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

Nature medicine, 2017-02, Vol.23 (2), p.164-173 [Peer Reviewed Journal]

ISSN: 1078-8956 ;EISSN: 1546-170X ;DOI: 10.1038/nm.4262 ;PMID: 28092666

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Title:
Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia
Author: Corder, Gregory ; Tawfik, Vivianne L ; Wang, Dong ; Sypek, Elizabeth I ; Low, Sarah A ; Dickinson, Jasmine R ; Sotoudeh, Chaudy ; Clark, J David ; Barres, Ben A ; Bohlen, Christopher J ; Scherrer, Grégory
Subjects: Analgesia ; Analgesics, Opioid - pharmacology ; Animals ; Chronic Pain ; Disease Models, Animal ; Drug Tolerance - genetics ; Gene Deletion ; Hyperalgesia - chemically induced ; Hyperalgesia - genetics ; Long-Term Potentiation - drug effects ; Long-Term Potentiation - genetics ; Mice ; Mice, Knockout ; Microglia - metabolism ; Morphine - pharmacology ; Naltrexone - analogs & derivatives ; Naltrexone - pharmacology ; Nociception - drug effects ; Nociceptors - metabolism ; Pain, Postoperative ; Quaternary Ammonium Compounds - pharmacology ; Receptors, Opioid, mu - antagonists & inhibitors ; Receptors, Opioid, mu - genetics ; Signal Transduction ; Spinal Cord - cytology ; Spinal Cord - metabolism
Is Part Of: Nature medicine, 2017-02, Vol.23 (2), p.164-173
Description: 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.
Publisher: United States
Language: English
Identifier: ISSN: 1078-8956
EISSN: 1546-170X
DOI: 10.1038/nm.4262
PMID: 28092666
Source: MEDLINE
ProQuest Central

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

ISSN: 1078-8956 ;EISSN: 1546-170X ;DOI: 10.1038/nm.4262 ;PMID: 28092666

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