Chronic morphine regulates TRPM8 channels via MOR-PKCβ signaling

Autor: Christophe Altier, Tuan Trang, Rithwik Ramachandran, Lilian Basso, Corinne Roland, Robyn Flynn, Charlie Kwok, Manon Defaye, Mircea Iftinca, Ahmed Hassan
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
Receptors
Opioid
mu
Pharmacology
lcsh:RC346-429
0302 clinical medicine
Desensitization (telecommunications)
Dorsal root ganglion
Ganglia
Spinal
Dorsal root ganglia (DRG) neurons
Phosphorylation
Cells
Cultured
Neurons
Morphine
Chemistry
Protein kinase C beta (PKCβ)
Mu opioid receptor (mor)
Cold hyperalgesia
3. Good health
Menthol
medicine.anatomical_structure
Hyperalgesia
Mu opioid receptor (MOR)
Protein kinase c beta (pkcβ)
Transient receptor potential channel subfamily m (melastatin) member 8 (trpm8)
Nociceptor
medicine.symptom
medicine.drug
Signal Transduction
TRPM Cation Channels
Models
Biological
03 medical and health sciences
Cellular and Molecular Neuroscience
Protein Kinase C beta
TRPM8
medicine
Animals
Humans
Protein kinase A
Molecular Biology
Protein kinase C
lcsh:Neurology. Diseases of the nervous system
Transient receptor potential channel subfamily M (melastatin) member 8 (TRPM8)
Research
Enzyme Activation
Mice
Inbred C57BL
030104 developmental biology
HEK293 Cells
Opioid
Dorsal root ganglia (drg) neurons
030217 neurology & neurosurgery
Zdroj: Molecular Brain, Vol 13, Iss 1, Pp 1-14 (2020)
Molecular Brain
Physiology and Pharmacology Publications
ISSN: 1756-6606
DOI: 10.1186/s13041-020-00599-0
Popis: Postoperative shivering and cold hypersensitivity are major side effects of acute and chronic opioid treatments respectively. TRPM8 is a cold and menthol-sensitive channel found in a subset of dorsal root ganglion (DRG) nociceptors. Deletion or inhibition of the TRPM8 channel was found to prevent the cold hyperalgesia induced by chronic administration of morphine. Here, we examined the mechanisms by which morphine was able to promote cold hypersensitivity in DRG neurons and transfected HEK cells. Mice daily injected with morphine for 5 days developed cold hyperalgesia. Treatment with morphine did not alter the expressions of cold sensitive TREK-1, TRAAK and TRPM8 in DRGs. However, TRPM8-expressing DRG neurons isolated from morphine-treated mice exhibited hyperexcitability. Sustained morphine treatment in vitro sensitized TRPM8 responsiveness to cold or menthol and reduced activation-evoked desensitization of the channel. Blocking phospholipase C (PLC) as well as protein kinase C beta (PKCβ), but not protein kinase A (PKA) or Rho-associated protein kinase (ROCK), restored channel desensitization. Identification of two PKC phosphorylation consensus sites, S1040 and S1041, in the TRPM8 and their site-directed mutation were able to prevent the MOR-induced reduction in TRPM8 desensitization. Our results show that activation of MOR by morphine 1) promotes hyperexcitability of TRPM8-expressing neurons and 2) induces a PKCβ-mediated reduction of TRPM8 desensitization. This MOR-PKCβ dependent modulation of TRPM8 may underlie the onset of cold hyperalgesia caused by repeated administration of morphine. Our findings point to TRPM8 channel and PKCβ as important targets for opioid-induced cold hypersensitivity.
Databáze: OpenAIRE
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