Spinal or supraspinal phosphorylation deficiency at the MOR C-terminus does not affect morphine tolerance in vivo.
The development of tolerance to morphine, one of the most potent analgesics, in the management of chronic pain is a significant clinical problem and its mechanisms are poorly understood. Morphine exerts its pharmacological effects via the μ-opioid receptor (MOR). Tolerance is highly connected to G-protein-coupled receptors (GPCR) phosphorylation and desensitization increase. Because morphine desensitization previously has been shown to be MOR phosphorylation- and ß-arrestin2-independent (in contrast to agonists such as fentanyl), we examined the contribution of phosphorylation of the entire C-terminus to the development of antinociceptive tolerance to the partial (morphine) and full (fentanyl) MOR agonists in vivo. In MOR knockout (MORKO) mice, we delivered via lentivirus the genes encoding the wild-type MOR (WTMOR) or a phosphorylation-deficient MOR (Cterm(-S/T)MOR) in which all of the serine and threonine residues were mutated to alanine into the ventrolateral periaqueductal grey matter (vlPAG) or lumbar spinal cord (SC), structures that are involved in nociception. We compared the analgesic ED50in WTMOR- and Cterm(-S/T)MOR-expressing MORKO mice before and after morphine or fentanyl tolerance was induced. Morphine acute antinociception was partially restored in WTMOR- or Cterm(-S/T)MOR-transferred MORKO mice. Fentanyl acute antinociception was observed only in MORKO mice with the transgenes expressed in the SC. Morphine antinociceptive tolerance was not affected by expressing Cterm(-S/T)MOR in the vlPAG or SC of MORKO mice. Fentanyl-induced tolerance in MORKO mice expressing WTMOR or Cterm(-S/T)MOR, is greater than morphine-induced tolerance. Thus, MOR C-terminus phosphorylation does not appear to be critical for morphine tolerance in vivo.
Department of Pharmacology and Basic Research Center on Molecular and Cell Biology of Drug Addiction, University of Minnesota, Minneapolis, MN 55455, USA. Electronic address: kibal001@umn.edu.
Cherkaouia
C
Kibaly
Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, MI 48073, USA.
Hong-Yiou
HY
Lin
Department of Pharmacology and Basic Research Center on Molecular and Cell Biology of Drug Addiction, University of Minnesota, Minneapolis, MN 55455, USA.
Horace H
HH
Loh
Department of Pharmacology and Basic Research Center on Molecular and Cell Biology of Drug Addiction, University of Minnesota, Minneapolis, MN 55455, USA.
Ping-Yee
PY
Law
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004361:Drug Tolerance; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009154:Mutation; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism
D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D009020:Morphine
C-terminus phosphorylation; Fentanyl; Fentanyl hydrochloride: CID: 83932; Formaldehyde − Paraformaldehyde: CID: 712; Isoflurane: CID: 3763; Ketamine: CID: 3821; Morphine; Morphine sulfate: CID: 16051935; Pentobarbital sodium: CID: 23676152; Tolerance; Xylazine hydrochloride: CID: 68554; mu-opioid receptor (MOR)