Stanford, California, USA.
Department of Neurosurgery, Stanford University, Stanford, California, USA.
Stanford Neurosciences Institute, Stanford, California, USA.
Stanford University Neuroscience Graduate Program, Stanford, California, USA.
Stanford University Biology Graduate Program, Stanford, California, USA.
Anesthesiology Service, Veteran's Affairs Palo Alto Health Care System, Palo Alto, California, USA.
Department of Neurobiology, Stanford University, Stanford, California, USA.


Opioid pain medications have detrimental side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). Tolerance and OIH counteract opioid analgesia and drive dose escalation. The cell types and receptors on which opioids act to initiate these maladaptive processes remain disputed, which has prevented the development of therapies to maximize and sustain opioid analgesic efficacy. We found that μ opioid receptors (MORs) expressed by primary afferent nociceptors initiate tolerance and OIH development. RNA sequencing and histological analysis revealed that MORs are expressed by nociceptors, but not by spinal microglia. Deletion of MORs specifically in nociceptors eliminated morphine tolerance, OIH and pronociceptive synaptic long-term potentiation without altering antinociception. Furthermore, we found that co-administration of methylnaltrexone bromide, a peripherally restricted MOR antagonist, was sufficient to abrogate morphine tolerance and OIH without diminishing antinociception in perioperative and chronic pain models. Collectively, our data support the idea that opioid agonists can be combined with peripheral MOR antagonists to limit analgesic tolerance and OIH.

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