title: Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia.
abstract: 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.
authors.affiliation: 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.
authors.forename: Gregory
authors.initials: G
authors.lastname: Corder
authors.affiliation: 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.
authors.forename: Vivianne L
authors.initials: VL
authors.lastname: Tawfik
authors.affiliation: 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.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, California, USA.|Stanford University Neuroscience Graduate Program, Stanford, California, USA.
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Sypek
authors.affiliation: 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.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Low
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, California, USA.|Stanford University Biology Graduate Program, Stanford, California, USA.
authors.forename: Jasmine R
authors.initials: JR
authors.lastname: Dickinson
authors.affiliation: 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.
authors.forename: Chaudy
authors.initials: C
authors.lastname: Sotoudeh
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, California, USA.|Anesthesiology Service, Veteran's Affairs Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: J David
authors.initials: JD
authors.lastname: Clark
authors.affiliation: Stanford Neurosciences Institute, Stanford, California, USA.|Department of Neurobiology, Stanford University, Stanford, California, USA.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Barres
authors.affiliation: Stanford Neurosciences Institute, Stanford, California, USA.|Department of Neurobiology, Stanford University, Stanford, California, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Bohlen
authors.affiliation: 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.
authors.forename: Grégory
authors.initials: G
authors.lastname: Scherrer
mesh_terms: D000698:Analgesia; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D059350:Chronic Pain; D004195:Disease Models, Animal; D004361:Drug Tolerance / Q000235:genetics*; D017353:Gene Deletion; D006930:Hyperalgesia / Q000139:chemically induced / Q000235:genetics*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D009020:Morphine / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D059225:Nociception / Q000187:drug effects; D009619:Nociceptors / Q000378:metabolism*; D010149:Postoperative Pain; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; C404943:Oprm protein, mouse; D000644:Quaternary Ammonium Compounds; D017450:Receptors, Opioid, mu; C032257:methylnaltrexone; D009271:Naltrexone; D009020:Morphine